Free Energy Calculations to Estimate Ligand-Binding Affinities in Structure-Based Drug Design

M.   Rami   Reddy; C.   Ravikumar   Reddy; R.   S.   Rathore; Mark   D.   Erion; P.      Aparoy; R.   Nageswara   Reddy; P.      Reddanna

doi:10.2174/13816128113199990604

Abstract

Post-genomic era has led to the discovery of several new targets posing challenges for structure-based drug design efforts to identify lead compounds. Multiple computational methodologies exist to predict the high ranking hit/lead compounds. Among them, free energy methods provide the most accurate estimate of predicted binding affinity. Pathway-based Free Energy Perturbation (FEP), Thermodynamic Integration (TI) and Slow Growth (SG) as well as less rigorous end-point methods such as Linear interaction energy (LIE), Molecular Mechanics-Poisson Boltzmann./Generalized Born Surface Area (MM-PBSA/GBSA) and λ-dynamics have been applied to a variety of biologically relevant problems. The recent advances in free energy methods and their applications including the prediction of protein-ligand binding affinity for some of the important drug targets have been elaborated. Results using a recently developed Quantum Mechanics (QM)/Molecular Mechanics (MM) based Free Energy Perturbation (FEP) method, which has the potential to provide a very accurate estimation of binding affinities to date has been discussed. A case study for the optimization of inhibitors for the fructose 1,6- bisphosphatase inhibitors has been described.

Keywords: Free energy perturbation, free energy calculations, FBPase, QM/MM FEP, ligand-binding affinity, structure-based drug design.

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