Molecular Mechanics Force Fields and their Applications in Drug Design

Raghuvir   R.S.   Pissurlenkar; Mushtaque   S.   Shaikh; Radhakrishnan   P.   Iyer; Evans   C.   Coutinho

doi:10.2174/187152109787846088

Abstract

The molecular structures, properties and energies of a molecule are better understood through the use of the “mechanical” molecular model. This model involves the development of a simple molecular mechanics energy equation representing the sum of various energy interaction terms comprised of bonds, angles, torsions of bonded, as well as, nonbonded atoms. Referred to as “force fields”, the model serves as a simple “descriptor” for vibrations in molecules. The concept of force fields is now widely employed as one of the simplest tools in molecular modeling. Force fields are fundamentally important in de novo drug design programs, in pharmacophore mapping, and represent the “scoring functions” in many docking programs. As scoring functions, force fields are used to rank “ligand poses” obtained by a docking algorithm, or in de novo ligand design programs to suggest placement of fragments in sites in the enzyme with the highest binding affinity. In all these applications, force fields are mainly used to compute the interaction energy between the protein and the ligand as pair-wise interaction potentials consisting of van der Waals and electrostatic interactions, in addition to H-bond energy between the ligand and the enzyme. Some examples of drug design software where force fields have been implemented as scoring functions are AMBER, GOLD AutoDock and DOCK. Force fields also play an important role in Free Energy perturbations (FEP) calculations that allow the design of newer analogs or inhibitors with an accurate prediction of their activity. This review will provide a historical overview including a discussion of the valence force field, the Urey-Bradley force field (UBFF), and the more recent Class II force fields such as Allingers MM2-MM4, Accelrys CFF91 and others that apply to a large class of molecules. The GROMOS force field will also be discussed since it takes into consideration the free energies of hydration and the non-polar solvation for a range of compounds. This approach takes into account the relative free enthalpy of solvation between polar and non-polar environments, which is a key property in many biomolecular processes of interest including protein folding, biomolecular association, membrane formation and transport. The review will also focus on the current status of force fields in the study of ligand – protein interactions with particular emphasis on applicability in structure-based drug design.

Keywords: Molecular Mechanics, Urey-Bradley force field (UBFF), Drug Design, force fields, descriptor

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