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

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

Volume: 20 Issue: 20

Author(s): M. Rami Reddy, C. Ravikumar Reddy, R. S. Rathore, Mark D. Erion, P. Aparoy, R. Nageswara Reddy and P. Reddanna

Affiliation:

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

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.

Cite this article as:

Reddy Rami M., Reddy Ravikumar C., Rathore S. R., Erion D. Mark, Aparoy P., Reddy Nageswara R. and Reddanna P., Free Energy Calculations to Estimate Ligand-Binding Affinities in Structure-Based Drug Design, Current Pharmaceutical Design 2014; 20 (20) . https://dx.doi.org/10.2174/13816128113199990604