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

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.