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

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

Journal Name: Current Pharmaceutical Design

Volume 20 , Issue 20 , 2014

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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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Article Details

VOLUME: 20
ISSUE: 20
Year: 2014
Page: [3323 - 3337]
Pages: 15
DOI: 10.2174/13816128113199990604
Price: $58

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