Free energy calculations to estimate ligand-binding affinities in structure-based drug design.
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.
M Rami
MR
Reddy
C Ravikumar
CR
Reddy
R S
RS
Rathore
Mark D
MD
Erion
P
P
Aparoy
R Nageswara
RN
Reddy
RR Labs, Inc., 8013 Los Sabalos Street, San Diego, CA 92126, USA. drmrreddy@yahoo.com.
P
P
Reddanna
D001665:Binding Sites; D015195:Drug Design; D008024:Ligands; D011789:Quantum Theory; D013816:Thermodynamics
D008024:Ligands