The Linear Response Approximation (LRA) approach provides a computationally affordable way of estimating absolute binding affinities with corresponding decomposition into electrostatic and non-electrostatic terms together with group contributions from molecular dynamics simulations.<br/>This presentation will cover insights gained with LRA which have influenced the design of molecules for lead optimization. As an example, we describe the observed structure-activity relationship for a congeneric series of enzyme inhibitors and identify the key residues and interactions involved in molecular recognition.<br/>Additionally, we discuss challenges and solutions to create an automatic and robust computational workflow capable of handling hundreds of ligands.

Interpretation of structure-activity relationship in congeneric series using the linear response approximation and free energy decomposition

255th National Meeting (2018)

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