Editorial [Hot Topic: Rational Drug Design (Executive Editor: M. Rami Reddy)]

Discovery of effective and safe drugs traditionally entails the synthesis and/or screening of large numbers of compounds. Considering that marketed compounds represent only one compound out of every 30,000 compounds synthesized, the pharmaceutical industry has devoted substantial efforts and finances to methodologies that have the potential to shorten the discovery process. One of the best strategies is to use “Rational Drug Design” to shorten the discovery time by dramatically narrowing the pool of potential drug candidates through calculation of drug-protein binding interaction energies. Although highly appealing in theory, in practice the efforts devoted to rational drug design in the 1980s and 1990s resulted in predictions that were frequently inaccurate due to the approximations and assumptions employed in the calculations. Advances in X-ray crystallography, NMR and extraordinary advances in available CPU computer power over the past decade have resulted in more accurate predictions. Greater accuracy is achieved through the use of higher levels of quantum mechanical theory to provide a more extensive and accurate set of molecular mechanics force field parameters for protein residues as well as small molecules, by inclusion of solvent effects, and by using computer simulation methods that exhaustively search conformational space. Improvements in computer simulation methods such as Molecular Dynamics and Monte Carlo and available 3-dimensional structures of protein-ligand complexes enable calculation of free energy differences which are important, since free energy differences are directly related to the experimental result. This issue on “Rational Drug Design” covers the recent advances in Computer Aided Drug Design (CADD) Methods as well as their successful application to a variety of drug discovery programs. The first article [1] focuses on various computational aspects for identification of leads to drug targets in silico. In addition the article discusses the fundamental issues and challenges associated with various CADD methods. The second article [2] describes the dynamical behavior of the binding pocket S1 in the apo forms of metalloproteinase types 2 and 3 using molecular dynamics simulations. Results from this study are useful in the design of specific metalloproteinase inhibitors. The third article [3] summarizes the role of unconventional hydrogen bonds in the recognition of small molecules by biological receptors of pharmaceutical relevance. The fourth article [4] describes predictive QSAR modeling and virtual screening of small molecule databases for several drug targets. The fifth article [5] focuses on lead inhibitor optimization strategies using the free energy perturbation approach and molecular mechanics methods and evaluates the merits of each method for predicting relative binding affinities of COX-2 inhibitors. The sixth article [6] summarizes use of molecular modeling and informatics tools for the discovery of anti-diabetic agents. The last article [7] reviews rational drug design strategies for development of antiviral agents directed against the influenza virus replication. Overall the issue provides computational and medicinal chemists in both academia and industry an extensive overview of the scope and limitations of CADD methods useful for rational drug design. As an Executive Editor of Current Pharmaceutical Design, I would like to thank all the authors for contributing to this issue on Rational Drug Design. I would also like to thank Dr. Mark Erion for his helpful suggestions, encouragement and support in editing this issue. References [1] Shaikh SA, Jain T, Sandhu G, Latha N, Jayaram B. From drug target to leads-sketching a physicochemical pathway for lead molecule design in silico. Curr Pham Des 2007; 13(34): 3454-3470. [2] de Oliveira CAF, Zissen M, Mongon J, Mccammon JA. Molecular dynamics simulations of metalloproteinases types 2 and 3 reveal differences in the dynamic behavior of the S1' binding pocket. Curr Pham Des 2007; 13(34): 3471-3475. [3] Toth G, Bowers SG, Truong AP, Probst G. The role and significance of unconventional hydrogen bonds in small molecule recognition by biological receptors of pharmaceutical relevance. Curr Pham Des 2007; 13(34): 3476-3493..