ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
1/1
2 files

Optimization of Protein-Ligand Electrostatic Interactions Using an Alchemical Free-Energy Method

preprint
submitted on 08.07.2019, 15:24 and posted on 09.07.2019, 14:17 by Alexander Wade, David Huggins

We present an alchemical free-energy method for optimizing the partial charges of a ligand to maximize the binding affinity with a receptor. This methodology can be applied to known ligand-protein complexes to determine an optimized set of ligand partial atomic changes. Three protein-ligand complexes have been optimized in this work: FXa, P38 and androgen receptor. The optimization of the ligand charges yielded improvements to binding affinity for all three systems. The sets of optimized charges can be used to identify design principles for chemical changes to the ligand which improve the binding affinity. In this work, beneficial chemical mutations are generated from these principles and the resulting molecules tested using free-energy perturbation calculations. We show that three quarters of our chemical changes are predicted to improve the binding affinity, with an average improvement of approximately 1 kcal/mol. The results demonstrate that charge optimization in explicit solvent is a useful tool for predicting beneficial chemical changes such as pyridinations, fluorinations, and oxygen to sulphur mutations.

History

Email Address of Submitting Author

dhuggins@tritdi.org

Institution

Tri-Institutional Therapeutics Discovery Institute

Country

United States

ORCID For Submitting Author

0000-0003-1579-2496

Declaration of Conflict of Interest

D.H. is a founder and shareholder of Integrated Biomedical Solutions Ltd.

Exports