Computer guided small molecule design is a common practice in structure-based drug discovery and computational binding affinity prediction is an integral part of the design cycle.  Here we report a blinded validation to simulate a real drug discovery project setting to evaluate the Single Step Free Energy Perturbation (SSFEP) method [Raman et al. J. Chem. Theor. Comput. 2012, 8, 3513] targeting the relative experimental binding affinities of inhibitors of p38 MAP kinase and ACK1 kinase. The SSFEP method implements a protocol to compute the relative free energies of binding of small ligand modifications involving a single non-hydrogen atom substitution by post-processing explicit solvent MD simulation data of the parent ligand-protein complex. In contrast to standard free energy calculations, SSFEP calculates the relative free energies of aqueous solvation and protein binding in a single step through use of the thermodynamic perturbation formula.  Implementation of the SSFEP method involves automatically generating conformational ensembles of arbitrarily modified ligands from the ensemble of the parent ligand in solution and in complex with the target protein, to efficiently compute the relative binding free energies of hundreds of possibilities for compound modifications. The method is applied in a blinded retrospective study to test its ability to reproduce experimentally measured relative binding affinities for congeneric series of ligands for the proteins p38 MAP kinase and ACK1 kinase. Results of our evaluation, rapid ligand modification idea generation and utility of SSFEP in lead optimization will be discussed.<br/>

Small molecule design using single step free energy perturbation (SSFEP): Blinded validation against the relative binding affinities of inhibitors of p38 and ACK1 kinases

249th National Meeting (2015)

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