Molecular Mechanical Study of Halogen Bonding in Drug Discovery

A halogen bond is a noncovalent bond between a halogen atom (X) and a Lewis base (Y). This type of bond is attributed to the anisotropic distribution of the charge density on the halogen atom, resulting in the formation of a positive cap (called the sigma-hole) centered on the A-X axis. The current research is the first reported molecular mechanical study of halogen bonding, the positive region centered on the halogen atom was represented by an extra-point (EP) of charge. The correlation between the X-EP distance and the X ... Y bond length was explored to determine the optimal position of the EP. A test set of 27 halogen-containing molecules complexed to various Lewis bases was studied using molecular mechanical potentials. The molecular mechanical minimized halogen bond lengths and binding energies were in good agreement with the corresponding quantum mechanical values. The EP inclusion on the halogen atom resulted in an improvement in the accuracy of the electrostatic-potential derived charges. The solvation free energies of halobenzene molecules relative to benzene were calculated with and without EP inclusion to assess the accuracy of the developed approach. Molecular mechanical study of halo derivatives of benzotriazole complexed to cyclin-dependent protein kinase 2 (CDK2) was performed, and MM-PB(GB)SA binding energies were calculated as a case study in finding potent halogenated inhibitors that can serve as antitumor drugs. (C) 2011 Wiley Periodicals, Inc. J Comput Chem 32: 2564-2574, 2011