Estimation of relative free energies of binding using pre‐computed ensembles based on the single‐step free energy perturbation and the site‐identification by Ligand competitive saturation approaches

Abstract

Accurate and rapid estimation of relative binding affinities of ligand-protein complexes is a requirement of computational methods for their effective use in rational ligand design. Of the approaches commonly used, free energy perturbation (FEP) methods are considered one of the most accurate, though they require significant computational resources. Accordingly, it is desirable to have alternative methods of similar accuracy but greater computational efficiency to facilitate ligand design. In the present study relative free energies of binding are estimated for one or two non-hydrogen atom changes in compounds targeting the proteins ACK1 and p38 MAP kinase using three methods. The methods include standard FEP, single-step FEP (SSFEP) and the site-identification by ligand competitive saturation (SILCS) ligand grid free energy (LGFE) approach. Results show the SSFEP and SILCS LGFE methods to be competitive with or better than the FEP results for the studied systems, with SILCS LGFE giving the best agreement with experimental results. This is supported by additional comparisons with published FEP data on p38 MAP kinase inhibitors. While both the SSFEP and SILCS LGFE approaches require a significant upfront computational investment, they offer a 1000-fold computational savings over FEP for calculating the relative affinities of ligand modifications once those pre-computations are complete. An illustrative example of the potential application of these methods in the context of screening large numbers of transformations is presented. Thus, the SSFEP and SILCS LGFE approaches represent viable alternatives for actively driving ligand design during drug discovery and development.

Computational Fluorine Scanning Using Free-Energy Perturbation

“…35 Follow-up studies showed that combining SSP with a ligand grid free energy approach offers a 1000-fold computational savings over traditional FEP for calculating the relative binding affinities once some upfront pre-computations are complete. 36 More recently, the method has been studied for bias 37 and applied to the efficient optimization of forcefields. 38 We expand on this SSP approach to perform computational fluorine scanning by comparing predictions from PFS for nine test systems to experimental data and to traditional alchemical calculations using FEP.…”

Study of the affinity between the protein kinase PKA and homoarginine‐containing peptides derived from kemptide: Free energy perturbation (FEP) calculations

“…These mechanisms are implicated in almost all cellular processes. FEP protocols have been previously used for studying interactions between PKs and ATP‐competitive ligands and rational design of PK inhibitors . It is possible to list merits of the FEP‐based protocol reported here.…”

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

“…Applying Equation (1) with no intermediate states is referred to as single step perturbation (SSP) and this is the primary free energy method used in this work. Numerous studies have used SSP [16][17][18][19] , demonstrating that it is applicable to relative free energy calculations 20,21 and can be significantly faster than standard FEP 22 . Most recently, the authors of this paper have used SSP to perform computational fluorine scanning 23 .…”