Binding Free Energy Calculation using Quantum Mechanics Aimed for Drug Lead Optimization

CAVASOTTO, CLAUDIO N

METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.)

Springer Nature

Año: 2020 vol. 2114 p. 257 - 268

1064-3745

The routine use of in silico tools is already established indrug lead design. Beside the use of molecular docking methods to screen largechemical libraries, and thus prioritize compounds for purchase or synthesis,more accurate calculations of protein-ligand binding free energy could guidelead optimization, thus saving time and resources. Theoretical developments andthe advance in computing power, have allowed quantum mechanical-based methodsapplied to calculations on biomacromolecules to be increasingly explored andused, with the purpose of providing a more accurate description ofprotein-ligand interactions, and an enhanced level of accuracy in thecalculation of binding affinities. It should be noted that the quantummechanical formulation includes, in principle, all contributions to theenergy, considering terms usually neglected in molecular mechanics force-fields,such as electronic polarization, metal coordination, and covalent binding; moreover,quantum mechanical approaches aresystematically improvable. By treatingall elements and interactions on equal footing, and avoiding the need ofsystem-dependent parameterizations, they provide a greater degree of transferability. Inthis review, we illustrate the increasing relevance of quantum mechanicalmethods for binding free energy calculation in the context of structure-baseddrug lead optimization, showing representative applications of the differentapproaches available.