Validation and Development of the Force Field Parameters for Drug and Drug-Like Molecules

Abstract

Highly optimized and well-validated parameters have been developed for structure refinement and computer simulation of biomolecules. However, the force fields for most drug and drug-like ligand molecules are not properly validated. Out of ∼100,000 X-ray crystal structures in the Protein Data Bank (2014), >25,000 structures contain at least one of >17,000 chemically diverse ligand molecules. In addition, there is over a million ligand molecules of interest in databases such as NCI and Pubchem. Understanding interatomic interactions of a given ligand with its target acceptor is crucial in molecular modelling and the lack of precise force field parameters for small heteromolecules may result in failure of drug design efforts.A web accessible Automated force field Topology Builder (ATB; http://compbio.biosci.uq.edu.au/atb/) and Repository was developed to facilitate the generation of force field parameters for chemically diverse ligand molecules. The ATB performs quantum mechanical calculations combined with a knowledge-based approach to ensure compatibility with a biomolecular force field. The topologies and parameters created can be used in simulations, computational drug design and X-ray refinement.Most importantly, a fully automated validation of the force field parameters has been incorporated into the ATB methodology. Recent work on the validation of parameters against structural and thermodynamic data as well as the outcome of participating in the SAMPL4 community challenge for the prediction of hydration free energy of drug-like molecules will be presented. Further refinement strategies to improve the parameters by scaling of the van der Waals and electrostatic interactions will be discussed as well.