Motivation Glycine receptors (GlyRs) mediate fast inhibitory neurotransmission in the brain and have been recognized as key pharmacological targets for pain. A large number of chemically diverse compounds that are able to modulate GlyR function both positively and negatively have been reported, which provides useful information for the development of pharmacological strategies and models for the allosteric modulation of these ion channels. Results Based on existing literature, we have collected 218 unique chemical entities with documented modulatory activities at homomeric GlyR-α1 and -α3 and built a database named GRALL. This collection includes agonists, antagonists, positive and negative allosteric modulators and a number of experimentally inactive compounds. Most importantly, for a large fraction of them a structural annotation based on their putative binding site on the receptor is provided. This type of annotation, which is currently missing in other drug banks, along with the availability of cooperativity factors from radioligand displacement experiments are expected to improve the predictivity of in silico methodologies for allosteric drug discovery and boost the development of conformation-based pharmacological approaches. Availability and implementation The GRALL library is distributed as a web-accessible database at the following link: https://ifm.chimie.unistra.fr/grall. For each molecular entry, it provides information on the chemical structure, the ligand-binding site, the direction of modulation, the potency, the 3D molecular structure and quantum-mechanical charges as determined by our in-house pipeline. Contact mcecchini@unistra.fr Supplementary information Supplementary data are available at Bioinformatics online.
In the era of big data in Chemistry, the need for automated tools for virtual screening is compelling. Here, we present PrepFlow a toolkit for chemical library preparation and management. Starting from a list of compounds in SMILES or 2D molecular format, PrepFlow outputs a set of 3D molecular structures ready for use in subsequent drug discovery projects. Our development stands out for speed and robustness of execution, the efficient exploitation of HPC resources, and the implementation of an archiving strategy to save computer time, storage, and human intervention. Using a random selection of 600 compounds from available drug banks, we show that the preparation time per ligand on a desktop computer is 6.6 s. Thanks to these performances and the automatic parallelization on HPC, a chemical library of the size of ChEMBL (2 M) was prepared in around 3 days on a computer cluster. PrepFlow is freely distributed at the following link: https://ifm.chimie.unistra.fr/prepflow.
The accurate prediction of protein–ligand binding affinities is a fundamental problem for the rational design of new drug entities. Current computational approaches are either too expensive or inaccurate to be effectively used in virtual high-throughput screening campaigns. In addition, the most sophisticated methods, e.g., those based on configurational sampling by molecular dynamics, require significant pre- and postprocessing to provide a final ranking, which hinders straightforward applications by nonexpert users. We present a novel computational platform named ChemFlow to bridge the gap between 2D chemical libraries and estimated protein–ligand binding affinities. The software is designed to prepare a library of compounds provided in SMILES or SDF format, dock them into the protein binding site, and rescore the poses by simplified free energy calculations. Using a data set of 626 protein–ligand complexes and GPU computing, we demonstrate that ChemFlow provides relative binding free energies with an RMSE < 2 kcal/mol at a rate of 1000 ligands per day on a midsize computer cluster. The software is publicly available at .
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