Use of quantum mechanics/molecular mechanics-based FEP method for calculating relative binding affinities of FBPase inhibitors for type-2 diabetes

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.