Drug attrition late in preclinical or clinical development is a serious economic problem in the f... more Drug attrition late in preclinical or clinical development is a serious economic problem in the field of drug discovery. These problems can be linked, in part, to the quality of the compound collections used during the hit generation stage and to the selection of compounds undergoing optimization. Here, we present FAF-Drugs3, a web server that can be used for drug discovery and chemical biology projects to help in preparing compound libraries and to assist decision-making during the hit selection/lead optimization phase. Since it was first described in 2006, FAF-Drugs has been significantly modified. The tool now applies an enhanced structure curation procedure, can filter or analyze molecules with user-defined or eight predefined physicochemical filters as well as with several simple ADMET (absorption, distribution, metabolism, excretion and toxicity) rules. In addition, compounds can be filtered using an updated list of 154 hand-curated structural alerts while Pan Assay Interferen...
Open screening endeavors play and will play a key role to facilitate the identification of new bi... more Open screening endeavors play and will play a key role to facilitate the identification of new bioactive compounds in order to foster innovation and to improve the effectiveness of chemical biology and drug discovery processes. In this line, we developed the new web server MTiOpenScreen dedicated to small molecule docking and virtual screening. It includes two services, MTiAutoDock and MTiOpenScreen, allowing performing docking into a user-defined binding site or blind docking using AutoDock 4.2 and automated virtual screening with AutoDock Vina. MTiOpenScreen provides valuable starting collections for screening, two in-house prepared drug-like chemical libraries containing 150 000 PubChem compounds: the Diverse-lib containing diverse molecules and the iPPI-lib enriched in molecules likely to inhibit protein-protein interactions. In addition, MTiOpenScreen offers users the possibility to screen up to 5000 small molecules selected outside our two libraries. The predicted binding pose...
Protein-protein interactions (PPI) are involved in vital cellular processes and are therefore ass... more Protein-protein interactions (PPI) are involved in vital cellular processes and are therefore associated to a growing number of diseases. But working with them as therapeutic targets comes with some major hurdles that require substantial mutations from our way to design drugs on historical targets such as enzymes and G-Protein Coupled Receptor (GPCR). Among the numerous ways we could improve our methodologies to maximize the potential of developing new chemical entities on PPI targets, is the fundamental question of what type of compounds should we use to identify the first hits and among which chemical space should we navigate to optimize them to the drug candidate stage. In this review article, we cover different aspects on PPI but with the aim to gain some insights into the specific nature of the chemical space of PPI inhibitors. We describe the work of different groups to highlight such properties and discuss their respective approach. We finally discuss a case study in which we...
Progress in biophysics and molecular biology, Jan 5, 2015
Protein-protein interactions (PPIs) are carrying out diverse functions in living systems and are ... more Protein-protein interactions (PPIs) are carrying out diverse functions in living systems and are playing a major role in the health and disease states. Low molecular weight (LMW) "drug-like" inhibitors of PPIs would be very valuable not only to enhance our understanding over physiological processes but also for drug discovery endeavors. However, PPIs were deemed intractable by LMW chemicals during many years. But today, with the new experimental and in silico technologies that have been developed, about 50 PPIs have already been inhibited by LMW molecules. Here, we first focus on general concepts about protein-protein interactions, present a consensual view about ligandable pockets at the protein interfaces and the possibilities of using fast and cost effective structure-based virtual screening methods to identify PPI hits. We then discuss the design of compound collections dedicated to PPIs. Recent financial analyses of the field suggest that LMW PPI modulators could be g...
Drug discovery is a time consuming and costly process. Thus, a trend towards the use of in silico... more Drug discovery is a time consuming and costly process. Thus, a trend towards the use of in silico approaches such as structure- and ligand-based virtual screening methods to speed up the process has gained significant momentum in recent years. Most of these in silico applications require a good quality 3D structure of the small drug-like molecules as input. This article reviews the algorithm and validation of the open-source software DG-AMMOS, a tool that generates the 3D conformation of small molecules using distance geometry construction and molecular mechanics optimization comparing its performance with some related free and commercial packages. The number of chemo/bioinformatics free and/or open-source tools assisting drug discovery projects is increasing, and many successful contributions making use of these computer programs have been reported. DG-AMMOS is an efficient 3D structure generator engine that provides fast and reliable generation of 3D structures and contributes to ...
Online resources enabling and supporting drug discovery have blossomed during the past ten years.... more Online resources enabling and supporting drug discovery have blossomed during the past ten years. However, drug hunters commonly find themselves overwhelmed by the proliferation of these computer-based resources. Ten years ago, we, the authors of this review, felt that a comprehensive list of in silico resources relating to drug discovery was needed. Especially because the internet provides a wealth of inspiring tools that, if fully exploited, could greatly assist the process. We present here a compilation of online tools and databases collected over the past decade. The tools were essentially found through literature and internet searches and, currently, our list contains over 1500 URLs. We also briefly highlight some recently reported services and comment about ongoing and future efforts in the field.
Drug attrition late in preclinical or clinical development is a serious economic problem in the f... more Drug attrition late in preclinical or clinical development is a serious economic problem in the field of drug discovery. These problems can be linked, in part, to the quality of the compound collections used during the hit generation stage and to the selection of compounds undergoing optimization. Here, we present FAF-Drugs3, a web server that can be used for drug discovery and chemical biology projects to help in preparing compound libraries and to assist decision-making during the hit selection/lead optimization phase. Since it was first described in 2006, FAF-Drugs has been significantly modified. The tool now applies an enhanced structure curation procedure, can filter or analyze molecules with user-defined or eight predefined physicochemical filters as well as with several simple ADMET (absorption, distribution, metabolism, excretion and toxicity) rules. In addition, compounds can be filtered using an updated list of 154 hand-curated structural alerts while Pan Assay Interferen...
Open screening endeavors play and will play a key role to facilitate the identification of new bi... more Open screening endeavors play and will play a key role to facilitate the identification of new bioactive compounds in order to foster innovation and to improve the effectiveness of chemical biology and drug discovery processes. In this line, we developed the new web server MTiOpenScreen dedicated to small molecule docking and virtual screening. It includes two services, MTiAutoDock and MTiOpenScreen, allowing performing docking into a user-defined binding site or blind docking using AutoDock 4.2 and automated virtual screening with AutoDock Vina. MTiOpenScreen provides valuable starting collections for screening, two in-house prepared drug-like chemical libraries containing 150 000 PubChem compounds: the Diverse-lib containing diverse molecules and the iPPI-lib enriched in molecules likely to inhibit protein-protein interactions. In addition, MTiOpenScreen offers users the possibility to screen up to 5000 small molecules selected outside our two libraries. The predicted binding pose...
Protein-protein interactions (PPI) are involved in vital cellular processes and are therefore ass... more Protein-protein interactions (PPI) are involved in vital cellular processes and are therefore associated to a growing number of diseases. But working with them as therapeutic targets comes with some major hurdles that require substantial mutations from our way to design drugs on historical targets such as enzymes and G-Protein Coupled Receptor (GPCR). Among the numerous ways we could improve our methodologies to maximize the potential of developing new chemical entities on PPI targets, is the fundamental question of what type of compounds should we use to identify the first hits and among which chemical space should we navigate to optimize them to the drug candidate stage. In this review article, we cover different aspects on PPI but with the aim to gain some insights into the specific nature of the chemical space of PPI inhibitors. We describe the work of different groups to highlight such properties and discuss their respective approach. We finally discuss a case study in which we...
Progress in biophysics and molecular biology, Jan 5, 2015
Protein-protein interactions (PPIs) are carrying out diverse functions in living systems and are ... more Protein-protein interactions (PPIs) are carrying out diverse functions in living systems and are playing a major role in the health and disease states. Low molecular weight (LMW) "drug-like" inhibitors of PPIs would be very valuable not only to enhance our understanding over physiological processes but also for drug discovery endeavors. However, PPIs were deemed intractable by LMW chemicals during many years. But today, with the new experimental and in silico technologies that have been developed, about 50 PPIs have already been inhibited by LMW molecules. Here, we first focus on general concepts about protein-protein interactions, present a consensual view about ligandable pockets at the protein interfaces and the possibilities of using fast and cost effective structure-based virtual screening methods to identify PPI hits. We then discuss the design of compound collections dedicated to PPIs. Recent financial analyses of the field suggest that LMW PPI modulators could be g...
Drug discovery is a time consuming and costly process. Thus, a trend towards the use of in silico... more Drug discovery is a time consuming and costly process. Thus, a trend towards the use of in silico approaches such as structure- and ligand-based virtual screening methods to speed up the process has gained significant momentum in recent years. Most of these in silico applications require a good quality 3D structure of the small drug-like molecules as input. This article reviews the algorithm and validation of the open-source software DG-AMMOS, a tool that generates the 3D conformation of small molecules using distance geometry construction and molecular mechanics optimization comparing its performance with some related free and commercial packages. The number of chemo/bioinformatics free and/or open-source tools assisting drug discovery projects is increasing, and many successful contributions making use of these computer programs have been reported. DG-AMMOS is an efficient 3D structure generator engine that provides fast and reliable generation of 3D structures and contributes to ...
Online resources enabling and supporting drug discovery have blossomed during the past ten years.... more Online resources enabling and supporting drug discovery have blossomed during the past ten years. However, drug hunters commonly find themselves overwhelmed by the proliferation of these computer-based resources. Ten years ago, we, the authors of this review, felt that a comprehensive list of in silico resources relating to drug discovery was needed. Especially because the internet provides a wealth of inspiring tools that, if fully exploited, could greatly assist the process. We present here a compilation of online tools and databases collected over the past decade. The tools were essentially found through literature and internet searches and, currently, our list contains over 1500 URLs. We also briefly highlight some recently reported services and comment about ongoing and future efforts in the field.
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Papers by David Lagorce