DFFR: A New Method for High-Throughput Recalibration of Automatic Force-Fields for Drugs

TitleDFFR: A New Method for High-Throughput Recalibration of Automatic Force-Fields for Drugs
Publication TypeJournal Article
Year of Publication2020
AuthorsMoreno, David, Zivanovic Sanja, Colizzi Francesco, Hospital Adam, Aranda Juan, Soliva Robert, and Orozco Modesto
JournalJournal of Chemical Theory and Computation
Date Published08/2020
ISBN Number1549-9618
Abstract

We present DFFR (drug force-field recalibration), a new method for the refining of automatic force-fields used to represent small drugs in docking and molecular dynamics simulations. The method is based on a fine-tuning of torsional terms to obtain ensembles that reproduce observables derived from reference data. DFFR is fast, flexible and can be easily automatized for a high-throughput regime, making it useful in drug design projects. We tested the performance of the method in a few model systems and also in a variety of drug-like molecules using reference data derived from: i) DFT/SCRF (density functional theory coupled to a self-consistent reaction field representation of solvent) calculations on highly populated conformers and ii) enhanced sampling QM/MM where the drug is reproduced at the QM level while the solvent is represented by classical force-fields. Extension of the method to include other sources of reference data is discussed.We present DFFR (drug force-field recalibration), a new method for the refining of automatic force-fields used to represent small drugs in docking and molecular dynamics simulations. The method is based on a fine-tuning of torsional terms to obtain ensembles that reproduce observables derived from reference data. DFFR is fast, flexible and can be easily automatized for a high-throughput regime, making it useful in drug design projects. We tested the performance of the method in a few model systems and also in a variety of drug-like molecules using reference data derived from: i) DFT/SCRF (density functional theory coupled to a self-consistent reaction field representation of solvent) calculations on highly populated conformers and ii) enhanced sampling QM/MM where the drug is reproduced at the QM level while the solvent is represented by classical force-fields. Extension of the method to include other sources of reference data is discussed.

URLhttps://doi.org/10.1021/acs.jctc.0c00306
Short TitleJ. Chem. Theory Comput.
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