Structure-based inhibitor modeling

In the recent studies, the enzyme shows that the overall polypeptide fold of chymotrypsin-like serine protease possesses essential SI specificity determinants characteristic of elastase using the multiple isomorphous replacement (MIR) method and refined to 2.3 A resolution Fig. (5). Structure-based inhibitor modeling demonstrated that EFEa s SI specificity pocket is preferable for elastase-specific small hydrophobic PI residues, while its accommodation of long and/or bulky PI residues is also feasible if enhanced binding of the substrate and induced fit of the SI pocket are achieved [Fig. (6) shows the active sites of serine protease]. EFEa is thereby endowed with relatively broad substrate specificity, including the dual fibrinolysis. This structure is the first report of an earthworm fibrinolytic enzyme component, a serine protease originated from annelid worm [17]. 

CS Ring, E Sun, JH McKerrow, GK Lee, PI Rosenthal, ID Kuntz, EE Cohen. Structure-based inhibitor design by using protein models for the development of antiparasitic agents. Proc Natl Acad Sci USA 90 3583-3587, 1993. 

Proc. Natl. Acad. Sci. U.S.A. 90, 3538 (1993). Structure-Based Inhibitor Design by Using Protein Models for the Development of Antiparasitic Agents. 

For each of the selected target proteins, a set of 10 pharmacophore models was generated based on receptor-inhibitor complexes from the PDB. The three allosteric sites of hepatitis C virus (HCV) polymerase were represented by three, five, and two models, respectively. Structure-based pharmacophore model generation was performed with the software LIGANDSCOUT using the default settings and... 

Structure-Based Pharmacophore Model for Selective COX-2 Inhibitors... 

Figure 12.6 Example for successful structure-based virtual screening to identify submicromolar tRNA-guanine transglycosylase (TGT) inhibitors based on X-ray structures of weaker ligands, (a) X-ray structure of Zymomonas mobilis TGT at 2.1 A resolution (PDB entry 1N2V). (b) Experimental binding mode for pyridazinedione scaffold (K 83 pM) including structural water molecules from 1N2V. (c) Definition of structure-based pharmacophore model with ligand interactions...

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