Academic literature on the topic 'DNA Ligase Inhibitors'
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Journal articles on the topic "DNA Ligase Inhibitors"
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Alomari, Arqam, Robert Gowland, Callum Southwood, Jak Barrow, Zoe Bentley, Jashel Calvin-Nelson, Alice Kaminski, et al. "Identification of Novel Inhibitors of Escherichia coli DNA Ligase (LigA)." Molecules 26, no. 9 (April 25, 2021): 2508. http://dx.doi.org/10.3390/molecules26092508.
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Present in all organisms, DNA ligases catalyse the formation of a phosphodiester bond between a 3′ hydroxyl and a 5′ phosphate, a reaction that is essential for maintaining genome integrity during replication and repair. Eubacterial DNA ligases use NAD+ as a cofactor and possess low sequence and structural homology relative to eukaryotic DNA ligases which use ATP as a cofactor. These key differences enable specific targeting of bacterial DNA ligases as an antibacterial strategy. In this study, four small molecule accessible sites within functionally important regions of Escherichia coli ligase (EC-LigA) were identified using in silico methods. Molecular docking was then used to screen for small molecules predicted to bind to these sites. Eight candidate inhibitors were then screened for inhibitory activity in an in vitro ligase assay. Five of these (geneticin, chlorhexidine, glutathione (reduced), imidazolidinyl urea and 2-(aminomethyl)imidazole) showed dose-dependent inhibition of EC-LigA with half maximal inhibitory concentrations (IC50) in the micromolar to millimolar range (11–2600 µM). Two (geneticin and chlorhexidine) were predicted to bind to a region of EC-LigA that has not been directly investigated previously, raising the possibility that there may be amino acids within this region that are important for EC-LigA activity or that the function of essential residues proximal to this region are impacted by inhibitor interactions with this region. We anticipate that the identified small molecule binding sites and inhibitors could be pursued as part of an antibacterial strategy targeting bacterial DNA ligases.
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Ciarrocchi, Giovanni, Donald G. MacPhee, Les W. Deady, and Leann Tilley. "Specific Inhibition of the Eubacterial DNA Ligase by Arylamino Compounds." Antimicrobial Agents and Chemotherapy 43, no. 11 (November 1, 1999): 2766–72. http://dx.doi.org/10.1128/aac.43.11.2766.
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ABSTRACT All known DNA ligases catalyze the formation of a phosphodiester linkage between adjacent termini in double-stranded DNA via very similar mechanisms. The ligase family can, however, be divided into two classes: eubacterial ligases, which require NAD+ as a cofactor, and other ligases, from viruses, archaea, and eukaryotes, which use ATP. Drugs that discriminate between DNA ligases from different sources may have antieubacterial activity. We now report that a group of arylamino compounds, including some commonly used antimalarial and anti-inflammatory drugs and a novel series of bisquinoline compounds, are specific inhibitors of eubacterial DNA ligases. Members of this group of inhibitors have different heterocyclic ring systems with a common amino side chain in which the two nitrogens are separated by four carbon atoms. The potency, but not the specificity of action, is influenced by the DNA-binding characteristics of the inhibitor, and the inhibition is noncompetitive with respect to NAD+. The arylamino compounds appear to target eubacterial DNA ligase in vivo, since a SalmonellaLig− strain that has been rescued with the ATP-dependent T4 DNA ligase is less sensitive than the parentalSalmonella strain.
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Shapiro, Adam B., Ann E. Eakin, Grant K. Walkup, and Olga Rivin. "A High-Throughput Fluorescence Resonance Energy Transfer-Based Assay for DNA Ligase." Journal of Biomolecular Screening 16, no. 5 (March 11, 2011): 486–93. http://dx.doi.org/10.1177/1087057111398295.
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DNA ligase is the enzyme that catalyzes the formation of the backbone phosphodiester bond between the 5′-PO4 and 3′-OH of adjacent DNA nucleotides at single-stranded nicks. These nicks occur between Okazaki fragments during replication of the lagging strand of the DNA as well as during DNA repair and recombination. As essential enzymes for DNA replication, the NAD+-dependent DNA ligases of pathogenic bacteria are potential targets for the development of antibacterial drugs. For the purposes of drug discovery, a high-throughput assay for DNA ligase activity is invaluable. This article describes a straightforward, fluorescence resonance energy transfer–based DNA ligase assay that is well suited for high-throughput screening for DNA ligase inhibitors as well as for use in enzyme kinetics studies. Its use is demonstrated for measurement of the steady-state kinetic constants of Haemophilus influenzae NAD+-dependent DNA ligase and for measurement of the potency of an inhibitor of this enzyme.
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Howes, Timothy R. L., Annahita Sallmyr, Rhys Brooks, George E. Greco, Darin E. Jones, Yoshihiro Matsumoto, and Alan E. Tomkinson. "Structure-activity relationships among DNA ligase inhibitors: Characterization of a selective uncompetitive DNA ligase I inhibitor." DNA Repair 60 (December 2017): 29–39. http://dx.doi.org/10.1016/j.dnarep.2017.10.002.
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TAN, Ghee T., Sangkook LEE, Ik-Soo LEE, Jingwen CHEN, Pete LEITNER, Jeffrey M. BESTERMAN, Douglas A. KINGHORN, and John M. PEZZUTO. "Natural-product inhibitors of human DNA ligase I." Biochemical Journal 314, no. 3 (March 15, 1996): 993–1000. http://dx.doi.org/10.1042/bj3140993.
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Enzymic activity mediated by recombinant human DNA ligase I (hLI), in conjunction with tannin removal procedures, has been applied to a natural-product screen involving ~1000 plant extracts and various pure compounds. The primary hLI activity assay involved the measurement of the amount of radiolabelled phosphate in a synthetic nucleic acid hybrid that becomes resistant to alkaline phosphatase as a result of ligation. A bioactivity-guided fractionation scheme resulted in the isolation of ursolic [IC50 = 100 μg/ml (216 μM)] and oleanolic [IC50 = 100 μg/ml (216 μM)] acids from Tricalysia niamniamensis Hiern (Rubiaceae), which demonstrated similar DNA ligase inhibition profiles to other triterpenes such as aleuritolic acid. Protolichesterinic acid [IC50 = 6 μg/ml (20 μM)], swertifrancheside [IC50 = 8 μg/ml (11 μM)] and fulvoplumierin [IC50 = 87 μg/ml (357 μM)] represent three additional natural-product structural classes that inhibit hLI. Fagaronine chloride [IC50 = 10 μg/ml (27 μM)] and certain flavonoids are also among the pure natural products that were found to disrupt the activity of the enzyme, consistent with their nucleic acid intercalative properties. Further analyses revealed that some of the hLI-inhibitory compounds interfered with the initial adenylation step of the ligation reaction, indicating a direct interaction with the enzyme protein. However, in all cases, this enzyme–inhibitor interaction did not disrupt the DNA relaxation activity mediated by hLI. These results indicate that, although the same enzyme active site may be involved in both enzyme adenylation and DNA relaxation, inhibitors may exert allosteric effects by inducing conformational changes that disrupt only one of these activities. Studies with inhibitors are important for the assignment of specific cellular functions to these enzymes, as well as for their development into clinically useful antitumour agents.
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Tobin, Lisa A., Aaron P. Rapoport, Ivana Gojo, Maria R. Baer, Alan E. Tomkinson, and Feyruz V. Rassool. "DNA Ligase III Alpha and (Poly-ADP) Ribose Polymerase (PARP1) Are Therapeutic Targets in Imatinib-Resistant (IR) Chronic Myeloid Leukemia (CML)." Blood 114, no. 22 (November 20, 2009): 853. http://dx.doi.org/10.1182/blood.v114.22.853.853.
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Abstract Abstract 853 Therapy with the tyrosine kinase inhibitor imatinib, targeting the constitutively active BCR-ABL kinase has been remarkably successful in Philadelphia chromosome-positive (Ph+) CML, but resistance to tyrosine kinase inhibitors is a growing clinical problem, prompting the search for new therapeutic targets. BCR-ABL expression leads to increased reactive oxygen species (ROS), repair errors and genomic instability. We have previously shown that an error-prone alternative non-homologous end-joining (ALT NHEJ) pathway involving PARP1 and DNA ligase IIIa/XRCC1 is upregulated in Ph+ CML, providing a mechanism for the repair errors and genomic instability. To determine whether ALT NHEJ components may be novel therapeutic targets in IR CML, we characterized two IR cell lines (P210Mo7eIR, Baf3P210IR) for DSB repair abnormalities. Both IR cell lines demonstrate significantly higher levels of DSBs and NHEJ abnormalities (P<0.05) compared with their imatinib-sensitive (IS) counterparts. Notably, whereas steady state levels of the ALT NHEJ components DNA ligase IIIa and PARP1 are increased in IS P210Mo7e and Baf3P210 cells, compared with parental Mo7e and Baf3, the levels of these proteins are increased even further in the IR cells. Presence of increased DNA ligase IIIa and PARP1 levels in the IR cell lines suggests that these enzymes may be targets for therapy using the DNA ligase inhibitors that we have previously identified and PARP1 inhibitors, which have been used successfully in the treatment of cancers with DSB repair defects. Initial tests for cytotoxicity in BCR-ABL-positive cell lines and parental controls showed that the DNA ligase inhibitor L67, which specifically inhibits DNA ligase I and IIIα, is cytotoxic in BCR-ABL-positive cells and parental controls at concentrations of >10 μM, and that cytotoxicity is not influenced by BCR-ABL1 expression. Therefore, we examined the effect of a subtoxic concentration of L67 (0.3 μM) in the presence or absence of the PARP1 inhibitor Nu1025 (Calbiochem) at 50 μM in IR versus IS and parental cells. Combined treatment with L67 and Nu1025 significantly (p<0.001) reduces survival of IR cells compared with IS and parental controls, which were not significantly affected. To determine whether cells from CML patients that are resistant to imatinib are also sensitive to the combination of DNA ligase and PARP inhibitors, we next tested primary bone marrow mononuclear cells (BM MNC) from 6 CML patients with IR disease, compared with normal BM MNC. Cells from 3 of the 6 patients demonstrated a significant decrease in colony survival in response to the combination of DNA repair inhibitors, similar to the sensitivity demonstrated by the two IR cell lines studied. Interestingly, the patient demonstrating the highest sensitivity to the combination of DNA repair inhibitors had significantly increased levels of both DNA ligase IIIa and PARP1, whereas patients demonstrating less sensitivity had increased levels of either DNA ligase IIIa or PARP1, compared with normal BM MNC. Importantly, sensitivity to the DNA repair inhibitors is not correlated with mutations in BCR-ABL because the BCR-ABL mutation T315I that is found in Baf3P210IR cells when overexpressed in Baf3 cells has no effect on colony survival following drug treatment. Together, our results suggest that the process of acquiring IR may select for cells with high levels of PARP1 and DNA ligase IIIa and/or may upregulate ALT NHEJ pathways. Thus, patients with high levels of these proteins are likely to benefit from therapy using inhibitors of ALT NHEJ. Disclosures: No relevant conflicts of interest to declare.
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Tomkinson, Alan E., Tasmin Naila, and Seema Khattri Bhandari. "Altered DNA ligase activity in human disease." Mutagenesis 35, no. 1 (October 20, 2019): 51–60. http://dx.doi.org/10.1093/mutage/gez026.
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Abstract The joining of interruptions in the phosphodiester backbone of DNA is critical to maintain genome stability. These breaks, which are generated as part of normal DNA transactions, such as DNA replication, V(D)J recombination and meiotic recombination as well as directly by DNA damage or due to DNA damage removal, are ultimately sealed by one of three human DNA ligases. DNA ligases I, III and IV each function in the nucleus whereas DNA ligase III is the sole enzyme in mitochondria. While the identification of specific protein partners and the phenotypes caused either by genetic or chemical inactivation have provided insights into the cellular functions of the DNA ligases and evidence for significant functional overlap in nuclear DNA replication and repair, different results have been obtained with mouse and human cells, indicating species-specific differences in the relative contributions of the DNA ligases. Inherited mutations in the human LIG1 and LIG4 genes that result in the generation of polypeptides with partial activity have been identified as the causative factors in rare DNA ligase deficiency syndromes that share a common clinical symptom, immunodeficiency. In the case of DNA ligase IV, the immunodeficiency is due to a defect in V(D)J recombination whereas the cause of the immunodeficiency due to DNA ligase I deficiency is not known. Overexpression of each of the DNA ligases has been observed in cancers. For DNA ligase I, this reflects increased proliferation. Elevated levels of DNA ligase III indicate an increased dependence on an alternative non-homologous end-joining pathway for the repair of DNA double-strand breaks whereas elevated level of DNA ligase IV confer radioresistance due to increased repair of DNA double-strand breaks by the major non-homologous end-joining pathway. Efforts to determine the potential of DNA ligase inhibitors as cancer therapeutics are on-going in preclinical cancer models.
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Mills, Scott D., Ann E. Eakin, Ed T. Buurman, Joseph V. Newman, Ning Gao, Hoan Huynh, Kenneth D. Johnson, et al. "Novel Bacterial NAD+-Dependent DNA Ligase Inhibitors with Broad-Spectrum Activity and Antibacterial EfficacyIn Vivo." Antimicrobial Agents and Chemotherapy 55, no. 3 (December 28, 2010): 1088–96. http://dx.doi.org/10.1128/aac.01181-10.
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ABSTRACTDNA ligases are indispensable enzymes playing a critical role in DNA replication, recombination, and repair in all living organisms. Bacterial NAD+-dependent DNA ligase (LigA) was evaluated for its potential as a broad-spectrum antibacterial target. A novel class of substituted adenosine analogs was discovered by target-based high-throughput screening (HTS), and these compounds were optimized to render them more effective and selective inhibitors of LigA. The adenosine analogs inhibited the LigA activities ofEscherichia coli,Haemophilus influenzae,Mycoplasma pneumoniae,Streptococcus pneumoniae, andStaphylococcus aureus, with inhibitory activities in the nanomolar range. They were selective for bacterial NAD+-dependent DNA ligases, showing no inhibitory activity against ATP-dependent human DNA ligase 1 or bacteriophage T4 ligase. Enzyme kinetic measurements demonstrated that the compounds bind competitively with NAD+. X-ray crystallography demonstrated that the adenosine analogs bind in the AMP-binding pocket of the LigA adenylation domain. Antibacterial activity was observed against pathogenic Gram-positive and atypical bacteria, such asS. aureus,S. pneumoniae,Streptococcus pyogenes, andM. pneumoniae, as well as against Gram-negative pathogens, such asH. influenzaeandMoraxella catarrhalis. The mode of action was verified using recombinant strains with altered LigA expression, an Okazaki fragment accumulation assay, and the isolation of resistant strains withligAmutations.In vivoefficacy was demonstrated in a murineS. aureusthigh infection model and a murineS. pneumoniaelung infection model. Treatment with the adenosine analogs reduced the bacterial burden (expressed in CFU) in the corresponding infected organ tissue as much as 1,000-fold, thus validating LigA as a target for antibacterial therapy.
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Howes, Timothy R. L., Annahita Sallmyr, Rhys Brooks, George E. Greco, Darin E. Jones, Yoshihiro Matsumoto, and Alan E. Tomkinson. "Erratum to “Structure-activity relationships among DNA ligase inhibitors; characterization of a selective uncompetitive DNA ligase I inhibitor” [DNA Repair 60C (2017) 29–39]." DNA Repair 61 (January 2018): 99. http://dx.doi.org/10.1016/j.dnarep.2017.12.001.
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Ando, Kiyohiro, Yusuke Suenaga, and Takehiko Kamijo. "DNA Ligase 4 Contributes to Cell Proliferation against DNA-PK Inhibition in MYCN-Amplified Neuroblastoma IMR32 Cells." International Journal of Molecular Sciences 24, no. 10 (May 19, 2023): 9012. http://dx.doi.org/10.3390/ijms24109012.
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Identifying the vulnerability of altered DNA repair machinery that displays synthetic lethality with MYCN amplification is a therapeutic rationale in unfavourable neuroblastoma. However, none of the inhibitors for DNA repair proteins are established as standard therapy in neuroblastoma. Here, we investigated whether DNA-PK inhibitor (DNA-PKi) could inhibit the proliferation of spheroids derived from neuroblastomas of MYCN transgenic mice and MYCN-amplified neuroblastoma cell lines. DNA-PKi exhibited an inhibitory effect on the proliferation of MYCN-driven neuroblastoma spheroids, whereas variable sensitivity was observed in those cell lines. Among them, the accelerated proliferation of IMR32 cells was dependent on DNA ligase 4 (LIG4), which comprises the canonical non-homologous end-joining pathway of DNA repair. Notably, LIG4 was identified as one of the worst prognostic factors in patients with MYCN-amplified neuroblastomas. It may play complementary roles in DNA-PK deficiency, suggesting the therapeutic potential of LIG4 inhibition in combination with DNA-PKi for MYCN-amplified neuroblastomas to overcome resistance to multimodal therapy.
Dissertations / Theses on the topic "DNA Ligase Inhibitors"
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Papillon, Julie. "Etude structurale et fonctionnelle des complexes de l'ADN gyrase, une ADN topoisomérase bactérienne de type II." Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAJ127.
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Les ADN topoisomérases (Topos) sont des éléments essentiels de la vie cellulaire eucaryote et procaryote. Ces enzymes interviennent lors de la réplication, de la réparation et également lors de la transcription en modulant la topologie de l'ADN. L'ADN gyrase, une Topoisomérase IIA (TopoIIA) bactérienne particulière, est la seule topoisomérase capable de surenrouler l’ADN négativement en présence d’ATP, une activité indispensable au génome bactérien. Les différentes études structurales et fonctionnelles sur ces enzymes ont permis de proposer un mécanisme catalytique de surenroulement très sophistiqué mais la vision morcelée de ces complexes multi-‐conformationnels laisse aujourd’hui de nombreuses questions mécanistiques en suspens. Ce travail de thèse a combiné une approche structurale et fonctionnelle pour essayer de répondre aux questions fondamentales mécanistiques encore non élucidées à propos des ADN topoisomérases de type II et à la découverte de nouveaux inhibiteurs « anti-‐Topo » face à l’émergence de populations bactériennes résistantes aux traitementsType II DNA topoisomerases (Topo2A) remodel DNA topology during replication, transcription and chromosome segregation. Most TopoIIA are able to perform ATP-‐dependent DNA relaxation or decatenation but the bacterial DNA gyraseis the sole type II DNA topoisomerase able to introduce negative supercoils. Several biochemical and structural studies haverevealed a highly sophisticated supercoiling catalytic mechanism but despite a wealth of information, the full architectureof Topo2A and the structural basis for DNA supercoiling remain elusive. Due to their physiological roles, topoisomerasesare also important targets for antibiotics targeting the bacterial enzyme but also anti-‐cancer molecules inhibiting the humanprotein. This presented work has combinedboth structural and functional approach to answer the fundamental mechanisticquestions still unveiled and to discover new inhibitors against the emergence of resistant bacterial population
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Menchon, Grégory. "Criblage virtuel et fonctionnel sur le complexe XRCC4/ADN ligase IV/Cer-XLF de ligature des cassures double-brin de l'ADN : application en radiosensibilisation tumorale." Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30395.
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En cancérologie, la radiothérapie est une des armes essentielles pour éradiquer les cellules tumorales. Les cassures des deux brins de l'ADN dites "double-brin" qu'elle induit sont particulièrement toxiques et constituent la principale cause de mort cellulaire. La NHEJ (Jonction d'Extrémités Non-Homologues) est la voie métabolique majeure de réparation de ces cassures double-brin de l'ADN et par ce mécanisme, les cellules humaines adoptent une résistance à la radiothérapie. Ce mécanisme de réparation constitue donc une cible de choix pour un traitement anticancéreux combiné en vue d'augmenter la sensibilité des cellules cancéreuses aux rayons ionisants (radiosensibilisation). Au cours du mécanisme NHEJ, la ligature finale des extrémités d'ADN est assurée par le complexe protéique tripartite: XRCC4/ADN Ligase IV/Cernunnos-XLF. Les interfaces protéiques concernées représentent toutes des cibles potentielles dans une stratégie rationnelle d'isolement de molécules inhibitrices, guidée par les structures tridimensionnelles de chaque protéine. A travers des expériences de criblage virtuel et de validation à la fois biophysique et biochimique, nous avons isolé les premières molécules capable de prévenir in vitro les interactions protéine-protéine pour les complexes XRCC4/Lig4 et XRCC4/Cer-XLF, respectivement. Ces composés sont des points de départ pour l'élaboration d'inhibiteurs potentiels de plus haute affinité grâce à l'apport de la biologie structurale, en vue d'un effet radiosensibilisant cellulaireRadiotherapy is a major weapon used against cancer. Radio-induced DNA double strand breaks (DSB) are the main lesions responsible for cell death. Non-homologous end-joining (NHEJ) is a predominant DSB repair mechanism which contributes to cancer cells resistance to radiotherapy. NHEJ is thus a good target for strategies which aim at increasing the radio-sensitivity of tumors. Through in silico screening and biophysical and biochemical assays, our objective was to find specific ligands for the XRCC4/Lig4 and XRCC4/Cer-XLF protein-protein interactions involved in NHEJ. Here, we isolated the first compounds able to prevent their interaction in vitro. These early stage inhibitors are promising tools for cancer therapy with the hope to develop more specific compounds for cellular assays through the 3D structure of the protein/inhibitor complexes
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Yu, Deyue. "Identification, caractérisation, et expression de nouveaux gènes chez Arabidopsis thaliana." Université Joseph Fourier (Grenoble), 1994. http://www.theses.fr/1994GRE10102.
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Nous avons participe au sequencage systematique du genome transcrit (etiquette de cdna) d'arabidopsis thaliana. Premierement, nous montrerons des donnees realises dans notre laboratoire et discuterons des interets. Deuxiemement, nous presenterons la caracterisation et l'expression de trois nouveaux clones de cdna. Le premier clone code pour un homologue d'un inhibiteur de proteinase (bowman birk). Le deuxieme clone code pour un homologue de la proteine a' du complexe snrnp u2. C'est le premier u2a' identifie dans le regne vegetal. Le troisieme clone code pour un homologue de la chaine alpha de succinyl-coa synthetase. La troisieme partie du travail concerne la caracterisation des clones correspondant aux genes fortement exprimes dans les boutons floraux. Trois clones de cdna ont ete caracterises representant deux familles divergentes de genes codant pour deux formes d'exopolygalacturonases. Cette divergence sera montree par les sequences et les expressions des genes correspondants. A la suite d'un criblage differentiel contre des cdnas de feuilles, un autre clone a ete isole. Ce clone code pour une proteine de reserve vegetatif. Le gene correspondant est fortement exprime dans les fleurs, les siliques, et les tiges. Dans les boutons floraux, les transcrits du gene sont localises dans les parois de carpelles
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Kim, Jihyun. "The function of CUL-4 ubiquitin ligase complexes in DNA replication and enhancers of cullin-inhibitor CAND-1 in C. elegans." 2009. http://purl.galileo.usg.edu/uga%5Fetd/kim%5Fjihyun%5F200905%5Fphd.
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Fleury, Hubert. "Implication des inhibiteurs de PARP dans le cancer de l’ovaire." Thèse, 2017. http://hdl.handle.net/1866/20221.
Full textBook chapters on the topic "DNA Ligase Inhibitors"
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Folk, Petr, and James L. Wittliff. "Dephosphorylation in Vitro Inhibits Ligand and DNA Binding Activities of Human Estrogen Receptor." In Tyrosine Phosphorylation/Dephosphorylation and Downstream Signalling, 287–90. Berlin, Heidelberg: Springer Berlin Heidelberg, 1993. http://dx.doi.org/10.1007/978-3-642-78247-3_35.
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Minovski, Nikola, and Marjana Novič. "Integrated in Silico Methods for the Design and Optimization of Novel Drug Candidates." In Oncology, 434–81. IGI Global, 2017. http://dx.doi.org/10.4018/978-1-5225-0549-5.ch016.
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Although almost fully automated, the discovery of novel, effective, and safe drugs is still a long-term and highly expensive process. Consequently, the need for fleet, rational, and cost-efficient development of novel drugs is crucial, and nowadays the advanced in silico drug design methodologies seem to effectively meet these issues. The aim of this chapter is to provide a comprehensive overview of some of the current trends and advances in the in silico design of novel drug candidates with a special emphasis on 6-fluoroquinolone (6-FQ) antibacterials as potential novel Mycobacterium tuberculosis DNA gyrase inhibitors. In particular, the chapter covers some of the recent aspects of a wide range of in silico drug discovery approaches including multidimensional machine-learning methods, ligand-based and structure-based methodologies, as well as their proficient combination and integration into an intelligent virtual screening protocol for design and optimization of novel 6-FQ analogs.
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Minovski, Nikola, and Marjana Novič. "Integrated in Silico Methods for the Design and Optimization of Novel Drug Candidates." In Quantitative Structure-Activity Relationships in Drug Design, Predictive Toxicology, and Risk Assessment, 269–317. IGI Global, 2015. http://dx.doi.org/10.4018/978-1-4666-8136-1.ch008.
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Although almost fully automated, the discovery of novel, effective, and safe drugs is still a long-term and highly expensive process. Consequently, the need for fleet, rational, and cost-efficient development of novel drugs is crucial, and nowadays the advanced in silico drug design methodologies seem to effectively meet these issues. The aim of this chapter is to provide a comprehensive overview of some of the current trends and advances in the in silico design of novel drug candidates with a special emphasis on 6-fluoroquinolone (6-FQ) antibacterials as potential novel Mycobacterium tuberculosis DNA gyrase inhibitors. In particular, the chapter covers some of the recent aspects of a wide range of in silico drug discovery approaches including multidimensional machine-learning methods, ligand-based and structure-based methodologies, as well as their proficient combination and integration into an intelligent virtual screening protocol for design and optimization of novel 6-FQ analogs.
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Gryk, M. R., and O. Jardetzky. "Flexibility and Function of the Excherichia coli trp Represser." In Biological NMR Spectroscopy. Oxford University Press, 1997. http://dx.doi.org/10.1093/oso/9780195094688.003.0011.
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The trp repressor from Escherichia coli is a DNA binding protein, which in the presence of the ami no acid tryptophan inhibits the transcription of at least five operons: trpEDCBA, trpR, aroH, mtr, and aroL (Zubay et al., 1972; Rose et al., 1973; Zurawski et al., 1981; Heatwole and Somerville, 1991, 1992). The ligand-free form (aporepressor) shows only weak binding (KD ~ 106 - 107 M) to DNA, independent of the nucleotide sequence (Carey, 1988; Hurlburt and Yanofsky, 1990). The tryptophan containing form (holorepressor) binds preferentially to specific operator sequences with a much higher binding constant (KD ~ 1010 - 1011 M) (Carey, 1988; Chou et al., 1989; Hurlburt and Yanofsky, 1990). The binding of the repressoris thus regulated by tryptophan, which acts as a corepressor (Rose et al., 1973). With a molecular weight of approximately 25kD, the trp repressoris one of the smallest regulatory systems known, which makes it attractive as a prototype for the study of the molecular mechanism of allosteric regulation. In the twelve years since it was isolated and purified (Joachimiak et al., 1983), it has become one of the most extensively studied allosteric systems. Although Perutz has justly pointed out that the trp repressoris not allosteric in a classical sense (Perutz, 1989), in fact, the control site is too close to the DNA binding site to separate direct and indirect (allosteric) effects, the system does manifest an essential feature of all allosteric control mechanisms - a structural change induced by ligand binding. Structures of both the apo- and the holorepressor have been determined both by x-ray diffraction (Zhang et al., 1987; Schevitz et al., 1985; Lawson et al., 1988) and by NMR (Arrowsmith et al., 1991a; Zhao et al., 1993). Structures of the operator DNA have also been reported (Lefèvre et al., 1987; Shakked et al., 1994a,b), and several structures of operator-repressor complexes are available: two crystal structures (Otwinowski et al., 1988, Lawson and Carey, 1993), and a family of NMR solution structures (Zhang et al., 1994).
Conference papers on the topic "DNA Ligase Inhibitors"
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Tseng, Hui-Min, David Shum, Hakim Djaballah, and David Scheinberg. "Abstract 3689: Identification of DNA ligase IV inhibitors as possible drug and probe candidates for enhancement of radiation treatment and chemotherapy." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-3689.
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Lin, Tingting, Zhilian Zhou, Lifeng Zhu, Yandan Fan, Xiaofen Ding, and Yingming Sun. "Abstract 3066: DNA ligase IV inhibitor and X-ray exert a synthetic lethal in loss-of-function p53 cells." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-3066.
Full textReports on the topic "DNA Ligase Inhibitors"
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Altstein, Miriam, and Ronald J. Nachman. Rational Design of Insect Control Agent Prototypes Based on Pyrokinin/PBAN Neuropeptide Antagonists. United States Department of Agriculture, August 2013. http://dx.doi.org/10.32747/2013.7593398.bard.
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The general objective of this study was to develop rationally designed mimetic antagonists (and agonists) of the PK/PBAN Np class with enhanced bio-stability and bioavailability as prototypes for effective and environmentally friendly pest insect management agents. The PK/PBAN family is a multifunctional group of Nps that mediates key functions in insects (sex pheromone biosynthesis, cuticular melanization, myotropic activity, diapause and pupal development) and is, therefore, of high scientific and applied interest. The objectives of the current study were: (i) to identify an antagonist biophores (ii) to develop an arsenal of amphiphilic topically active PK/PBAN antagonists with an array of different time-release profiles based on the previously developed prototype analog; (iii) to develop rationally designed non-peptide SMLs based on the antagonist biophore determined in (i) and evaluate them in cloned receptor microplate binding assays and by pheromonotropic, melanotropic and pupariation in vivo assays. (iv) to clone PK/PBAN receptors (PK/PBAN-Rs) for further understanding of receptor-ligand interactions; (v) to develop microplate binding assays for screening the above SMLs. In the course of the granting period A series of amphiphilic PK/PBAN analogs based on a linear lead antagonist from the previous BARD grant was synthesized that incorporated a diverse array of hydrophobic groups (HR-Suc-A[dF]PRLa). Others were synthesized via the attachment of polyethylene glycol (PEG) polymers. A hydrophobic, biostablePK/PBAN/DH analog DH-2Abf-K prevented the onset of the protective state of diapause in H. zea pupae [EC50=7 pmol/larva] following injection into the preceding larval stage. It effectively induces the crop pest to commit a form of ‘ecological suicide’. Evaluation of a set of amphiphilic PK analogs with a diverse array of hydrophobic groups of the formula HR-Suc-FTPRLa led to the identification of analog T-63 (HR=Decyl) that increased the extent of diapause termination by a factor of 70% when applied topically to newly emerged pupae. Another biostablePK analog PK-Oic-1 featured anti-feedant and aphicidal properties that matched the potency of some commercial aphicides. Native PK showed no significant activity. The aphicidal effects were blocked by a new PEGylated PK antagonist analog PK-dF-PEG4, suggesting that the activity is mediated by a PK/PBAN receptor and therefore indicative of a novel and selective mode-of-action. Using a novel transPro mimetic motif (dihydroimidazole; ‘Jones’) developed in previous BARD-sponsored work, the first antagonist for the diapause hormone (DH), DH-Jo, was developed and shown to block over 50% of H. zea pupal diapause termination activity of native DH. This novel antagonist development strategy may be applicable to other invertebrate and vertebrate hormones that feature a transPro in the active core. The research identifies a critical component of the antagonist biophore for this PK/PBAN receptor subtype, i.e. a trans-oriented Pro. Additional work led to the molecular cloning and functional characterization of the DH receptor from H. zea, allowing for the discovery of three other DH antagonist analogs: Drosophila ETH, a β-AA analog, and a dF analog. The receptor experiments identified an agonist (DH-2Abf-dA) with a maximal response greater than native DH. ‘Deconvolution’ of a rationally-designed nonpeptide heterocyclic combinatorial library with a cyclic bis-guanidino (BG) scaffold led to discovery of several members that elicited activity in a pupariation acceleration assay, and one that also showed activity in an H. zea diapause termination assay, eliciting a maximal response of 90%. Molecular cloning and functional characterization of a CAP2b antidiuretic receptor from the kissing bug (R. prolixus) as well as the first CAP2b and PK receptors from a tick was also achieved. Notably, the PK/PBAN-like receptor from the cattle fever tick is unique among known PK/PBAN and CAP2b receptors in that it can interact with both ligand types, providing further evidence for an evolutionary relationship between these two NP families. In the course of the granting period we also managed to clone the PK/PBAN-R of H. peltigera, to express it and the S. littoralis-R Sf-9 cells and to evaluate their interaction with a variety of PK/PBAN ligands. In addition, three functional microplate assays in a HTS format have been developed: a cell-membrane competitive ligand binding assay; a Ca flux assay and a whole cell cAMP ELISA. The Ca flux assay has been used for receptor characterization due to its extremely high sensitivity. Computer homology studies were carried out to predict both receptor’s SAR and based on this analysis 8 mutants have been generated. The bioavailability of small linear antagonistic peptides has been evaluated and was found to be highly effective as sex pheromone biosynthesis inhibitors. The activity of 11 new amphiphilic analogs has also been evaluated. Unfortunately, due to a problem with the Heliothis moth colony we were unable to select those with pheromonotropic antagonistic activity and further check their bioavailability. Six peptides exhibited some melanotropic antagonistic activity but due to the low inhibitory effect the peptides were not further tested for bioavailability in S. littoralis larvae. Despite the fact that no new antagonistic peptides were discovered in the course of this granting period the results contribute to a better understanding of the interaction of the PK/PBAN family of Nps with their receptors, provided several HT assays for screening of libraries of various origin for presence of PK/PBAN-Ragonists and antagonists and provided important practical information for the further design of new, peptide-based insecticide prototypes aimed at the disruption of key neuroendocrine physiological functions in pest insects.