Journal ArticleDOI
SwissParam: a fast force field generation tool for small organic molecules.
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TLDR
A fast force field generation tool, called SwissParam, able to generate, for arbitrary small organic molecule, topologies, and parameters based on the Merck molecular force field, but in a functional form that is compatible with the CHARMM force field is presented.Abstract:
The drug discovery process has been deeply transformed recently by the use of computational ligand-based or structure-based methods, helping the lead compounds identification and optimization, and finally the delivery of new drug candidates more quickly and at lower cost. Structure-based computational methods for drug discovery mainly involve ligand-protein docking and rapid binding free energy estimation, both of which require force field parameterization for many drug candidates. Here, we present a fast force field generation tool, called SwissParam, able to generate, for arbitrary small organic molecule, topologies, and parameters based on the Merck molecular force field, but in a functional form that is compatible with the CHARMM force field. Output files can be used with CHARMM or GROMACS. The topologies and parameters generated by SwissParam are used by the docking software EADock2 and EADock DSS to describe the small molecules to be docked, whereas the protein is described by the CHARMM force field, and allow them to reach success rates ranging from 56 to 78%. We have also developed a rapid binding free energy estimation approach, using SwissParam for ligands and CHARMM22/27 for proteins, which requires only a short minimization to reproduce the experimental binding free energy of 214 ligand-protein complexes involving 62 different proteins, with a standard error of 2.0 kcal mol(-1), and a correlation coefficient of 0.74. Together, these results demonstrate the relevance of using SwissParam topologies and parameters to describe small organic molecules in computer-aided drug design applications, together with a CHARMM22/27 description of the target protein. SwissParam is available free of charge for academic users at www.swissparam.ch.read more
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GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers
Mark Abraham,Teemu Murtola,Roland Schulz,Roland Schulz,Szilárd Páll,Jeremy C. Smith,Jeremy C. Smith,Berk Hess,Erik Lindahl,Erik Lindahl +9 more
TL;DR: GROMACS is one of the most widely used open-source and free software codes in chemistry, used primarily for dynamical simulations of biomolecules, and provides a rich set of calculation types.
Journal ArticleDOI
SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules
TL;DR: The new SwissADME web tool is presented that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar are presented.
Journal ArticleDOI
ZINC 15 – Ligand Discovery for Everyone
Teague Sterling,John J. Irwin +1 more
TL;DR: A suite of ligand annotation, purchasability, target, and biology association tools, incorporated into ZINC and meant for investigators who are not computer specialists, offer new analysis tools that are easy for nonspecialists yet with few limitations for experts.
Journal ArticleDOI
SwissDock, a protein-small molecule docking web service based on EADock DSS
TL;DR: SwissDock, a web server dedicated to the docking of small molecules on target proteins, is presented, based on the EADock DSS engine, combined with setup scripts for curating common problems and for preparing both the target protein and the ligand input files.
Journal ArticleDOI
SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules
TL;DR: The 2019 version of SwissTargetPrediction is described, which represents a major update in terms of underlying data, backend and web interface, and high levels of predictive performance were maintained despite more extended biological and chemical spaces to be explored.
References
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In Silico Discovery of β-Secretase Inhibitors
TL;DR: An in silico screening approach consisting of fragment-based docking, ligand conformational search by a genetic algorithm, and evaluation of free energy of binding was used to identify low-molecular-weight inhibitors of BACE-1, which has emerged as an important but difficult protein target.
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AffinDB: a freely accessible database of affinities for protein–ligand complexes from the PDB
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Journal ArticleDOI
Discovery of kinase inhibitors by high-throughput docking and scoring based on a transferable linear interaction energy model.
TL;DR: In this paper, the linear interaction energy method with continuum electrostatics (LIECE) was evaluated in depth on five kinases and two multiplicative coefficients for the van der Waals energy and electrostatic free energy were shown to be transferable among different kinases.