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Editorial [ Structure-Based Drug Design in the 21st Century ]

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Bringing affordable, safe and therapeutically useful drugs to patients globally is a primary goal for many governmental, academic and pharmaceutical scientists worldwide. The Frontier in Drug Design and Discovery series is dedicated to assembling these eminent scientists and allowing them to present comprehensive reviews with fresh new ideas on drug design and drug discovery. The first volume (2005) brought together experts to review and discuss the advantages and limitations of modern screening techniques used in the drug discovery process to identify potential drug candidates. The second volume (2006) discussed new technological and conceptual approaches to accelerate and to improve the predictability of the discoveries made in the laboratory into clinical testing. In the third volume of this series, reviews and discussions are presented applying structurebased design to identify potent lead drug candidates for a variety of diseases using techniques such as in-silico virtual screening, peptidomimetics, fragment-based approaches, protein crystallography, and NMR spectroscopy.

The importance of understanding the fundamentals of the energetics of a drug molecule binding to a biomacromolecule target has emerged over the years enabling scientists to think intelligently about molecular modifications that will impact binding of a designed drug. Understanding the energetic of a drug interacting with a target has had a profound impact not only on drug design, but also on the elucidation of molecular mechanism of disease. An early structure of hemoglobin allowed the study of the basis of sickle-cell anemia as well as the mechanism of drugs that inhibited sickling. Initially, structurebased drug design was based on structural determination of related proteins where the protein of interest was yet unsolved. For example, drug design for important targets such as angiotensin converting enzyme and renin were aided by determination of related enzymes such as thermolysin and fungal aspartyl proteases. However today, higher throughput protein crystallography, NMR spectroscopy and computational techniques are providing key insights on a large variety of drug-protein complexes.

The drug design field has continued to evolve to encompass de novo design of ligands based on protein structure, transformation of peptide ligands into smaller, more druglike compounds and structure-based design of inhibitors of heretofore challenging classes such as protein-protein interfaces. In addition, NMR has come into its own as a new means of structure-based design. Technical advances in robotics, crystallization screens and computational analysis has raised x-ray crystallography to the level where it can support fragment-based design; where co-structures of small fragments are solved and the fragments are pieced together to yield tighter binding ligands.

We have selected authors that have contributed 22 chapters to the review of a range of topics involving drug design. D.J. Parks and colleagues have contributed a chapter outlining how the uses of small molecules that mimic key secondary motifs, such as α-helical mimetics, have been successful in disrupting protein-protein interactions. The chapter by I.T. Weber and colleagues gives an interesting review on how intelligent data mining approaches, along medicinal chemistry, kinetic and X-ray crystallographic analysis, can be used to overcome HIV drug resistance. S. Costanzi and colleagues introduces the reader to the use of computational approaches to study various rhodopsin-based homology models of the adenosine receptors. R.L DesJarlais, M.D. Cummings and A.C Gibbs give an overview of how virtual docking and scoring techniques can be used to select lead screening candidates. D.F. Wyss and H.L. Eaton give a well-balanced review of fragment-based approaches in drug discovery. G. Noronha and colleagues describe a novel conceptual design process to obtain potent inhibitors targeting the active form of Src, a cellular tyrosine kinase that plays a role in cellular proliferation and growth.

The chapter by C. McInnes summarizes the progress made in the development of new structure based approaches for the discovery of protein kinase inhibitor drugs. M. Schade has prepared a chapter reviewing NMR techniques for fragment-based drug discovery. R.L. Magolda and colleagues have contributed a chapter highlighting the strategies and challenges facing the design of specific ligands for nuclear hormone receptors using X-ray crystallographic analysis and molecular modeling methods. K. Buchholz and colleagues present an interesting review on the major current structural-based antimalarial approaches and an overview of inhibitors that have been developed on the basis of these known parasite protein structures. Along these same lines, A.K Bhattacharjee presents a review on how in-silico methodologies have been successfully applied to virtual screening of compound libraries, to aid in the discovery and design of antimalarial and antileishmanial agents. R. Gupta and R. M. Brosh Jr. have prepared a review for the rational development of helicase inhibitors for improved chemotherapeutic options for treating cancers.

P. Cozzini introduces the reader to the problems related to docking/scoring techniques for in-silico screening. K. Kuca and colleagues have contributed a chapter highlighting acetylcholinesterase reactivators (i.e., oximes) that are drug used to treat intoxications of organophosphorus pesticides. The main structural requirements for this class of drugs are discussed. A.J. Chubb and colleagues discuss the history and advances in peptide synthesis as it relates to peptidomimetics development. F. Han and colleagues present a novel therapeutic strategy for ischemic brain edema. H. Gohlke and colleagues give a well-balanced review of how to incorporate the influence of protein flexibility and mobility into drug design approaches.

G.M. Keserμ and T. Polgar have written an excellent chapter describing structure-based virtual screening approaches using various case studies. A. Lavecchia presents a review on the current status of G protein-coupled receptor modeling highlighting alternative computational approaches for rhodopsin-based homology building. R. Tang and colleagues present an interesting review on how monoclonal antibody-drug conjugates are used to target cancers. In the review, antibody engineering, the process of drug selection, and the development of linker to optimize clinical trials are discussed. M. Saviano and colleagues have contributed a chapter outlining the structural properties of the main constrained non-coded amino acids to illustrate the use of peptidomimetic approaches. M.J. Dascombe and colleagues review the evolution and drug design of clinically effective antimalarial drugs such as 4-aminoquinolines, 8-aminoquinolines and 9-amino acridines.
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Document Type: Research Article

Publication date: March 1, 2007

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