Abstract

This work is concerned with rational drug design at the atomic level. Some fundamental stages of rational drug design are addressed, namely the atomic level understanding on disease-related enzymatic mechanisms and inhibition, which is a pre-requisite to any attempt to rationally design new, better inhibitors; the rational optimization of a lead compound, through chemical modifications that increase its affinity and/or specificity for the target receptor; and the design of new drugs based mainly on the knowledge of the electrostatic potentials of the drug and its receptor, with simultaneous optimization of shape and size complementarity. All methods described here offer interesting approaches to rational drug design, the choice of the method being dependent on the amount of previous knowledge of the system. Examples include the study of the inhibition mechanism of Class Ia Ribonucleotide Reductase, an important anti-cancer target, a brief description of the optimization of the anti HIV lead compound 15-Deoxy-Δ12,14-Prostaglandin J2, through chemical substitutions in the original drug, which is an antagonist for the Nuclear Factor Kappa B:DNA binding, thus precluding HIV gene expression, and the development of new anti-malaria drugs, mainly based on the shape/size of the receptor complemented with the analysis of the electrostatic potentials. A large number of computational techniques are needed for these approaches, ranging from the high level quantum mechanics to the more approximate docking calculations, with the intermediate level hybrid methods and molecular mechanics included. The basic principles for the applications of these techniques are also discussed.

Keywords: Drug design, lead compound, affinity, specificity, enzymatic inhibition, hybrid methods, homology modelling, molecular docking, molecular electrostatic potential, molecular mechanics