Rational Drug Design: One Target, Many Paths to It

Introduction

Once, a US General summarized his philosophy on warfare in just four concise statements, “The art of war is simple enough. Find out where your enemy is. Get at him as soon as you can. Strike him as hard as you can, and keep moving.” Although these overarching statements formed the basic premise of modern war strategies, the same concepts have been applied in designing new drugs aimed at combating a broad range of diseases. In this context, rational drug design (Hao, Yang, & Zhan, 2012; Hedvat et al., 2012; Mandal, Moudgil, & Mandal, 2009) has been established as an exciting research approach aimed at developing safer and more efficacious drugs using modern computational tools which are fast and inexpensive compared to traditional methods. The ultimate goal of this research is to design small organic non-peptidic compounds that bind to a specific molecular target, and result in the inhibition (or less frequently, activation) of a particular protein or enzyme involved in a given cellular pathway, i.e. a blockage of a specific protein-protein interaction. The development of such drugs has been recognized early on by the pharmaceutical industry as a principal foundation that provides it with the necessary return on investment to fuel further research and development (Szymkowski, 2005) leading to a discovery and development cycle.

Our understanding of cell mechanisms and pathways at a molecular level becomes deeper and clearer every day. This is largely due to the great efforts and hard work of genomic and proteomic research groups who add novel targets for drug intervention on a regular basis (Drews, 2000; Fishman & Porter, 2005; Hopkins & Groom, 2002). Thus far, several hundred proteins have been synthetically expressed and many of them are currently evaluated for their druggability (Hopkins & Groom, 2002). These targets involve several families comprised of G-protein coupled receptors (GPCRs), ligand-gated ion channels (LGICs), cytoskeleton proteins, phosphatases, kinases, nuclear receptors (NRs) and DNA repair proteins. The growing list of potential drug targets encourages a bold question if it is in principle possible to restore any diseased cell to a healthy state by uncovering a drug for every potential druggable target? Certainly, if this dream is ever realized, many diseases will be cured and relegated to the dustbin of history in a manner similar to the effect of the discovery of vaccines in the 19^th and early 20^th century. We think this is most definitely achievable as a result of rapid progress made in the computational drug discovery area.