Ligand Binding Affinity Prediction for Membrane Proteins with Alchemical Free Energy Calculation Methods

Overview

Journal J Chem Inf Model

Publisher American Chemical Society

Specialties Chemistry
Medical Informatics

Date 2024 Jul 3

PMID 38959405

Authors

Han Zhang

Wonpil Im

Affiliations

Soon will be listed here.

Abstract

Alchemical relative binding free energy (ΔΔ) calculations have shown high accuracy in predicting ligand binding affinity and have been used as important tools in computer-aided drug discovery and design. However, there has been limited research on the application of ΔΔ methods to membrane proteins despite the fact that these proteins represent a significant proportion of drug targets, play crucial roles in biological processes, and are implicated in numerous diseases. In this study, to predict the binding affinity of ligands to G protein-coupled receptors (GPCRs), we employed two ΔΔ calculation methods: thermodynamic integration (TI) with AMBER and the alchemical transfer method (AToM) with OpenMM. We calculated ΔΔ values for 53 transformations involving four class A GPCRs and evaluated the performance of AMBER-TI and AToM-OpenMM. In addition, we conducted tests using different numbers of windows and varying simulation times to achieve reliable ΔΔ results and to optimize resource utilization. Overall, both AMBER-TI and AToM-OpenMM show good agreement with the experimental data. Our results validate the applicability of AMBER-TI and AToM-OpenMM for optimization of lead compounds targeting membrane proteins.

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