Academic literature on the topic 'Amas hydrophobes'

Apical membrane antigen 1 (AMA1) is an essential component of the moving junction complex used by Plasmodium falciparum to invade human red blood cells. AMA1 has a conserved hydrophobic cleft that is the site of key interactions with the rhoptry neck protein complex. Our goal is to develop small molecule inhibitors of AMA1 with broad strain specificity, which we are pursuing using a fragment-based approach. In our screening campaign, we identified fragments that bind to the hydrophobic cleft with a hit rate of 5 %. The high hit rate observed strongly suggests that a druggable pocket is present within the cleft.

Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a valuable vaccine candidate and exported on the merozoite surface at the time of erythrocyte invasion. PfAMA1 interacts with rhoptry neck protein PfRON2, a component of the rhoptry protein complex, which forms the tight junction at the time of invasion. Phage display studies have identified a 15-residue (F1) and a 20-residue (R1) peptide that bind to PfAMA1 and block the invasion of erythrocytes. Cocrystal structures of central region of PfAMA1 containing disulfide-linked clusters (domains I and II) with R1 peptide and a peptide derived from PfRON2 showed strong structural similarity in binding. The peptides bound to a hydrophobic groove surrounded by domain I and II loops. In this study, peptidomimetics based on the crucial PfAMA1-binding residues of PfRON2 peptide have been identified. Top 5 peptidomimetics when checked for their docking on the region of PfAMA1 encompassing the hydrophobic groove were found to dock on the groove. Drug-like molecules having structural similarity to the top 5 peptidomimetics were identified based on their binding ability to PfAMA1 hydrophobic groove in blind docking. These inhibitors provide potential lead compounds, which could be used in the development of antimalarials targeting PfAMA1.

ABSTRACT Apical membrane antigen 1 (AMA1) is expressed in schizont-stage malaria parasites and sporozoites and is thought to be involved in the invasion of host red blood cells. AMA1 is an important vaccine candidate, as immunization with this antigen induces a protective immune response in rodent and monkey models of human malaria. Additionally, anti-AMA1 polyclonal and monoclonal antibodies inhibit parasite invasion in vitro. We have isolated a 20-residue peptide (R1) from a random peptide library that binds to native AMA1 as expressed by Plasmodium falciparum parasites. Binding of R1 peptide is dependent on AMA1 having the proper conformation, is strain specific, and results in the inhibition of merozoite invasion of host erythrocytes. The solution structure of R1, as determined by nuclear magnetic resonance spectroscopy, contains two structured regions, both involving turns, but the first region, encompassing residues 5 to 10, is hydrophobic and the second, at residues 13 to 17, is more polar. Several lines of evidence reveal that R1 targets a “hot spot” on the AMA1 surface that is also recognized by other peptides and monoclonal antibodies that have previously been shown to inhibit merozoite invasion. The functional consequence of binding to this region by a variety of molecules is the inhibition of merozoite invasion into host erythrocytes. The interaction between these peptides and AMA1 may further our understanding of the molecular mechanisms of invasion by identifying critical functional regions of AMA1 and aid in the development of novel antimalarial strategies.

The ternary complexes of formulae cis-[(NH3)2Pt(nucl)(amac)]NO3, where nucl = guo and cyd (guanosine and cytidine) and amac = the deprotonated aminoacids glycine (gly), L-alanine (ala), L-2-aminobutyric acid (2-aba), L-norvaline (nval) and L-norleucine (nleu), were prepared from the reactions of the binary chelated ones cis-[(NH3)2Pt(amac)]NO3 with the nucleosides.They were characterized by H1, C13 and Pt195 NMR and IR spectra, together with elemental analysis and conductivity measurements. The aminoacids coordinate with Pt(II) in the ternary complexes with their terminal -NH2 groups, guo through N7 and cyd through N3. Ligand-ligand hydrophobic interactions were also observed in the ternary complexes and were stronger with longer aliphatic chains of the aminoacids. The E3 sugar conformation increased by 5-7% in the ternary systems, as compared to the free nucleosides, while the percentage of the gg conformation remained almost constant and the one of the anti conformation of the sugar increased also slightly. Finally, the h conformer around the Cα-Cβ bonds of the aminoacids reached a maximum in the binary systems and decreased again considerably in the ternary ones.

The estrogen receptor alpha (ERα) plays an important role in breast development and pro-proliferation signal activation in the normal and cancerous breast. The ERα inhibitors were potentially active as cytotoxic agents against breast cancer. This study was conducted in order to find Asymmetrical Hexahydro-2H-Indazole Analogs of Curcumin (AIACs) as hits of ERα inhibitor. A training set of 17 selected ERα inhibitors was used to create 10 pharmacophore models using LigandScout 4.2. The pharmacophore models were validated using 383 active compounds as positive data and 20674 decoys as negative data obtained from DUD.E. Model 2 was found as the best pharmacophore model and consisted of three types of pharmacophore features, viz. one hydrophobic, one hydrogen bond acceptor, and aromatic interactions. Model 2 was utilized for ligand-based virtual screening 186 of AIACs, AMACs, intermediates, and Mannich base derivative compounds. The hits obtained were further screened using molecular docking, analyzed using drug scan, and tested for its synthesis accessibility. Fourteen compounds were fulfilled as hits in pharmacophore modeling, in which 10 hits were selected by molecular docking, but only seven hits met Lipinski’s rule of five and had medium synthesis accessibility. In conclusion, seven compounds were suggested to be potentially active as ERα inhibitors and deserve to be synthesized and further investigated.

Biokatalis heterogen memerlukan penyangga yang sesuai melalui teknik imobilisasi enzim, terutama jika digunakan dalam industri makanan. Dalam sintesis perisa ester alami, busa poliuretan (PUF) dipilih sebagai penyangga imobilisasi lipase, karena memiliki sifat kaku inert, dan porositas tinggi. PUF perlu dilapisi dengan co-immobilized, yang terdiri dari campuran surfaktan yang aman yaitu gelatin, lecithin, PEG, MgCl2, sehingga menjadi satu kesatuan sebagai penyangga PUF hidrofobik. Interaksi hidrofobik antara lipase dan surfaktan pada PUF dapat memicu lipase yang mengaktifkan antarmuka untuk bereaksi lebih banyak dengan substrat melalui sisi aktifnya. Penelitian ini bertujuan untuk mempelajari kemampuan penyerapan PUF pada co-immobilized lipase sebagai biokatalis heterogen. Tahapan yang dilakukan adalah PUF direndam dalam co-immobilized dengan perbandingan 1:10; 1:20; 1:30 (b/b) selama 1-5 jam, kemudian dikeringkan, hasilnya direndam dalam lipase dan dikeringkan, menghasilkan biokatalis heterogen, hasil terbaik biokatalis heterogen diuji pada sintesis perisa ester alami. Hasil penelitian menunjukkan bahwa kondisi penyerapan surfaktan terbaik diperoleh selama 3 jam perendaman pada semua perbandingan PUF: co immobilized 1:10; 1:20; 1:30 (b/b) masing - masing 6,95 g/g; 23,54 g/g; 19,95 g/g, dan aktivitasnya berturut turut 2 U/g PUF; 5,86 U/g PUF; 3,34 U/g PUF. Hasil biokatalis heterogen terbaik pada rasio PUF: co immobilized 1:20 (b/b) diuji pada sintesis perisa alami melalui reaksi esterifikasi asam laurat dari minyak kelapa dan sitronelol dari minyak sereh, menghasilkan konversi 55% perisa alami citronellyl laurat.Heterogeneous biocatalysts prepared through the enzyme immobilization technique require an appropriate carrier, especially if they are used in the food industry. In the synthesis of natural ester flavor, polyurethane foam (PUF) was chosen as the lipase immobilization carrier, because it has rigid properties, inert, and high porosity. Carrier PUF needs to be coated with a food-safe surfactant known as co-immobilized, consisting of a mixture of gelatin, lecithin, PEG, and MgCl2, so that it becomes a single unit as support for hydrophobic PUF. The interaction hydrophobic between lipases and surfactants in PUF can trigger interface-activating lipases to react more with substrates through their active sites. This study aims to study the sorption capability of PUF on co-immobilized lipase as a heterogeneous biocatalyst. The steps taken were PUF was immersed in co-immobilized in a ratio of 1:10; 1:20; 1:30 (w/w) for 1-5 h, then dried, the results were soaked in lipase and dried, producing heterogeneous biocatalysts, the best results of heterogeneous biocatalysts were tested by natural flavor ester synthesis. The results showed that the best sorption conditions were obtained for 3 hours of immersion in all PUF: immobilized co ratio 1:10; 1:20; 1:30 (w/w) was 6.95 g/g; 23.54 g/g; 19.95 g/g, and each activity was 2 U/gram PUF; 5.86 U/gram PUF; 3.34 U/gram PUF. The best result of heterogeneous biocatalyst at the ratio of PUF: co immobilized 1:20 (w/w) was tested on the synthesis of natural flavors through the esterification reaction of lauric acid from coconut oil and citronellol from citronella oil, resulting in a conversion of 55% to citronellyl laurate natural flavor.

<p>Membran Polyethersulfone (PES) bersifat hidrofobik yang memiliki ketahanan rendah terhadap sifat fouling. Fouling pada membran mengakibatkan penurunan kinerja membrane selama proses operasi. Oleh karena itu, modifikasi membran perlu dilakukan untuk meningkatkan sifat hidrofilik membrane. Pada penelitian ini modifikasi dilakukan dengan penambahan nanopartikel Mg(OH)<sub>2</sub> yang bersifat tidak beracun, murah, dan mudah diperoleh. Penambahan aditif nanopartikel Mg(OH)<sub>2</sub> pada membran PES dilakukan dengan cara pencampuran polimer dengan metode <em>non solvent induced phase separation</em> (NIPS) menggunakan pelarut <em>dimethyl sulfoxide</em> (DMSO). DMSO merupakan pelarut polar aprotik yang dapat melarutkan senyawa organik maupun anorganik dengan baik. DMSO juga merupakan pelarut yang tidak beracun, sehingga lebih aman dan ramah lingkungan. Penelitian ini bertujuan untuk menghasilkan membran PES hidrofilik dengan penambahan nanopartikel Mg(OH)<sub>2</sub> dengan unjuk kerja terbaik. Pengaruh penambahan nanopartikel Mg(OH)<sub>2</sub> dalam sistem membran dievaluasi dengan menganalisis perubahan struktur kimia PES menggunakan ATR-FTIR, perubahan morfologi menggunakan SEM, porositas menggunakan metoda gravimetri, serta pengujian kinerja (permeabilitas dan rejeksi) membran. Hasil penelitian menunjukkan bahwa penambahan nanopartikel Mg(OH)<sub>2</sub>, mengakibatkan perubahan pada struktur atau morfologi membrane PES, yang berpengaruh terhadap peningkatan permeabilitas membran. Penambahan nanopartikel Mg(OH)<sub>2</sub> juga meningkatkan porositas membran dari 12% ‒ 40%. Kehadiran gugus hidroksil (-OH) dalam matriks membran dikonfirmasi dengan uji FTIR. Kinerja membran optimum diperoleh pada nilai permeabilitas air sebesar 56,4 L/m<sup>2</sup>.jam.bar, dengan rejeksi asam humus sebesar 61%.</p><p><strong>Modification of Polyethersulfone Membrane with the Addition of Mg(OH)<sub>2 </sub>Nanoparticles in Dimethyl Sulfoxide Solvent. </strong>Polyethersulfone (PES) membrane has hydrophobic characteristics and low resistance to fouling properties. The fouling on the membrane results in a decrease in the performance of the membrane during the operation process. Therefore, membrane modification needs to be done to increase the hydrophilic properties of the membrane. In this study, modifications were made by adding Mg(OH)<sub>2</sub> nanoparticles which are non-toxic, inexpensive, and easy to obtain. The addition of Mg(OH)<sub>2</sub> nanoparticle additives to PES membranes was carried out by blending polymers with the non-solvent induced phase separation (NIPS) method using dimethyl sulfoxide (DMSO) as solvent. DMSO is an aprotic polar solvent that can dissolve both organic and inorganic compounds well. DMSO is also a non-toxic solvent, making it safer and more environmentally friendly. This study aims to produce a hydrophilic PES membrane with the addition of Mg(OH)<sub>2</sub> nanoparticles with the best performance. The effect of adding Mg(OH)<sub>2</sub> nanoparticles in the membrane system was evaluated by analyzing changes in the chemical structure of PES using ATR-FTIR, morphological changes using SEM, porosity using the gravimetric method, and testing the performance (permeability and rejection) of the membrane. The results showed that the addition of Mg(OH)<sub>2</sub> nanoparticles resulted in changes in the structure or morphology of the PES membrane, which affected the increase in membrane permeability. The addition of Mg(OH)<sub>2</sub> nanoparticles also increased the porosity of the membrane from 12% to 40%. The presence of hydroxyl groups (-OH) in the membrane matrix was confirmed by FTIR analysis. The optimum membrane performance was obtained at the water permeability value of 56.4 L/m<sup>2</sup>.h.bar with 61% rejection of humic acid.</p>

Les domaines proteiques globulaires de taille courante sont le resultat d'une separation quasiment parfaite entre la surface composee d'acides amines essentiellement hydrophiles, et le coeur, constitue par des acides amides amines hydrophobes. L'etude realisee a consiste dans un premier temps, a mettre en evidence la sur-representation et la sous-representation d'un certain nombre de classes d'amas hydrophobes au sens hca en comparant les nombres d'occurrences des amas dans des banques de sequences non redondantes a ceux obtenus dans des banques de sequences aleatoires de composition identique en acide amines, en se basant sur les valeurs de zscores pour chaque amas. Dans cette etude, les acides amines v, i, l, f, m, y, w sont hydrophobes et p est considere comme etant interrupteur. Ensuite, la liste d'acides amines hydrophobes ainsi que l'acide amine interrupteur, furent modifies pour mettre en evidence le role joue par l'alphabet utilise lors de l'extraction des amas hydrophobes et evaluer l'impact specifique de chaque acide amine hydrophobe ou hydrophile sur les resultats. 118 alphabets differents ont ete testes. Une etude complementaire menee sur des banques de structures a abouti a l'identification de la relation presque univoque qui existe entre certains amas et les structures secondaires regulieres des proteines globulaires. La combinaison des resultats issus des banques de structures et des banques de sequences constitue une mine d'information precieuse qui pourra etre exploitee pour l'amelioration des methodes de prediction de structure des domaines globulaires.

Nous avons d’abord exploré les caractéristiques 3D des amas d’acides aminés hydrophobes issus de la méthode "Hydrophobic Cluster Analysis" (HCA), au travers d’une représentation originale en tesselation de Voronoï. Chaque amas peut être ainsi caractérisé dans ses conformations  ou  et ses affinités préférentielles pour d’autres amas peuvent être décrites. Le repliement protéique peut alors être décrit comme l’assemblage de ces amas HCA 3D. Nous avons ensuite construit, en utilisant des outils d’alignement tels que HCA, des modèles 3D des formes oligomériques solubles du peptide A. Ce peptide, impliqués dans la maladie d’Alzheimer, serait neurotoxique sous cette forme soluble. Ce travail nous a permis de proposer une hypothèse expliquant le comportement différencié de p3, sans la région N-terminale d’A. Enfin, nous avons pu mettre en évidence la présence d’un ou plusieurs "points chauds" communs aux protéines amyloïdes, pouvant être à l’origine de leur propriété à former des fibres.

Une fraction significative des protéomes reste non annotée, laissant inaccessible une partie du répertoire fonctionnel de la vie, incluant des innovations moléculaires ayant une valeur thérapeutique ou environnementale. Le manque d'annotation fonctionnelle est en partie dû aux limites des approches actuelles pour la détection de relations cachées, ou à des caractéristiques spécifiques telles que le désordre. L'objectif de ma thèse a été de développer des approches méthodologiques reposant sur les signatures structurales des domaines repliés, afin de caractériser plus avant les séquences protéiques dont la fonction est inconnue, même en l'absence d'informations évolutives. Tout d'abord, j'ai développé un score permettant d'estimer le potentiel de repliement d'une séquence d'acides aminés, basé sur sa densité en amas hydrophobes, correspondant principalement aux structures secondaires régulières. J'ai décrit le continuum entre l'ordre et le désordre, couvrant différents états allant des conformations étendues aux globules fondus et ai caractérisé des cas d'ordre conditionnel. Ensuite, j'ai combiné ce score avec les prédictions de structure 3D d'AlphaFold2 (AF2) disponibles pour 21 protéomes de référence. Une grande fraction des acides aminés des modèles AF2 associés à un très faible index de confiance est incluse dans des segments non repliables, soutenant la qualité d'AF2 comme prédicteur du désordre. Cependant, dans chaque protéome, de longs segments repliables avec des prédictions AF2 de faible confiance présentent également des caractéristiques de domaines solubles et repliés. Cela suggère un ordre caché (conditionnel ou inconditionnel), qui n'est pas détecté par AF2 en raison du manque d'informations évolutives, ou des motifs de repliement non répertoriés. Enfin, à l'aide de ces outils, j'ai effectué une exploration préliminaire de protéines ou de régions non annotées, identifiées via le développement et l'application d'une nouvelle procédure d'annotation. Bien que ces séquences soient enrichies en désordre, une part importante d'entre elles présente des caractéristiques de type globulaire soluble. Ces séquences constituent de bons candidats pour de futures validations et caractérisations expérimentales. De plus, l'analyse de gènes de novo validés expérimentalement m'a permis de contribuer au débat encore ouvert sur les caractéristiques structurales des protéines codées par ces gènes, qui présentent un enrichissement en désordre et une grande diversité d'états structuraux<br>A significant fraction of the proteomes remains unannotated, leaving inaccessible a part of the functional repertoire of life, including molecular innovations with therapeutic or environmental value. Lack of functional annotation is partly due to the limitations of the current approaches in detecting hidden relationships, or to specific features such as disorder. The aim of my PhD thesis was to develop methodological approaches based on the structural signatures of folded domains, in order to further characterize the protein sequences with unknown function even in absence of evolutionary information. First, I developed a scoring system in order to estimate the foldability potential of an amino acid sequence, based on its density in hydrophobic clusters, which mainly correspond to regular secondary structures. I disentangled the continuum between order and disorder, covering various states from extended conformations (random coils) to molten globules and characterize cases of conditional order. Next, I combined this scoring system with the AlphaFold2 (AF2) 3D structure predictions available for 21 reference proteomes. A large fraction of the amino acids with very low AF2 model confidence are included in non-foldable segments, supporting the quality of AF2 as a predictor of disorder. However, within each proteome, long segments with very low AF2 model confidence also exhibit characteristics of soluble, folded domains. This suggests hidden order (conditional or unconditional), which is undetected by AF2 due to lack of evolutionary information, or unrecorded folding patterns. Finally, using these tools, I made a preliminary exploration of unannotated proteins or regions, identified through the development and application of a new annotation workflow. Even though these sequences are enriched in disorder, an important part of them showcases soluble globular-like characteristics. These would make good candidates for further experimental validation and characterization. Moreover, the analysis of experimentally validated de novo genes allowed me to contribute to the still-open debate on the structural features of proteins encoded by these genes, enriched in disorder and displaying a great diversity of structura

Numerous antimicrobial peptides (AMP) obtained from natural sources are currently tested in clinical or preclinical settings for treating infections triggered by antimicrobial-resistant bacteria. Several experiments with cyclic, linear and diastereomeric AMPs have proved that the geometry, along with the chemical properties of an AMP, is important for the microbiological activities of these compounds. It is understood that the combination of the hydrophobic and hydrophilic nature of AMPs is crucial for the adsorption and destruction of the bacterial membrane. However, the application of AMPs in therapeutics is still limited due to their poor pharmacokinetics, low bacteriological efficacy and overall high manufacturing costs. To overcome these problems, a variety of newly synthesized cationic amphiphiles have recently appeared, which imitate not only the amphiphilic nature but also the potent antibacterial activities of the AMPs with better pharmacokinetic properties and lesser in vitro toxicity. Thus, amphiphiles of this new genre have enough potential to deliver several antibacterial molecules in years to come.