Rational Drug Design: One Target, Many Paths to It

Rational Drug Design: One Target, Many Paths to It

Khaled H. Barakat (Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Canada & Department of Engineering, Mathematics and Physics, Fayoum University, Fayoum, Egypt), Michael Houghton (Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Canada), D. Lorne Tyrrel (Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada) and Jack A. Tuszynski (Department of Oncology, Department of Physics, University of Alberta, Edmonton, Canada)
DOI: 10.4018/ijcmam.2014010104
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Abstract

For the past three decades rationale drug design (RDD) has been developing as an innovative, rapid and successful way to discover new drug candidates. Many strategies have been followed and several targets with diverse structures and different biological roles have been investigated. Despite the variety of computational tools available, one can broadly divide them into two major classes that can be adopted either separately or in combination. The first class involves structure-based drug design, when the target's 3-dimensional structure is available or it can be computationally generated using homology modeling. On the other hand, when only a set of active molecules is available, and the structure of the target is unknown, ligand-based drug design tools are usually used. This review describes some recent advances in rational drug design, summarizes a number of their practical applications, and discusses both the advantages and shortcomings of the various techniques used.
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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 19th and early 20th century. We think this is most definitely achievable as a result of rapid progress made in the computational drug discovery area.

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