Design new inhibitors

Before designing new inhibitors using the constructed homology model of the target protein, it is necessary to identify location(s) of drug-binding site(s) and to analyze their properties. 

Understanding how HLE inhibitors work and/or designing new inhibitors requires a model of HLE s active-site and an understanding of its mechanism of action. All serine proteinases share a similar catalytic region and mechanism of action but differ in several amino acids in the extended substrate-binding region. These changes are responsible for the specificity differences between HLE and other serine proteinases. In some cases analysis of the enzyme-inhibitor interactions has only been carried out with other related enzymes, and those results are referenced as appropriate. One closely related enzyme, porcine pancreatic elastase (PPE, EC 3.4.21.36) has... 

Excluded volume The difference between the shapes of a compound that binds to, for example, an enzyme and one that does not. Some of the volume areas in a model of the inactive compound, with van der Waals radii around atoms, will not fit in the active site of the enzyme. These areas should be avoided when designing new inhibitors. 

ENR from M.tuberculosis is the target site for tuberculosis treatment by the drug isoniazid. Unfortunately resistance to this treatment is building up in the causative agent. A way forward would be to design new inhibitors based on the information derived from structural studies on the enzyme inhibitor complex. 

W. Draber, 2. Naturforsch., Sect. C, 42, 713 (1987). Can Quantitative Structure Activity Analyses and Molecular Graphics Assist in Designing New Inhibitors of Photosystem-II ... 

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... 

For most of the different dephospho oligonucleotide analogs, no extensive investigations were reported so that no detailed practical procedures can be given in this chapter. The main scope of this chapter IS therefore to show which types of dephospho oligonucleotides have been synthesized so far, what their chemical properties are, and whether their physical characteristics provide a basis to design new inhibitors of gene expression of potential therapeutic value. 

Trehan, L, Morandi, F., Blaszczak, L.C., Shoichet, B.K. Using steric hindrance to design new inhibitors of class C (l-lactamases. Chem. Biol. 2002,9(9), 971—980. 

In the frame of a medicinal project at J J Pharmaceutical Research and Development aimed at designing new potent and selective glycogen synthase kinase-3/i (GSK-3/3) inhibitors, the C-3 derivatization of the 1-methyl-4-[l-alkyl-lff-indol-3-yl]-lff-pyrrole-2,5-dione scaffold was explored [31]. Microwave-assisted Stille reaction of 3-chloro-l-methyl-4-[l-alkyl-lff-indol-3-yl]-lH-pyrrole-2,5-diones with (2,4-dimethoxy-5-pyrimidinyl)(tributyl) stannane at 200 °C yielded in 6 min the desired 3,4-diaryl-lff-pyrrole-2,5-diones in moderate yields (Scheme 12). 

Teodori E, Dei S, Martelli C, Scapecchi S, Gualtieri F (2006) The functions and structure of ABC transporters Implications for the design of new inhibitors of P-gp and MRP1 to control multidrug resistance (MDR). Curr Drug Targets 7 893-909. 

The remainder of this work will focus on the approaches to designing and identifying new inhibitors of Bcr-Abl including (1) more potent analogs of imatinib (2) non-ATP competitive inhibitors of Bcr-Abl and (3) dual inhibitors of both Bcr-Abl and members of the Src family of kinases (SFKs) that bind to the active form of Bcr-Abl. The status of the new Bcr-Abl inhibitors currently in the chnic will be summarized. 

R. Haubner, D. Finsinger, H. Kessler, Stereoisomeric peptide libraries and peptido-mimetics for designing selective inhibitors of the alpha-v-beta-3 integrin for a new cancer therapy, Angew. Chem. Int. Ed. Engl. (1997) 1374-1389. 

Determination of the crystal structures of HIV PR gave new impetus to the design of novel inhibitors. One measure of the intensity with which new inhibitors were designed or discovered is the total number of crystal structures of inhibitory complexes, currently exceeding 250, that have been determined over the past 5 years. Very detailed crystallographic analysis combined with extensive biochemical characterization and site-specific mutagenesis studies made HIV PR perhaps the best characterized enzyme to date. 

---