Use of quantum mechanics/molecular mechanics-based FEP method for calculating relative binding affinities of FBPase inhibitors for type-2 diabetes |
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Authors: | R S Rathore R Nageswara Reddy A K Kondapi P Reddanna and M Rami Reddy |
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Institution: | (1) Bioinformatics Infrastructure Facility, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India;(2) Rational Labs Pvt Ltd, Plot # 177, IDA Mallapur, Hyderabad, 500076, India;(3) Department of Animal Sciences, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India;(4) RR Labs, Inc., 8013 Los Sabalos Street, San Diego, CA 92126, USA;(5) Centre for Modeling, Simulations and Design, University of Hyderabad, Hyderabad, 500046, India; |
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Abstract: | A quantum mechanics (QM)/molecular mechanics (MM)-based free energy perturbation (FEP) method, developed recently, provides
most accurate estimation of binding affinities. The validity of the method was evaluated for a large set of diverse inhibitors
for fructose 1,6-bisphosphatase (FBPase), a target enzyme for type-II diabetes mellitus. The validation set comprises of 22 important structurally different mutations. The calculated relative binding free energies
using the QM/MM-based FEP method reproduce the experimental values with exceptional precision of less than ±0.5 kcal/mol.
The CPU requirements for QM/MM-based FEP are about fivefold greater than conventional FEP methods, but it is superior in accuracy
of predictions. In addition, the QM/MM-based FEP method eliminates the need for time-consuming development of MM force field
parameters, which are frequently required for novel inhibitors described by MM. Future automation of the method and parallelization
of the code for 128/256/512 cluster computers is expected to enhance the speed and increase its use for drug design and lead
optimization. The present application of QM/MM-based FEP method for structurally diverse set of analogs serves to enhance
the scope of FEP method and demonstrate the utility of QM/MM-based FEP method for its potential in drug discovery. |
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