Hybrid Usage of Computational Tools in Drug Synthesis

Abstract

We describe several computational methodologies used in aiding the chemical synthesis of drugs. We first summarize quantum mechanical approaches that weigh thermodynamical and kinetic factors in selecting the possible pathways during synthesis. The two major problems encountered in computational approaches are the efficient sampling of the conformational space and the incorporation of solvent effect into the system of interest. Thus, conformational search methodologies of small to medium sized molecules, with emphasis on cyclic molecules, are reviewed. Also, the analysis of the solvent effect on the synthesis of drug molecules and yield, using continuum methodologies as well as molecular dynamics, is discussed. How results from these studies are in turn fed back into detailed quantum mechanical calculations with supermolecules of solvent and reaction site are outlined. It is shown that the usage of several computational techniques hand-in-hand provides a plethora of information that may be utilized during the actual synthesis of drug molecules. Keywords: Conformational analysis, molecular dynamics, quantum chemical computations, rational drug design, solvent effect, macrolide antibiotics