Mechanism based design, protein

Parang K, Till JH, Ablooglu AJ, Kohanski RA, Hubbard SR, Cole PA. Mechanism-based design of a protein kinase inhibitor. Nat. Struct. Biol. 2001 8 37-41. 

Figure 13 Chemical structures of mechanism-based designed bisubstrate analog inhibitors of protein kinase.

Protein engineering has to date been tackled according to two quite different philosophies. The first of these can broadly be termed mechanism-based design. This involves describing protein function as completely as possible so that desired changes can be effected by calculation fiom first principles. Typically the protein mechanic first asks what tiiree dimensional structure an amino acid sequence will adopt, then what function will be performed by such a structure and finally how alterations to the structure may... 

The starting point for much of the work described in this article is the idea that quinone methides (QMs) are the electrophilic species that are generated from ortho-hydro-xybenzyl halides during the relatively selective modification of tryptophan residues in proteins. Therefore, a series of suicide substrates (a subtype of mechanism-based inhibitors) that produce quinone or quinonimine methides (QIMs) have been designed to inhibit enzymes. The concept of mechanism-based inhibitors was very appealing and has been widely applied. The present review will be focused on the inhibition of mammalian serine proteases and bacterial serine (3-lactamases by suicide inhibitors. These very different classes of enzymes have however an analogous step in their catalytic mechanism, the formation of an acyl-enzyme intermediate. Several studies have examined the possible use of quinone or quinonimine methides as the latent... 

CONTENTS Introduction to the Series An Editor s Foreword, Albert Padwa. Preface, Bruce E. Maryanoff and Cynthia A. Maryanoff. Computer Assisted Molecular Design Related to the Protein Kinase C Receptor, Paul A. Wenderand Cynthia M. Cribbs. Chemistry and Biology of the Immunosuppressant (-)-FK-506, Ichiro Shinkai and Nolan H. Sigal. The Development of Ketorolac Impact on Pyrrole Chemistry and on Pain Therapy, Joseph M. Muchowski. Application of Silicon Chemistry in the Corticosteroid Field, Douglas A. Livingston. Hu-perzine A-A Possible Lead Structure in the Treatment of Alzheimers Disease, Alan P. Kozikowski, X.C, Tang and Israel Hanin. Mechanism-Based-Dual-Action Cephalosporins, Harry A. Albrecht and James G. Christenson. Some Thoughts on Enzyme Inhibitors and the Quiescent Affinity Label Concept, Mien Krantz Index. 

Clearly, identification of resistance mechanisms and of potential intracellular targets all lead to information which would be very useful for the development of novel anti-infective drugs by peptide-based design, once the structure of these targets is known. In addition, identification of transport proteins that may... 

As seen in the previous sections, directed probe scaffolds already cover a large set of important protein classes with crucial functions in many diseases. However, for a number of protein families, selective active site-directed probes are difficult to design in part due to a lack of knowledge concerning their precise catalytic mechanisms and a lack of corresponding mechanism-based inhibitors or high-affinity labels. In order to close this gap, several undirected probes have been developed and will be discussed in this section. 

AutoDock (http //autodock.scripps.edu/) which is designed to predict how small molecules, such as substrates or drug candidates, bind to a receptor of known 3D structure. AutoDock has applications in X-ray crystallography, lead optimization, structure-based design, combinatorial chanistry, protein-protein docking and chemical mechanism studies... 

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