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Готові списки джерел за темами / Optimisation de hit en lead / Статті в журналах

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Статті в журналах з теми "Optimisation de hit en lead"

Автор: Grafiati

Опубліковано: 29 березня 2025

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1

Padalino, Gilda, Nelly El-Sakkary, Lawrence J. Liu, Chenxi Liu, Danielle S. G. Harte, Rachel E. Barnes, Edward Sayers, et al. "Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation." European Journal of Medicinal Chemistry 226 (December 2021): 113823. http://dx.doi.org/10.1016/j.ejmech.2021.113823.

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2

El Bakali, Jamal, Lucie Maingot, Julie Dumont, Helene Host, Akila Hocine, Nicolas Cousaert, Sandrine Dassonneville, Florence Leroux, Benoit Deprez, and Rebecca Deprez-Poulain. "Novel selective inhibitors of neutral endopeptidase: discovery by screening and hit-to-lead optimisation." MedChemComm 3, no. 4 (2012): 469. http://dx.doi.org/10.1039/c2md00287f.

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3

Bobrovs, Raitis, Jekaterina Bolsakova, Jhon Alexander Rodriguez Buitrago, Larisa Varaceva, Marija Skvorcova, Iveta Kanepe, Anastasija Rudnickiha, Emilio Parisini, and Aigars Jirgensons. "Structure-based identification of salicylic acid derivatives as malarial threonyl tRNA-synthetase inhibitors." PLOS ONE 19, no. 4 (April 1, 2024): e0296995. http://dx.doi.org/10.1371/journal.pone.0296995.

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Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Threonyl t-RNA synthetase (ThrRS) is one of the enzymes involved in this pathway, and it has been validated as an anti-malarial drug target. Here, we present 9 structurally diverse low micromolar Plasmodium falciparum ThrRS inhibitors that were identified using high-throughput virtual screening (HTVS) and were verified in a FRET enzymatic assay. Salicylic acid-based compound (LE = 0.34) was selected as a most perspective hit and was subjected to hit-to-lead optimisation. A total of 146 hit analogues were synthesised or obtained from commercial vendors and were tested. Structure-activity relationship study was supported by the crystal structure of the complex of a salicylic acid analogue with a close homologue of the plasmodium target, E. coli ThrRS (EcThrRS). Despite the availability of structural information, the hit identified via virtual screening remained one of the most potent PfThrRS inhibitors within this series. However, the compounds presented herein provide novel scaffolds for ThrRS inhibitors, which could serve as starting points for further medicinal chemistry projects targeting ThrRSs or structurally similar enzymes.

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4

Mostarda, Serena, Tugçe Gür Maz, Alessandro Piccinno, Bruno Cerra, and Erden Banoglu. "Optimisation by Design of Experiment of Benzimidazol-2-One Synthesis under Flow Conditions." Molecules 24, no. 13 (July 3, 2019): 2447. http://dx.doi.org/10.3390/molecules24132447.

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A novel flow-based approach for the preparation of benzimidazol-2-one (1) scaffold by the 1,1′-carbonyldiimidazole (CDI)-promoted cyclocarbonylation of o-phenylenediamine (2) is reported. Starting from a preliminary batch screening, the model reaction was successfully translated under flow conditions and optimised by means of design of experiment (DoE). The method allowed the efficient preparation of this privileged scaffold and to set up a general protocol for the multigram-scale preparation in high yield, purity, and productivity, and was successfully applied for the multigram flow synthesis of N-(2-chlorobenzyl)-5-cyano-benzimidazol-2-one, which is a key synthon for hit-to-lead explorations in our anti-inflammatory drug discovery program.

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5

Osborne, James, Stanislava Panova, Magdalini Rapti, Tatsuya Urushima, and Harren Jhoti. "Fragments: where are we now?" Biochemical Society Transactions 48, no. 1 (January 27, 2020): 271–80. http://dx.doi.org/10.1042/bst20190694.

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Fragment-based drug discovery (FBDD) has become a mainstream technology for the identification of chemical hit matter in drug discovery programs. To date, the food and drug administration has approved four drugs, and over forty compounds are in clinical studies that can trace their origins to a fragment-based screen. The challenges associated with implementing an FBDD approach are many and diverse, ranging from the library design to developing methods for identifying weak affinity compounds. In this article, we give an overview of current progress in fragment library design, fragment to lead optimisation and on the advancement in techniques used for screening. Finally, we will comment on the future opportunities and challenges in this field.

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6

Taki, Aya C., Joseph J. Byrne, Tao Wang, Brad E. Sleebs, Nghi Nguyen, Ross S. Hall, Pasi K. Korhonen, et al. "High-Throughput Phenotypic Assay to Screen for Anthelmintic Activity on Haemonchus contortus." Pharmaceuticals 14, no. 7 (June 26, 2021): 616. http://dx.doi.org/10.3390/ph14070616.

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Parasitic worms cause very significant diseases in animals and humans worldwide, and their control is critical to enhance health, well-being and productivity. Due to widespread drug resistance in many parasitic worms of animals globally, there is a major, continuing demand for the discovery and development of anthelmintic drugs for use to control these worms. Here, we established a practical, cost-effective and semi-automated high throughput screening (HTS) assay, which relies on the measurement of motility of larvae of the barber’s pole worm (Haemonchus contortus) using infrared light-interference. Using this assay, we screened 80,500 small molecules and achieved a hit rate of 0.05%. We identified three small molecules that reproducibly inhibited larval motility and/or development (IC50 values of ~4 to 41 µM). Future work will critically assess the potential of selected hits as candidates for subsequent optimisation or repurposing against parasitic nematodes. This HTS assay has a major advantage over most previous assays in that it achieves a ≥ 10-times higher throughput (i.e., 10,000 compounds per week), and is thus suited to the screening of libraries of tens of thousands to hundreds of thousands of compounds for subsequent hit-to-lead optimisation or effective repurposing and development. The current assay should be adaptable to many socioeconomically important parasitic nematodes, including those that cause neglected tropical diseases (NTDs). This aspect is of relevance, given the goals of the World Health Organization (WHO) Roadmap for NTDs 2021–2030, to develop more effective drugs and drug combinations to improve patient outcomes and circumvent the ineffectiveness of some current anthelmintic drugs and possible drug resistance.

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7

Zaidi, Norburhanuddin Johari, Adib Afandi Abdullah, Choon Han Heh, Chun-Hung Lin, Rozana Othman, and Abdullah Al Hadi Ahmad Fuaad. "Hit-to-Lead Short Peptides against Dengue Type 2 Envelope Protein: Computational and Experimental Investigations." Molecules 27, no. 10 (May 18, 2022): 3233. http://dx.doi.org/10.3390/molecules27103233.

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Data from the World Health Organisation show that the global incidence of dengue infection has risen drastically, with an estimated 400 million cases of dengue infection occurring annually. Despite this worrying trend, there is still no therapeutic treatment available. Herein, we investigated short peptide fragments with a varying total number of amino acid residues (peptide fragments) from previously reported dengue virus type 2 (DENV2) peptide-based inhibitors, DN58wt (GDSYIIIGVEPGQLKENWFKKGSSIGQMF), DN58opt (TWWCFYFCRRHHPFWFFYRHN), DS36wt (LITVNPIVTEKDSPVNIEAE), and DS36opt (RHWEQFYFRRRERKFWLFFW), aided by in silico approaches: peptide–protein molecular docking and 100 ns of molecular dynamics (MD) simulation via molecular mechanics using Poisson–Boltzmann surface area (MMPBSA) and molecular mechanics generalised Born surface area (MMGBSA) methods. A library of 11,699 peptide fragments was generated, subjected to in silico calculation, and the candidates with the excellent binding affinity and shown to be stable in the DI-DIII binding pocket of DENV2 envelope (E) protein were determined. Selected peptides were synthesised using conventional Fmoc solid-phase peptide chemistry, purified by RP-HPLC, and characterised using LCMS. In vitro studies followed, to test for the peptides’ toxicity and efficacy in inhibiting the DENV2 growth cycle. Our studies identified the electrostatic interaction (from free energy calculation) to be the driving stabilising force for the E protein–peptide interactions. Five key E protein residues were also identified that had the most interactions with the peptides: (polar) LYS36, ASN37, and ARG350, and (nonpolar) LEU351 and VAL354; these residues might play crucial roles in the effective binding interactions. One of the peptide fragments, DN58opt_8-13 (PFWFFYRH), showed the best inhibitory activity, at about 63% DENV2 plague reduction, compared with no treatment. This correlates well with the in silico studies in which the peptide possessed the lowest binding energy (−9.0 kcal/mol) and was maintained steadily within the binding pocket of DENV2 E protein during the MD simulations. This study demonstrates the use of computational studies to expand research on lead optimisation of antiviral peptides, thus explaining the inhibitory potential of the designed peptides.

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8

Kandil, Sahar B., Samuel R. Jones, Sonia Smith, Stephen E. Hiscox, and Andrew D. Westwell. "Structure-Based Virtual Screening, Synthesis and Biological Evaluation of Potential FAK-FAT Domain Inhibitors for Treatment of Metastatic Cancer." Molecules 25, no. 15 (July 31, 2020): 3488. http://dx.doi.org/10.3390/molecules25153488.

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Focal adhesion kinase (FAK) is a tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. In cancer cells, FAK promotes the progression and metastasis of tumours. In this study, we used structure-based virtual screening to filter a library of more than 210K compounds against the focal adhesion targeting FAK-focal adhesion targeting (FAT) domain to identify 25 virtual hit compounds which were screened in the invasive breast cancer line (MDA-MB-231). Most notably, compound I showed low micromolar antiproliferative activity, as well as antimigratory activity. Moreover, examination in a model of triple negative breast cancer (TNBC), revealed that, despite not effecting FAK phosphorylation, compound I significantly impairs proliferation whilst impairing focal adhesion growth and turnover leading to reduced migration. Further optimisation and synthesis of analogues of the lead compound I using a four-step synthetic procedure was performed, and analogues were assessed for their antiproliferative activity against three breast cancer (MDA-MB-231, T47D, BT474) cell lines and one pancreatic cancer (MIAPaCa2) cell line. Compound 5f was identified as a promising lead compound with IC50 values in the range of 4.59–5.28 μM in MDA-MB-231, T47D, BT474, and MIAPaCa2. Molecular modelling and pharmacokinetic studies provided more insight into the therapeutic features of this new series.

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9

Scanlon, Martin. "Monash Fragment Platform." Impact 2018, no. 3 (June 15, 2018): 32–34. http://dx.doi.org/10.21820/23987073.2018.3.32.

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The Monash Fragment Platform (MFP) provides academic and commercial researchers with access to fragment-based drug discovery (FBDD) technologies for their therapeutic targets. The facilities are located at the Monash Institute for Pharmaceutical Sciences (MIPS) in Parkville, Australia's largest and most successful pharmaceutical institute. FBDD screening uses our high-quality, in-house fragment library designed to maximise chemical space coverage and enable rapid hit optimisation. Screening cascades are tailored for each target and can be performed using a variety of techniques including NMR spectroscopy and our state-of-the-art surface plasmon resonance (SPR) facility. Structural biology and medicinal chemistry expertise utilising our standardized REFIL strategy enables the rapid elaboration of fragments into leads without the requirement for a large chemistry program.

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10

Mager, Magnus. "Noise performance of the ALPIDE-based ALICE Inner Tracking System." Journal of Physics: Conference Series 2374, no. 1 (November 1, 2022): 012062. http://dx.doi.org/10.1088/1742-6596/2374/1/012062.

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The new ALICE Inner Tracking System is the first large-scale MAPS-based tracking system. It is covering an active surface of 10 m2, with a total of 12.5 billion pixels. Several optimisations of the pixel chip lead to a quasi-noise-free operation, with measured fake-hit rates of below 1 hit per pixel and billion events (system level numbers), numbers compatible with the order of magnitude expected from cosmic and natural background radiation. This contribution covers a detailed study of fake hits as recorded in the inner-most detector barrels, made of the highest quality chips. It reveals a localised noise pattern that could be traced down to originate from decoupling capacitors present on the detector module. It can most likely be explained by the radioactive decay of 210Pb, which is present in trace amounts in the solder that was used to mount decoupling capacitors on the detector modules. This hypothesis is substantiated with a dedicated simulation study and laboratory measurements.

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11

Richardson, Caroline J., Mladen Vincovic, Charlotte East, Nicola Wallis, George Ward, and Andrew Woodhead. "Abstract A142: Fragment based discovery of inhibitors of the eIF4E:eIF4G interaction." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): A142. http://dx.doi.org/10.1158/1535-7163.targ-23-a142.

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Abstract eIF4E is the rate limiting factor for cap-dependent protein translation, forming an essential part of the translation initiation complex, eIF4F and is a key signalling convergence point for the major oncogenic pathways MAPK and PI3K/AKT/MTOR. eIF4E has been shown to be overexpressed in cancer, which has been associated with poor prognosis and resistance to chemotherapeutics and targeted agents such as mTOR and MAPK inhibitors. eIF4E is therefore a promising target for cancer treatment but has so far been difficult to target with small molecules due to a lack of druggable pockets. Fragment based crystallographic screening is a powerful technique for probing the surface of proteins to identify potentially druggable binding sites. Here, we describe our fragment-based approach and hit optimisation campaign to generate potent compounds binding to eIF4E For the fragment screen, we generated an engineered form of eIF4E, where the N-terminal (residues 1-35) were removed and replaced a short, tethered peptide based on the canonical binding sequence of the eIF4E binding protein 4E-BP1, and screened 1400 fragments using a combination of Xray crystallography and NMR. Several low affinity (mM) fragment hits were identified, binding to both the mRNA cap- binding site and at an additional binding site of unknown functional relevance. Using a combination of biophysical and biochemical assays, subsequent rounds of iterative structure-based drug design of yielded potent lead molecules against both binding sites. For the cap-binding site, lead compounds of low nM potency were generated but due to the polar nature of the binding site, the molecules had very poor permeability properties and did not inhibit cell proliferation. For the non-canonical binding site, lead compounds with potency of 100nM alongside less potent enantiomers were generated which provided useful tools for probing the function of the binding site in vitro. We developed a MSD (Meso-scale discovery) assay to determine that the lead compound and not the inactive enantiomer could disrupt the eIF4E:eIF4G interaction in HeLa cell lysates with an IC50 of 1uM. Using a HeLa extract in vitro translation assay, we could also demonstrate that both the cap site and non-canonical site lead compounds could inhibit cap-dependent but not IRES driven protein translation. This work demonstrates the power of fragment screening to identify novel functional pockets on difficult to drug proteins such as eIF4E. Citation Format: Caroline J Richardson, Mladen Vincovic, Charlotte East, Nicola Wallis, George Ward, Andrew Woodhead. Fragment based discovery of inhibitors of the eIF4E:eIF4G interaction [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A142.

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12

Zahrychuk, O. H., U. O. Matyashchuk, V. V. Korjovska, I. I. Milian, D. O. Poliovyi, H. Ya Zahrychuk та A. Ye Demyd. "ВИКОРИСТАННЯ МЕТОДІВ ДОСЛІДЖЕНЬ IN SILICO ДЛЯ ПРОГНОЗУВАННЯ ФАРМАКОКІНЕТИЧНИХ ВЛАСТИВОСТЕЙ ТА ПОШУКУ БІОЛОГІЧНО АКТИВНИХ РЕЧОВИН". Фармацевтичний часопис, № 3 (30 вересня 2024): 53–67. http://dx.doi.org/10.11603/2312-0967.2024.3.14868.

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Мета роботи. Здійснити огляд й проаналізувати комп’ютерні програми, програмні пакети та бази даних, які доцільно використати для проведення досліджень in silico з метою прогнозування фармакокінетичних властивостей та пошуку біологічно активних сполук. Матеріали і методи. Загальнонауковий метод аналізу та синтезу англомовних наукових статей, опублікованих упродовж останнього десятиріччя з використанням баз даних «PubMed», «Google Scolar», «Elsevier», «ResearchGate»; методи систематизації, узагальнення та порівняльного аналізу баз даних комп’ютерних програм, програмних пакетів та даних для проведення досліджень in silicо; абстрактно-логічний метод використано при формуванні висновків. Результати й обговорення. У статті описано використання комп’ютерних програм, програмних пакетів та баз даних для проведення досліджень in silico – методів досліджень за допомогою комп’ютера або комп’ютерної симуляції, для застосування яких доцільно враховувати молекулярні механізми перебігу захворювання, пошук та аналіз біологічних мішеней для запропонованих лігандів, розрахунок фармакокінетичних параметрів, ідентифікацію сайтів метаболізму лігандів, моделювання міжмолекулярної взаємодії з метою визначення найкращої афінності ліганду з мішенню, що в цілому приводить до скорочення часових, фінансових та людський затрат під час пошуку біологічно активних сполук. Завдяки молекулярному докінгу можна прогнозувати ефективність взаємодії ліганд-мішень на молекулярному рівні, а інші методи дослідження in silico дозволяють окреслювати взаємозв’язки «структура-активність» (SAR-, QSAR-аналіз). Досягнення останніх років у галузі хемоінформатики дозволили дослідникам використовувати комп’ютерні програми, програмні пакети та бази даних, які знаходяться у вільному доступі, для моделювання типів міжмолекулярних взаємодій, розрахунку енергії зв’язування, площі поверхні молекули, значень показників гідрофільності, ліпофільності, лікоподібності тощо. Висновки. Дослідження in silico – це реальний інструмент для пошуку нових біологічно активних сполук, прогнозування поліфармакології та побічних реакцій для вже схвалених ліків, дослідження небажаної фармакокінетики та токсичності, для ефективного використання якого доцільно використовувати певні алгоритми, що складаються з наступних кроків: 1) вибір захворювання та ідентифікація мішені для біологічно активних сполук (target identification and validation); 2) дослідження природи та структури діючих речовин лікарських засобів (ЛЗ) та скринінговий аналіз сполук для виявлення нових сполук (Hit discovery) через високопродуктивний скринінг (HTS) або методи in silico, зокрема, віртуальний скринінг (VS); 3) моделювання лігандів із урахуванням властивостей ADME/Tox (Lead optimisation); 4) вибір цільового рецептора, його підготовка до дослідження in silico, вибір сайту зв’язування ліганду з рецептором; 5) пошук у базах даних хімічних сполук, ЛЗ, їх модифікація або віртуальне моделювання ліганду з урахуванням дескрипторів лікоподібності; 6) аналіз результатів взаємодії лігандів із рецептором, візуалізація результатів молекулярного докінгу.

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13

Мосула, Л. М., В. О. Клепко, В. С. Мосула та Д. Б. Коробко. "Virtual design and in silico evaluation of the properties of a series of ethyl (Е)-5-(2-(7-alkyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)hydrazinylidene)-hexanoates". Farmatsevtychnyi zhurnal, № 3 (24 червня 2024): 53–65. http://dx.doi.org/10.32352/0367-3057.3.24.05.

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The study of 7,8-disubstituted 1,3-dimethylxanthine derivatives is a promising area in the search for new biologically active substances. In silico screening saves time and money in selecting the most promising compounds for synthesis and in vitro and in vivo studies, as well as eliminates unpromising compounds. The aim of work was to carry out a virtual design of new ethyl (Е)-5-(2-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)hydrazineylidene)hexanoates by introducing linear and branched alkyl substituents at the 7th position of the basic heterocycle. Based on the molecular structure of the model molecules to predict their ADME parameters, to carry out in silico assessment of the spectrum of biological activity and the probability of each action. For the study we chose 12 model compounds of ethyl (Е)-5-(2-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)hydrazineylidene)hexanoates with linear and branched alkyl substituents at the 7th position of the basic heterocycle: methyl-, ethyl-, n-propyl-, n-butyl-, i-butyl-, n-amyl-, i-amyl-, n-hexyl-, n-heptyl-, n-octyl-, n-nonyl-, n-decyl-. Research methods – freely available web tools SwissADME and PASS Online. A wide range of biological activities is predicted for the model compounds, however, the most likely action is vasodilatory with a probability of impact on peripheral vessels is about 80%. All the derivatives of the investigated series can be considered drug-like and are characterised by moderate oral bioavailability (BS = 0.55), and they are predicted to be quite easy to synthesise (SA from 3.51 to 4.59). Compounds with short alkyl radicals (methyl, ethyl) at the 7th position of the basic heterocycle have an optimal ADME profile and are orally bioavailable. Based on the analysis of the structure-activity relationship, we have derived a certain regularity: the extension of the alkyl substituent leads to a deterioration in the properties of the studied molecules, reduces their oral bioavailability, but does not radically affect their biological activity profile and the values of Pa and Pi. Two derivatives (compounds 1 and 2) were selected for synthesis and further in-depth studies. The results of the computer prediction of biological activity, physicochemical, pharmacokinetic parameters for determination of drug-like properties, oral bioavailability and value of compounds for medicinal chemistry indicate the prospects of searching for biologically active substances among 7-alkyl-8-hydrazineylidene derivatives of 1,3-dimethylxanthine. Taking into account the high potential of compounds 1 and 2, it is advisable to carry out targeted synthesis of hit compounds and thorough in vitro, in vivo studies, and for compounds with violated physicochemical criteria, – structural optimisation of molecules in order to find a lead compound with a high probability of vasodilatory action.

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Keserű, György M., and Gergely M. Makara. "Hit discovery and hit-to-lead approaches." Drug Discovery Today 11, no. 15-16 (August 2006): 741–48. http://dx.doi.org/10.1016/j.drudis.2006.06.016.

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15

Workman, Paul. "Abstract IA014: From targeted phenotypic screen to NXP800: A clinical stage activator of the integrated stress response for the treatment of ARID1A-mutated ovarian carcinoma." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): IA014. http://dx.doi.org/10.1158/1535-7163.targ-23-ia014.

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Abstract My presentation will describe our work on the discovery, nonclinical antitumor properties, mechanism of action (MOA), identification of initial target patient population, and early clinical development of NXP-800. We discovered this agent in our academic drug discovery centre at ICR following our initial identification of the ‘bisamide’ hit CCT245232 from a diverse ~200,000-compound library using an innovative, imaging-based (ArrayScan™) phenotypic screen for inhibitors of the HSF1-mediated activation of the heat shock response in U2OS human osteosarcoma cells. Subsequent multiparameter medicinal chemistry optimisation of the bisamide series, containing the N,N′-4-methyl-1,3-phenylenediamide core, focused on establishing the cell-based SAR for both inhibition of cell proliferation and linked HSF-1 mediated HSP72 induction in the sensitive ARID1A-mutant, platinum-resistant SK-OV-3 human ovarian carcinoma cell line. This generated our orally bioavailable, in vivo-active lead compound and chemical tool CCT251236 – exhibiting oral antitumor efficacy in the SK-OV-3 human ovarian cancer xenograft model in nude mice (Cheeseman et al J Med Chem 60 180-201 2017). Final multiparameter optimization yielded the clinical development candidate CCT361814/NXP800 (Pasqua et al J Med Chem 66 5907-36 2023). With the screening hit bisamide compound already active in the single to low double digit nanomolar range, the early focus was on improving kinetic solubility while retaining the desired antiproliferative and linked HSF1 pathway inhibitory activity together with simultaneous optimisation of PK/PD properties to maximize oral antitumour efficacy; finally requiring modification to the fluorobisamide NXP800 to eliminate PGP-mediated efflux and achieve optimal PK/PD, Pharmacologic Audit Trail, antitumor efficacy and tolerability. In view of these properties, its clean safety panel profile, clear therapeutic index and acceptable dose-to-human prediction, NXP800 was progressed into clinical development. Evaluation in a mini-panel of human cancer cell lines and tumor xenografts revealed high sensitivity to NXP800 in ARIDIA-deficient human ovarian cancer models, confirmed in the large Sanger cancer cell line panel and in isogenic pair systems. Activity exceeded that of cisplatin in both platinum-sensitive and platinum-resistant ARID1A-mutant ovarian cancer xenograft models. By RNA-Seq we identified two sets of consistent, major gene expression profile changes in human cancer cell lines exposed to NXP800, namely: 1) the expected changes in HSF1-regulated genes, together with 2) activation of the integrated stress response (ISR), including ATF4-regulated gene expression. This latter did not indicate a global stress response to NXP800 as we saw no activation of the unfolded protein response (UPR). Physiologically, ISR activation is mediated by phosphorylation of EIF2α which is tightly regulated by four stress-controlled kinases, GCN2, HRI, PKR and PERK. Using each of systematic siRNA knockdown or pharmacologic inhibition by two small-molecule tool compounds from different chemotypes, we discovered that GCN2 alone was necessary and sufficient for ISR activation and cell growth inhibition by NXP800 in SK-OV-3 ovarian cancer cells. Also, orthogonal siRNA depletion or pharmacologic inhibition of GCN2 both markedly reduced the antiproliferative activity of NXP800 in these cells. Global phospho-proteome analysis demonstrated defined changes in response to NXP800 which were reversed by co-treatment with a GCN2 inhibitor. Other follow-on studies at the protein level demonstrated that pharmacological concentrations of NXP800 induced GCN2-dependent phosphorylation of EIF2α, inhibition of global cap-dependent protein translation, and selective translation of ATF4 – a transcription factor that activates downstream genes such as CHAC1 and CHOP in the ISR – both in ARID1A-mutant human ovarian cells in vitro and in corresponding tumor xenograft models in vivo. Using siRNA silencing, we showed that prevention of ATF4 induction substantially reduced the antiproliferative response of SK-OV-3 human ovarian carcinoma cells to NXP800 treatment. Controls used in these experiments included a closely matched, inactive regioisomer. Furthermore, we showed that ISR induction by NXP800 inhibited HSF1 activation, in SK-OV-3 cells, confirming the mechanistic link between ISR activation and inhibition of HSF1-mediated transcription. We further showed that GCN2 activation was not due to the canonical mechanism of amino acid starvation. In summary, we used an HSF1 pathway-focused phenotypic screen to discover the mechanistically novel, first-in-class drug NXP800, which acts potently on ARID1A-mutant, human ovarian cancer cells to stimulate GCN2 and thereby activate the ISR pathway, leading to ATF4 induction and inhibition of HSF1-mediated gene transcription in ARID1A-mutant, platinum-resistant human ovarian cancer cells. Through this mechanism, NXP800 shows highly promising activity in models of this cancer type, including potent inhibition of proliferation in vitro and substantial regression of tumor xenografts in vivo. Studies are currently underway to determine precisely how NXP800 stimulates GCN2 activity and the role of ARID1A deficiency in its pharmacological effects. Recent ChIP-Seq studies are informing on the molecular interactions between ARID1A mutation and the expression of ISR/ATF4 and HSF1-regulated genes. With Nuvectis Pharma, the Phase 1a dose escalation study has been completed and a multicentre Phase 1b expansion cohort study in ARID1A-mutated, platinum-resistant ovarian cancer – a high unmet medical need – has been initiated (NCT05226507) in collaboration with the GOG Foundation and the European Network of Gynaecological Oncological Trial Group (ENGOT). FDA has issued a Fast Track designation to NXP800 in this setting. In addition, NXP800 shows therapeutic potential in non-clinical models of endometrial, gastro-intestinal and bile duct cancer, with FDA Orphan Drug status granted in the last of these indications. Citation Format: Paul Workman. From targeted phenotypic screen to NXP800: A clinical stage activator of the integrated stress response for the treatment of ARID1A-mutated ovarian carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA014.

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Pellecchia, Maurizio, Barbara Becattini, Kevin J. Crowell, Roberto Fattorusso, Martino Forino, Marco Fragai, Dawoon Jung, Tomas Mustelin, and Lutz Tautz. "NMR-based techniques in the hit identification and optimisation processes." Expert Opinion on Therapeutic Targets 8, no. 6 (December 2004): 597–611. http://dx.doi.org/10.1517/14728222.8.6.597.

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17

McCrory, John P., Matthew R. Pearson, Rhys Pullin, and Karen M. Holford. "Optimisation of acoustic emission wavestreaming for structural health monitoring." Structural Health Monitoring 19, no. 6 (April 16, 2020): 2007–22. http://dx.doi.org/10.1177/1475921720912174.

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Structural health monitoring has gained wide appeal for applications with high inspection costs, such as aircraft and wind turbines. As the structures and materials used in these industries evolve, so too must the technologies used to monitor them. Acoustic emission is a passive method of detecting damage which lends itself well to structural health monitoring. One form of acoustic emission monitoring, known as wavestreaming, involves intermittently recording data for set periods of time and using the sequential recordings to detect changes in the state of the structure. However, at present, there is no standard method for selecting appropriate wavestream recording parameters, such as their length or their interval of collection. This article investigates a method of optimising acoustic emission wavestreaming for structural health monitoring purposes by introducing the novel concept of adjoining consecutive discrete acoustic emission hit signals to create synthetic wavestreams. To this end, a pre-notched 492 mm × 67.5 mm × 20 mm, 300M grade steel cantilever specimen was subject to cyclic loading and both acoustic emission hit data and conventional wavestreams were collected as a crack grew in the notched region; crack growth activity was also monitored using digital image correlation for comparison. To demonstrate the proposed optimisation process, four sets of synthetic wavestreams were created from the hit data, 0.25, 0.5, 1.0 and 1.5 s in length, and compared with the 1.5-s-long conventional wavestreams. The activity of the peak frequency and frequency centroid bands of interest within the conventional and synthetic wavestreams were examined to determine whether or not cracking activity could be inferred through them. Across comparisons of all data, it was found that the 0.5-s-long synthetic wavestreams contained enough information to identify the same trends as the conventional wavestreams for this application; thus, the use of synthetic wavestreams as a tool for selecting an appropriate wavestream recording length was demonstrated.

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18

Clark, David E., and Christopher G. Newton. "Outsourcing lead optimisation – the quiet revolution." Drug Discovery Today 9, no. 11 (June 2004): 492–500. http://dx.doi.org/10.1016/s1359-6446(04)03102-2.

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19

Yagci, Semih, Mahmut Gozelle, Selen Gozde Kaya, Yesim Ozkan, Ahmet Bugra Aksel, Filiz Bakar-Ates, Yasemin Dundar, and Gokcen Eren. "Hit-to-lead optimization on aryloxybenzamide derivative virtual screening hit against SIRT." Bioorganic & Medicinal Chemistry 30 (January 2021): 115961. http://dx.doi.org/10.1016/j.bmc.2020.115961.

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20

Pickett, Stephen D., Iain M. McLay, and David E. Clark. "Enhancing the Hit-to-Lead Properties of Lead Optimization Libraries†." Journal of Chemical Information and Computer Sciences 40, no. 2 (March 2000): 263–72. http://dx.doi.org/10.1021/ci990261w.

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21

Gopalsamy, A. "Hit to Lead Generation for Oncology Targets." AACR Education book 2008, no. 1 (April 12, 2008): 265–67. http://dx.doi.org/10.1158/aacr.edb-08-8250.

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22

Leach, Andrew R., and Darren V. S. Green. "Computational Chemistry in Lead Identification, Library Design and Lead Optimisation." Molecular Simulation 26, no. 1 (January 2001): 33–49. http://dx.doi.org/10.1080/08927020108024199.

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23

Borrotti, Matteo, Davide De March, Debora Slanzi, and Irene Poli. "Designing Lead Optimisation of MMP-12 Inhibitors." Computational and Mathematical Methods in Medicine 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/258627.

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The design of new molecules with desired properties is in general a very difficult problem, involving heavy experimentation with high investment of resources and possible negative impact on the environment. The standard approach consists of iteration among formulation, synthesis, and testing cycles, which is a very long and laborious process. In this paper we address the so-called lead optimisation process by developing a new strategy to design experiments and modelling data, namely, the evolutionary model-based design for optimisation (EDO). This approach is developed on a very small set of experimental points, which change in relation to the response of the experimentation according to the principle of evolution and insights gained through statistical models. This new procedure is validated on a data set provided as test environment by Pickett et al. (2011), and the results are analysed and compared to the genetic algorithm optimisation (GAO) as a benchmark. The very good performance of the EDO approach is shown in its capacity to uncover the optimum value using a very limited set of experimental points, avoiding unnecessary experimentation.

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24

Cavalla, David. "A quiet revolution in lead optimisation services?" Drug Discovery Today 9, no. 15 (August 2004): 635–36. http://dx.doi.org/10.1016/s1359-6446(04)03133-2.

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25

Jacoby, Edgar, Herman Van Vlijmen, Olivier Querolle, Ian Stansfield, Lieven Meerpoel, Matthias Versele, George Hynd, and Ricardo Attar. "FEP+ calculations predict a stereochemical SAR switch for first-in-class indoline NIK inhibitors for multiple myeloma." Future Drug Discovery 2, no. 3 (July 1, 2020): FDD43. http://dx.doi.org/10.4155/fdd-2020-0004.

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In the search for first-in-class NIK inhibitors for multiple myeloma, we discovered an azaindoline hit class generated from a biochemical NIK autophosphorylation high-throughput screening assay which was optimized to the final cyanoindoline compound class. During the hit-to-lead phase, a prominent stereochemical SAR switch was observed which was accurately predicted by in silico FEP+ calculations. Crystallographic and computational analysis showed that for both stereoisomers comparable contacts, both in nature and number, could be formed by the switching hydroxyl group, making this system particularly interesting from an interaction energy viewpoint. We provide a detailed analysis of our FEP+ and WaterMap calculations and show how this type of computational chemistry methods are useful during hit-to-lead and lead optimization phases.

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26

Bleicher, Konrad H., Hans-Joachim Böhm, Klaus Müller, and Alexander I. Alanine. "Hit and lead generation: beyond high-throughput screening." Nature Reviews Drug Discovery 2, no. 5 (May 2003): 369–78. http://dx.doi.org/10.1038/nrd1086.

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27

Poulain, Rébecca, Dragos Horvath, Béatrice Bonnet, Christian Eckhoff, Béatrice Chapelain, Marie-Christine Bodinier, and Benoît Déprez. "From Hit to Lead. Analyzing Structure−Profile Relationships." Journal of Medicinal Chemistry 44, no. 21 (October 2001): 3391–401. http://dx.doi.org/10.1021/jm010878g.

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28

Goodnow, Robert A. "Hit and lead identification: Integrated technology-based approaches." Drug Discovery Today: Technologies 3, no. 4 (December 2006): 367–75. http://dx.doi.org/10.1016/j.ddtec.2006.12.009.

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Huang, Lingkai. "Research on Deep Bomb Delivery Strategy Based on Monte Carlo Simulation and Adaptive Optimization Algorithm." Transactions on Computer Science and Intelligent Systems Research 8 (October 24, 2024): 35–43. http://dx.doi.org/10.62051/ghch2015.

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Aiming at the problem of insufficient precision of deep bomb delivery in traditional anti-submarine warfare, this paper proposes a novel algorithm combining Monte Carlo simulation and adaptive optimization [1]. The algorithm optimises the deep bomb delivery strategy by defining the probability distribution of the submarine position. Specifically, Monte Carlo simulation is used to generate samples of possible submarine positions, analyse the effect of the submarine's three-dimensional positional error underwater on the probability of hitting a single depth charge, and explore the role of the dual-fuse detonation mechanism [2]. On this basis, the submarine's orientation error in 3D space is further considered, and an optimisation model is used to determine the optimal fixed-depth fuse detonation depth to maximise the hit probability of a single deep bomb [3]. In addition, this paper extends to the case of multiple depth charges, and optimises the overall hit probability by designing the array of charges and plane spacing to ensure that at least one depth charge can hit the submarine [4]. The experimental results show that the algorithm significantly improves the hit probability of the deep bomb, effectively reduces the impact of positioning error on the combat effect and demonstrates its potential application in practical anti-submarine warfare.

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30

Pleban, Karin, and Gerhard Ecker. "Inhibitors of P-Glycoprotein - Lead Identification and Optimisation." Mini-Reviews in Medicinal Chemistry 5, no. 2 (February 1, 2005): 153–63. http://dx.doi.org/10.2174/1389557053402729.

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31

Eastwood, Paul, Jacob González, Elena Gómez, Francisco Caturla, Cristina Balagué, Adelina Orellana та María Domínguez. "Indolin-2-one p38α inhibitors II: Lead optimisation". Bioorganic & Medicinal Chemistry Letters 21, № 18 (вересень 2011): 5270–73. http://dx.doi.org/10.1016/j.bmcl.2011.07.033.

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32

Morley, Andrew D., Sarah King, Bryan Roberts, Sarah Lever, Barry Teobald, Adrian Fisher, Tony Cook, et al. "Lead optimisation of pyrazoles as novel FPR1 antagonists." Bioorganic & Medicinal Chemistry Letters 22, no. 1 (January 2012): 532–36. http://dx.doi.org/10.1016/j.bmcl.2011.10.090.

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33

Mulyadi,*, B., and J. Soemarsono. "TROMBOSITOPENIA PADA PENGOBATAN DENGAN HEPARIN." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 13, no. 3 (March 15, 2018): 114. http://dx.doi.org/10.24293/ijcpml.v13i3.913.

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Heparin induced thrombocytopenia (HIT), a well known side effect of heparin therapy, occurs in 1–5% of adults exposed to heparin.Unlike other drug induced thrombocytopenia, HIT does not usually cause bleeding, but instead cause thrombosis about 50% of HIT.The thrombosis in HIT can lead to limb gangrene or even death. The Importance to know the HIT is the wide use of heparin led tothe increasing recognition of untoward complications including HIT, relatively uncommon but severe side effect of heparin therapy,unpredictable, and difficulty in diagnosing and treating HIT. HIT is mediated by an antibody that recognizes an epitope on the plateletfactor (PF4)-heparin complex. The platelet factor (PF4)-heparin complex binds to FcgRII receptor on the platelet surface and crosslinksthereceptors.Thisinducesintenseplateletactivationandaggregationandsimultaneouslyactivatesbloodcoagulationpathways,thesechangesareprobablythebasisofthethrombosiseventsinHIT.HITwasclassifiedintotype1and2baseonthepathogenesisandtheseverityofHIT.RegularplateletcountmonitoringisbestsuitedforearlydiagnosisofHIT.Functional(serotoninrelease,plateletaggregationtest)andantigenassays(solidphaseenzymeimmunoassay,fluidphase,andparticlegelimmunoassay)areavailabletoconfirmHIT.HITwasmadebaseontheclinicalfindingandlaboratoryexamination.OnceHITisclinicallysuspected,heparinshouldbestoppedimmediatelyandtreatmentwithanalternativeanticoagulant,waitingforlaboratoryconfirmationmaybecatastrophic.Earlydiagnosisof HIT will decrease the morbidity and mortality.

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34

Löfås, Stefan. "Optimizing the Hit-to-Lead Process Using SPR Analysis." ASSAY and Drug Development Technologies 2, no. 4 (August 2004): 407–16. http://dx.doi.org/10.1089/adt.2004.2.407.

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35

McKew, John C., Megan A. Foley, Paresh Thakker, Mark L. Behnke, Frank E. Lovering, Fuk-Wah Sum, Steve Tam та ін. "Inhibition of Cytosolic Phospholipase A2α: Hit to Lead Optimization". Journal of Medicinal Chemistry 49, № 1 (січень 2006): 135–58. http://dx.doi.org/10.1021/jm0507882.

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36

Floyd, David M., Philip Stein, Zheng Wang, Jian Liu, Steve Castro, Julie A. Clark, Michele Connelly, et al. "Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides." Journal of Medicinal Chemistry 59, no. 17 (August 25, 2016): 7950–62. http://dx.doi.org/10.1021/acs.jmedchem.6b00752.

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37

Zou, D., H. X. Zhai, J. Eckman, P. Higgins, M. Gillard, L. Knerr, S. Carre, P. Pasau, P. Collart, and J. Grassi. "Novel, Acidic CCR2 Receptor Antagonists: From Hit to Lead." Letters in Drug Design & Discovery 4, no. 3 (April 1, 2007): 185–91. http://dx.doi.org/10.2174/157018007780077381.

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38

Löfås, Stefan. "Optimizing the Hit-to-Lead Process Using SPR Analysis." Assay and Drug Development Technologies 2, no. 4 (August 1, 2004): 407–15. http://dx.doi.org/10.1089/1540658041850661.

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39

Wu, Tao, Advait Nagle, Kelli Kuhen, Kerstin Gagaring, Rachel Borboa, Caroline Francek, Zhong Chen, et al. "Imidazolopiperazines: Hit to Lead Optimization of New Antimalarial Agents." Journal of Medicinal Chemistry 54, no. 14 (June 6, 2011): 5116–30. http://dx.doi.org/10.1021/jm2003359.

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40

Tasler, Stefan, Roland Baumgartner, Astrid Ammendola, Josef Schachtner, Tanja Wieber, Marcus Blisse, Sandra Rath та ін. "Thienopyrimidines as β3-adrenoceptor agonists: Hit-to-lead optimization". Bioorganic & Medicinal Chemistry Letters 20, № 20 (жовтень 2010): 6108–15. http://dx.doi.org/10.1016/j.bmcl.2010.08.039.

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41

Bhuniya, Debnath, Rao Mukkavilli, Rahul Shivahare, Delphine Launay, Ravindra T. Dere, Anil Deshpande, Aditya Verma, et al. "Aminothiazoles: Hit to lead development to identify antileishmanial agents." European Journal of Medicinal Chemistry 102 (September 2015): 582–93. http://dx.doi.org/10.1016/j.ejmech.2015.08.013.

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42

Sorokin, Boris, Alla Filimonova, Anna Emelianova, Vadim Kublitski, Artem Gvozd, Vladimir Shmygarev, Ilia Yampolsky, Elena Guglya, Evgeniy Gusev, and Denis Kuzmin. "Novel Triazeneindole Antibiotics: Synthesis and Hit-to-Lead Optimization." International Journal of Molecular Sciences 26, no. 5 (February 21, 2025): 1870. https://doi.org/10.3390/ijms26051870.

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Bacterial antibiotic resistance represents a major healthcare problem. In 2019, 4.95 million deaths were associated with antibiotic resistance, and it is estimated that, by 2050, up to 3.8% of the global gross domestic product could be lost due to this problem. Methicillin-resistant Staphylococcus aureus is one of the leading sources of hospital-acquired infections associated with increased mortality, length of hospital stay, and higher cost of treatment. Here, we describe the de novo synthesis of a library of 22 triazeneindole derivatives with high activity against a wide panel of multidrug-resistant MRSA clinical isolates. Leading compound BX-SI043 (ethyl 6-fluoro-3-[pyrrolidin-1-yl-azo]-1H-indole-2-carboxylate) showed high activity (minimal inhibitory concentration range, 0.125–0.5 mg/L) against 41 multidrug-resistant MRSA strains, as well as relatively low in vitro cytotoxicity (selectivity index, 76) and in vivo acute toxicity (maximum tolerated dose, 600 mg/kg), via intragastric administration in rats. These data suggest that BX-SI043 is a promising drug candidate for the development a novel MRSA treatment.

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43

Yoneyama-Hirozane, Mariko, Kohei Deguchi, Takeshi Hirakawa, Tsuyoshi Ishii, Tomoyuki Odani, Junji Matsui, Yoshihide Nakano, et al. "Identification and Characterization of a New Series of Ghrelin O-Acyl Transferase Inhibitors." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 2 (August 28, 2017): 154–63. http://dx.doi.org/10.1177/2472555217727097.

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Ghrelin O-acyl transferase (GOAT; MBOAT4) catalyzes O-acylation at serine-3 of des-acyl ghrelin. Acyl ghrelin is secreted by stomach X/A-like cells and plays a role in appetite and metabolism. Therefore, GOAT has been expected to be a novel antiobesity target because it is responsible for acyl ghrelin production. Here, we report homogeneous time-resolved fluorescence (HTRF) and enzyme-linked immunosorbent assay (ELISA) methods utilizing human GOAT-expressing microsomes as a novel high-throughput assay system for the discovery of hit compounds and optimization of lead compounds. Hit compounds exemplified by compound A (2-[(2,4-dichlorobenzyl)sulfanyl]-1,3-benzoxazole-5-carboxylic acid) were identified by high-throughput screening using the HTRF assay and confirmed to have GOAT inhibitory activity using the ELISA. Based on the hit compound information, the novel lead compound (compound B, (4-chloro-6-{[2-methyl-6-(trifluoromethyl)pyridin-3-yl]methoxy}-1-benzothiophen-3-yl)acetic acid) was synthesized and exhibited potent GOAT inhibition with oral bioavailability. Both the hit compound and lead compound showed octanoyl-CoA competitive inhibitory activity. Moreover, these two compounds decreased acyl ghrelin production in the stomach of mice after their oral administration. These novel findings demonstrate that GOAT is a druggable target, and its inhibitors are promising antiobesity drugs.

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44

Reilly, Michael P., Uma Sinha, Pierrette André, Scott M. Taylor, Yvonne Pak, Francis R. DeGuzman, Nisha Nanda, et al. "PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model." Blood 117, no. 7 (February 17, 2011): 2241–46. http://dx.doi.org/10.1182/blood-2010-03-274969.

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AbstractHeparin-induced thrombocytopenia (HIT) is a major cause of morbidity and mortality resulting from the associated thrombosis. Extensive studies using our transgenic mouse model of HIT have shown that antibodies reactive with heparin-platelet factor 4 complexes lead to FcγRIIA-mediated platelet activation in vitro as well as thrombocytopenia and thrombosis in vivo. We tested PRT-060318 (PRT318), a novel selective inhibitor of the tyrosine kinase Syk, as an approach to HIT treatment. PRT318 completely inhibited HIT immune complex-induced aggregation of both human and transgenic HIT mouse platelets. Transgenic HIT model mice were treated with KKO, a mouse monoclonal HIT-like antibody, and heparin. The experimental group received orally dosed PRT318, whereas the control group received vehicle. Nadir platelet counts of PRT318-treated mice were significantly higher than those of control mice. When examined with a novel thrombosis visualization technique, mice treated with PRT318 had significantly reduced thrombosis. The Syk inhibitor PRT318 thus prevented both HIT immune complex-induced thrombocytopenia and thrombosis in vivo, demonstrating its activity in HIT.

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45

Yamane, Junji, Min Yao, Yong Zhou, Yasuyuki Hiramatsu, Kenichiro Fujiwara, Tohru Yamaguchi, Hiroto Yamaguchi, et al. "In-crystal affinity ranking of fragment hit compounds reveals a relationship with their inhibitory activities." Journal of Applied Crystallography 44, no. 4 (June 8, 2011): 798–804. http://dx.doi.org/10.1107/s0021889811017717.

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Fragment-based drug discovery (FBDD), which is a molecular build-up strategy from small scaffolds, has recently become a promising approach for lead-compound generation. Although high-throughput protein crystallography is usually used to determine the protein–ligand complex structure and identify potential hit compounds, the relationship between the quality of theFo–Fcmaps of hit compounds and their inhibitory activities has rarely been examined. To address this issue, crystallographic competition experiments were carried out to determine the relative order of the in-crystal binding affinities using five hit compounds of bovine pancreatic trypsin inhibitors. Soaking experiments of all combinations of the five hit compounds were used to define the in-crystal affinity ranking. Based on characterization by a high-concentration bioassay, a clear correlation was observed between in-crystal binding affinities and the inhibitory activities in solution. Moreover, the correlation analysis revealed that X-ray-based screening can detect a weak hit compound with inhibitory activity below the limit of detection, even in a high-concentration assay. The proposed crystallographic competition method could function as a valuable tool, not only to select a plausible starting scaffold for subsequent synthetic efforts but also to access structure–activity relationships using fragment compounds with a wider detection limit than a biological assay. The crystallographic validation methodology described here will greatly accelerate the hit-to-lead process during fragment-based and structure-based drug design.

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46

Martínez Serrano, Iraide. "“Lead Me Home”." Zeszyty Pracy Socjalnej 27, no. 2 (2022): 35–37. http://dx.doi.org/10.4467/24496138zps.22.006.15713.

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The present reflection is based on the documentary “Lead me home” by Pedro Kos and Jon Shenk (2021). This report aims to make the reader aware of the precariousness that exists in the United States today. This documentary also addresses different issues such as the growing humanitarian crisis that is beginning to unfold in the country due to the COVID-19 pandemic, the abysmal differences between classes, racism, and precarious salaries, among many other issues. It can be concluded that people living in precarious situations are always the hardest hit in crisis situations, and even more so if they belong to a social minority.

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Janin, Yves L. "On drug discovery against infectious diseases and academic medicinal chemistry contributions." Beilstein Journal of Organic Chemistry 18 (September 29, 2022): 1355–78. http://dx.doi.org/10.3762/bjoc.18.141.

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This perspective is an attempt to document the problems that medicinal chemists are facing in drug discovery. It is also trying to identify relevant/possible, research areas in which academics can have an impact and should thus be the subject of grant calls. Accordingly, it describes how hit discovery happens, how compounds to be screened are selected from available chemicals and the possible reasons for the recurrent paucity of useful/exploitable results reported. This is followed by the successful hit to lead stories leading to recent and original antibacterials which are, or about to be, used in human medicine. Then, illustrated considerations and suggestions are made on the possible inputs of academic medicinal chemists. This starts with the observation that discovering a “good” hit in the course of a screening campaign still rely on a lot of luck – which is within the reach of academics –, that the hit to lead process requires a lot of chemistry and that if public–private partnerships can be important throughout these stages, they are absolute requirements for clinical trials. Concerning suggestions to improve the current hit success rate, one academic input in organic chemistry would be to identify new and pertinent chemical space, design synthetic accesses to reach these and prepare the corresponding chemical libraries. Concerning hit to lead programs on a given target, if no new hits are available, previously reported leads along with new structural data can be pertinent starting points to design, prepare and assay original analogues. In conclusion, this text is an actual plea illustrating that, in many countries, academic research in medicinal chemistry should be more funded, especially in the therapeutic area neglected by the industry. At the least, such funds would provide the intensive to secure series of hopefully relevant chemical entities which appears to often lack when considering the results of academic as well as industrial screening campaigns.

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48

Kingsland, R., and P. Bryant. "Optimisation of Lead Titanate Ceramics for Hydrostatic Sensor Applications." Materials Science Forum 34-36 (January 1991): 249–53. http://dx.doi.org/10.4028/www.scientific.net/msf.34-36.249.

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49

Ahmad, Nadia M. "Solubility-driven lead optimisation: Recent examples and personal perspectives." Bioorganic & Medicinal Chemistry Letters 26, no. 13 (July 2016): 2975–79. http://dx.doi.org/10.1016/j.bmcl.2016.04.049.

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50

Scott, James S., and Michael J. Waring. "Practical application of ligand efficiency metrics in lead optimisation." Bioorganic & Medicinal Chemistry 26, no. 11 (July 2018): 3006–15. http://dx.doi.org/10.1016/j.bmc.2018.04.004.

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