Inhibitors, design using molecular modeling

Application of molecular modeling techniques to the biorational design of selective and environmentally safe crop protection chemicals is addressed. Sulfonylurea herbicides are used as an example to illustrate the kinds of biological information that can be known with modern technologies. An example of selective inhibitor design using computer graphics is presented. 

Flynn et al.- at Merrell Dow Research Institute took the approach of designing an ACE inhibitor that was intended to mimic the three carboxy-terminus amino acids of angiotensin I, the substrate of the enzyme. This tripeptide fragment, N-benzyloxycarbonyl-Phe-His-Leu-OH, is known to be a modest inhibitor of ACE (K 10 M). The authors used molecular modeling to confirm that the tricyclic compound 9 could serve as a conformationally con-... 

The classic approach to pharmacophore development has been through the visual analysis of low-energy ligand conformer superpositions using molecular modeling packages. The work undertaken by Bures et al. to design new inhibitors of auxin transport provides an excellent example of the use of... 

HIV protease is a dimer in which each monomer has an active site containing one or two aspartate residues. Using crystallographic three-dimensional data and molecular modeling studies, drugs have been designed to be transition-state mimetics, aligning at the enzyme active site. Some of the successful protease inhibitors include saquinavir (9.25), ritonavir (9.26), indinavir (9.27), nelfinavir (9.28), and amprenavir (9.29). 

We determined the structure of human PNP by x-ray crystallography and used these results in combination with computer-assisted molecular modeling to design inhibitor candidates. We examined how well the shape and chemical... 

Kumar A, Siddiqi MI, Miertus S (2010) New molecular scaffolds for the design of Mycobacterium tuberculosis type II dehydro-quinase inhibitors identified using ligand and receptor based virtual screening. J Mol Model 16 693-712... 

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