NEW METHOD TO CALCULATE BINDING FREE ENERGY

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Computational chemistry and molecular modeling are an essential part of the modern drug design process. At present, however, molecular modeling methods can only provide rather qualitative information on the affinity of different compounds for a given target site. The only rigorous approach to this type of problem today is the free energy perturbation (FEP) technique which is more or less limited to "small perturbations". Drug design in practice, however, often deals with relatively large inhibitors that differ considerably from each other so that neither relative nor absolute free energies can be obtained with the FEP/MD method within reasonable computing time. This dilemma led Aqvist et al to devise a simplified approach that does not involve the "mutational paths" which are mainly what hampers the FEP methods. We followed Aqvist's idea and are trying to develop it. We found that one parameter in the Aqvist method depends on the nature of the target site. Several protein/ligand systems were checked and the calculated results are in reasonable agreement with the experimental data which is very encouraging.