Advancing Drug Discovery through Enhanced Free Energy Calculations

5 years ago

Advancing Drug Discovery through Enhanced Free Energy Calculations

B. J. Berne, Richard A. Friesner, Lingle Wang, Robert Abel, Edward D. Harder

A principal goal of drug discovery project is to design molecules that can tightly and selectively bind to the target protein receptor. Accurate prediction of protein–ligand binding free energies is therefore of central importance in computational chemistry and computer aided drug design. Multiple recent improvements in computing power, classical force field accuracy, enhanced sampling methods, and simulation setup have enabled accurate and reliable calculations of protein–ligands binding free energies, and position free energy calculations to play a guiding role in small molecule drug discovery. In this Account, we outline the relevant methodological advances, including the REST2 (Replica Exchange with Solute Temperting) enhanced sampling, the incorporation of REST2 sampling with convential FEP (Free Energy Perturbation) through FEP/REST, the OPLS3 force field, and the advanced simulation setup that constitute our FEP+ approach, followed by the presentation of extensive comparisons with experiment, demonstrating sufficient accuracy in potency prediction (better than 1 kcal/mol) to substantially impact lead optimization campaigns. The limitations of the current FEP+ implementation and best practices in drug discovery applications are also discussed followed by the future methodology development plans to address those limitations. We then report results from a recent drug discovery project, in which several thousand FEP+ calculations were successfully deployed to simultaneously optimize potency, selectivity, and solubility, illustrating the power of the approach to solve challenging drug design problems.

Publisher URL: http://dx.doi.org/10.1021/acs.accounts.7b00083

DOI: 10.1021/acs.accounts.7b00083