MLP Tools: a PyMOL plugin for using the molecular lipophilicity potential in computer-aided drug design

The molecular lipophilicity potential (MLP) is a well-established method to calculate and visualize lipophilicity on molecules. We are here introducing a new computational tool named MLP Tools, written in the programming language Python, and conceived as a free plugin for the popular open source molecular viewer PyMOL. The plugin is divided into several sub-programs which allow the visualization of the MLP on molecular surfaces, as well as in three-dimensional space in order to analyze lipophilic properties of binding pockets. The sub-program Log MLP also implements the virtual log P which allows the prediction of the octanol/water partition coefficients on multiple three-dimensional conformations of the same molecule. An implementation on the recently introduced MLP GOLD procedure, improving the GOLD docking performance in hydrophobic pockets, is also part of the plugin. In this article, all functions of the MLP Tools will be described through a few chosen examples

How to Increase the Safety and Efficacy of Compounds against Neurodegeneration? A Multifunctional Approach

Successful drug design requires not only the detailed knowledge of the pharmacokinetic and pharmacodynamic profiles of the drug candidate portfolio but also a thorough documentation of the possible toxic effects on humans and the environment. Thus, experimental and computational strategies able to measure or predict specific profiles of designed compounds related to their potential toxicity are highly desired. Moreover, a strategy to avoid toxic effects thus enhancing the potential efficacy of drug candidates is of great interest. To fulfil this aim, the pharmacochemistry research unit at the EPGL has recently developed and improved methodologies that detect the potential human health and environmental hazards of compounds active against neurodegeneration at an early stage. A three-step strategy is presented herein. In particular, i) an alternative index to model the bioconcentration of chemicals in the environment was determined; ii) the antioxidant activity of chemical species against free radicals was evaluated. Moreover, since antioxidants play a key role in both toxicity prevention and neuroprotection, iii) the potential interaction of such compounds with enzymatic targets involved in the neurodegenerative cascade was investigated in silico

Small Molecules as Toll-like Receptor 4 Modulators Drug and In-House Computational Repurposing

The innate immunity toll-like receptor 4 (TLR4) system is a receptor of paramount importance as a therapeutic target. Virtual screening following a “computer-aided drug repurposing” approach was applied to the discovery of novel TLR4 modulators with a non-lipopolysaccharide-like structure. We screened almost 29,000 approved drugs and drug-like molecules from commercial, public, and in-house academia chemical libraries and, after biological assays, identified several compounds with TLR4 antagonist activity. Our computational protocol showed to be a robust approach for the identification of hits with drug-like scaffolds as possible inhibitors of the TLR4 innate immune pathways. Our collaborative work broadens the chemical diversity for inspiration of new classes of TLR4 modulators.This work was financially supported by the Spanish Ministry for Science and Innovation (grants CTQ2014-57141-R, CTQ2017-88353-R, and PID2020-113588RB-I00 for S.M.S.; grants BES-2012-053653 for L.P.R., BES-2015-071588 for J.G.C. and PID2021-124983OB-I00 for J.C.M.), the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (MINECO/FEDER; SAF2016-75988-R), and the Community of Madrid (S-2010/BMD-2332) for M.F

Development of cross metathesis for the design of HDAC inhibitors

Epigenetic histones post translational modifications are key players in the regulation of gene expression. Amongst all possible modifications, the N-acetylation of the lysine side chains located at the N-terminal tail of histones is involved in the relaxation of chromatine and contributes to gene transcription. This acetylation status is controlled by histone acetyl transferases (HAT) and histone deacetylases (HDAC and SIRT). The abnormal expression of HDAC has been linked to the progression of several human diseases such as cancers. Therefore, the development of HDAC inhibitors has emerged as a valuable therapeutic strategy, with currently four compounds approved by the FDA and a fifth one in China. Recent data suggested that combination therapies with HDAC inhibitors may contribute to better clinical results. HDACs are zinc-dependant enzymes grouped in a family of 11 proteins (HDAC1-11), grouped in three classes: class I (HDAC1-3,8), class Il (HDAC4-7,9,10) and class IV (HDAC11). The fourth group of deacetylases contains the class Ill NADH+-dependent sirtuins (SIRT1-7). The standard pharmacophore for HDAC inhibitors involves a zinc-binding group (ZBG) linked through a spacer to a “cap” group in interaction with the external solvent accessible surface. We were interested in alternative chemistries to access HDAC inhibitors in which the intermediate spacer could be build out of two similar building blocks, one bearing the ZBG and on bearing the cap group. By selecting linear alkyl-based spacer, cross metathesis appeared to be a short and flexible strategy, provided it supports the presence of highly oxophile functional groups such as carbonyl groups. This poster summarizes our findings in the application of cross metathesis and the biological evaluations of some of the compounds obtained

Etudes in silico des interactions protéines-carbohydrates

Different molecular docking approaches have been compared on calcium-dependent lectin - carbohydrate systems in order to reproduce the experimental data. Using the most appropriate docking method, the binding site of human lectin Langerin has been studied, unraveling the mechanism of recognition of the epitope of the HIV virus. The characteristics of Pseudomonas aeruginosa lectin I have also been studied by molecular docking, molecular dynamics simulations and free energy calculations. A conformational analysis of Nod factors, bacterial signals required for the symbiosis induction, revealed specific conformational states in agreement with the results obtained by NMR. The homology models of the LysM2 domain and the catalytic domain of the kinase LYK3, hypothetical Nod factor receptors expressed on the root cells of Medicago truncatula, have been built and used as support for biological data.Différentes approches d'amarrage moléculaire sur des systèmes lectines calcium dépendantes – glucides ont été comparées, afin de reproduire les données expérimentales. En utilisant la méthode d'amarrage la plus appropriée, le site de liaison de la lectine humaine Langerine a été étudié, en rationalisant le mécanisme de reconnaissance de l'épitope du virus VIH. Les caractéristiques de la lectine Pseudomonas aeruginosa I ont été également étudiées par des calculs d'amarrage moléculaire, de dynamique moléculaire et d'énergie libre. Une analyse conformationnelle des facteurs Nod, signaux bactériens nécessaires à l'induction de la symbiose, a révélé des états conformationnels spécifiques en accord avec les résultats obtenus par RMN. Les modèles par homologie du domaine LysM2 et du domaine catalytique de la kinase LYK3, récepteurs hypothétiques des facteurs Nod exprimés sur les cellules racinaires de Medicago truncatula, ont été construits et utilisés comme support des données biologiques

Etudes in silico des interactions proteines-glucides

Différentes approches d'amarrage moléculaire sur des systèmes lectines calcium dépendantes - glucides ont été comparées, afin de reproduire les données expérimentales. En utilisant la méthode d'amarrage la plus appropriée, le site de liaison de la lectine humaine Langerine a été étudié, en rationalisant le mécanisme de reconnaissance de l'épitope du virus VIH. Les caractéristiques de la lectine Pseudomonas aeruginosa l'ont été également étudiées par des calculs d'amarrage moléculaire, de dynamique moléculaire et d'énergie libre. Une analyse conformationnelle es facteurs Nod, signaux bactériens nécessaires à l'induction de la symbiose, a révélé des états conformationnels spécifiques en accord avec les résultats obtenus par RMN. Les modèles par homologie du domaine LysM2 et du domaine catalytique de la kinase LYK3, récepteurs hypothétiques des facteurs Nod exprimés sur les cellules racinaires de Medicago truncatula, ont été construits et utilisés comme support des données biologiques.Different molecular docking approaches have been compared on calcium-dependentlectin - carbohydrate systems in order to reproduce the experimental data. Using the most appropriate docking method, the binding site of human lectin Langerin has been studied, unraveling the mechanism of recognition of the epitopeof the HIV virus. The characteristics of Pseudomonas aeruginosa lectin 1 have a/so been studied by mo/eculardocking, molecu/ardynamics simulations and free energy calculations. A conformational analysis of Nod factors, bacterial signais required for the symbiosis induction, revealed specific conformationa/states in agreement with the results obtained by NMR. The hom%gy mode/s of the LysM2 domain and the cata/ytic do main of the kinase LYK3, Hypothetica/ Nod factorreceptors expressed on the root cells of Medicago truncatula, have been built and used as support for biological data.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Non-specific SIRT inhibition as a mechanism for the cytotoxicity of ginkgolic acids and urushiols

Ginkgolic acids and urushiols are natural alkylphenols known for their mutagenic, carcinogenic and genotoxic potential. However, the mechanism of toxicity of these compounds has not been thoroughly elucidated so far. Considering that the SIRT inhibitory potential of anacardic acids has been hypothesized by in silico techniques, we herein demonstrated through both in vitro and computational methods that structurally related compounds such as ginkgolic acids and urushiols are able to modulate SIRT activity. Moreover, their SIRT inhibitory profile and cytotoxicity were comparable to sirtinol, a non-specific SIRT inhibitor (SIRT1 and SIRT2), and different from EX-527, a SIRT1 specific inhibitor. This is the first report on the SIRT inhibition of ginkgolic acids and urushiols. The results reported here are in line with previously observed effects on the induction of apoptosis by this class of compounds, and the non-specific SIRT inhibition is suggested as a new mechanism for their in vitro cytotoxicity

HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?

Histone deacetylase (HDAC) inhibitors have been demonstrated to be beneficial in animal models of neurodegenerative diseases. Such results were mainly associated with the epigenetic modulation caused by HDACs, especially those from class I, via chromatin deacetylation. However, other mechanisms may contribute to the neuroprotective effect of HDAC inhibitors, since each HDAC may present distinct specific functions within the neurodegenerative cascades. Such an example is HDAC6 for which the role in neurodegeneration has been partially elucidated so far. The strategy to be adopted in promising therapeutics targeting HDAC6 is still controversial. Specific inhibitors exert neuroprotection by increasing the acetylation levels of α-tubulin with subsequent improvement of the axonal transport, which is usually impaired in neurodegenerative disorders. On the other hand, an induction of HDAC6 would theoretically contribute to the degradation of protein aggregates which characterize various neurodegenerative disorders, including Alzheimer's, Parkinson's and Hutington's diseases. This review describes the specific role of HDAC6 compared to the other HDACs in the context of neurodegeneration, by collecting in silico, in vitro and in vivo results regarding the inhibition and/or knockdown of HDAC6 and other HDACs. Moreover, structure, function, subcellular localization, as well as the level of HDAC6 expression within brain regions are reviewed and compared to the other HDAC isoforms. In various neurodegenerative diseases, the mechanisms underlying HDAC6 interaction with other proteins seem to be a promising approach in understanding the modulation of HDAC6 activity

Molecular Docking Using the Molecular Lipophilicity Potential as Hydrophobic Descriptor: Impact on GOLD Docking Performance

GOLD is a molecular docking software widely used in drug design. In the initial steps of docking, it creates a list of hydrophobic fitting points inside protein cavities that steer the positioning of ligand hydrophobic moieties. These points are generated based on the Lennard-Jones potential between a carbon probe and each atom of the residues delimitating the binding site. To thoroughly describe hydrophobic regions in protein pockets and properly guide ligand hydrophobic moieties toward favorable areas, an in-house tool, the MLP filter, was developed and herein applied. This strategy only retains GOLD hydrophobic fitting points that match the rigorous definition of hydrophobicity given by the molecular lipophilicity potential (MLP), a molecular interaction field that relies on an atomic fragmental system based on 1-octanol/water experimental partition coefficients (log <i>P</i>_oct). MLP computations in the binding sites of crystallographic protein structures revealed that a significant number of points considered hydrophobic by GOLD were actually polar according to the MLP definition of hydrophobicity. To examine the impact of this new tool, ligand–protein complexes from the Astex Diverse Set and the PDB bind core database were redocked with and without the use of the MLP filter. Reliable docking results were obtained by using the MLP filter that increased the quality of docking in nonpolar cavities and outperformed the standard GOLD docking approach

Structural insights of SIR2rp3 proteins as promising biotargets to fight against Chagas disease and leishmaniasis

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2014-10-09T12:15:48Z No. of bitstreams: 1 Sacconay L Structural insights of.....pdf: 3564842 bytes, checksum: 8dc81c9737f752f76bb479baab61728a (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2014-10-09T12:21:54Z (GMT) No. of bitstreams: 1 Sacconay L Structural insights of.....pdf: 3564842 bytes, checksum: 8dc81c9737f752f76bb479baab61728a (MD5)Made available in DSpace on 2014-10-09T12:36:36Z (GMT). No. of bitstreams: 1 Sacconay L Structural insights of.....pdf: 3564842 bytes, checksum: 8dc81c9737f752f76bb479baab61728a (MD5) Previous issue date: 2013University of Geneva. University of Lausanne. Pharmacochemistry and Phytochemistry & Bioactive Natural Products. School of Pharmaceutical Sciences. Geneva, SwitzerlandHellenic Pasteur Institute. Laboratory of Molecular Parasitology. Microbiology Dept. Athens, GreeceUniversity of Geneva. University of Lausanne. Pharmacochemistry and Phytochemistry & Bioactive Natural Products. School of Pharmaceutical Sciences. Geneva, SwitzerlandUniversity of Geneva. University of Lausanne. Pharmacochemistry and Phytochemistry & Bioactive Natural Products. School of Pharmaceutical Sciences. Geneva, SwitzerlandFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Salvador, BA, BrazilUniversity of Geneva. University of Lausanne. Pharmacochemistry and Phytochemistry & Bioactive Natural Products. School of Pharmaceutical Sciences. Geneva, SwitzerlandUniversity of Geneva. University of Lausanne. Pharmacochemistry and Phytochemistry & Bioactive Natural Products. School of Pharmaceutical Sciences. Geneva, SwitzerlandTrypanosoma cruzi and Leishmania spp. are protozoan pathogens responsible for Chagas disease and leishmaniasis, respectively. Current therapies rely only on a very small number of drugs, most of them are inadequate because of their severe host toxicity or drug-resistance phenomena. In order to find therapeutic alternatives, the identification of new biotargets is highly desired. In this study, homology modelling, docking and molecular dynamics simulations have been used to generate robust 3D models of NAD(+)-dependent deacetylases from Trypanosoma and Leishmania spp., known as SIR2rp3, whose structures have never been described before. Molecular docking of known inhibitors revealed strong analogies with the mitochondrial human SIRT5 in terms of binding mode and interaction strength. On the other hand, by extending the analysis to the channel rims, regions of difference between host and parasitic targets, useful for future selective drug design projects, were pointed out