1g2k

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spinqualitylabelsall models 1g2k, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

HIV-1 PROTEASE WITH CYCLIC SULFAMIDE INHIBITOR, AHA047

Overview

We have previously reported on the unexpected flipped conformation in the, cyclic sulfamide class of inhibitors. An attempt to induce a symmetric, binding conformation by introducing P2/P2' substituents foreseen to bind, preferentially in the S2/S2' subsite was unsuccessful. On the basis of the, flipped conformation we anticipated that nonsymmetric sulfamide, inhibitors, with P2/P2' side chains modified individually for the S1' and, S2 subsites, should be more potent than the corresponding symmetric, analogues. To test this hypothesis, a set of 18 cyclic sulfamide, inhibitors (11 nonsymmetric and 7 symmetric) with different P2/P2', substituents was prepared and evaluated in an enzyme assay. To rationalize, the structure-activity relationship (SAR) and enable the alignment of the, nonsymmetric inhibitors, i.e., which of the P2/P2' substituents of the, nonsymmetric inhibitors interact with which subsite, a CoMFA study was, performed. The CoMFA model, constructed from the 18 inhibitors in this, study along with seven inhibitors from previous work by our group, has, successfully been used to rationalize the SAR of the cyclic sulfamide, inhibitors. Furthermore, from the information presented herein, the SAR of, the cyclic sulfamide class of inhibitors seems to differ from the SAR of, the related cyclic urea inhibitors reported by DuPont and DuPont-Merck.

About this Structure

1G2K is a Single protein structure of sequence from Human immunodeficiency virus 1 with NM1 as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.

Reference

Synthesis and comparative molecular field analysis (CoMFA) of symmetric and nonsymmetric cyclic sulfamide HIV-1 protease inhibitors., Schaal W, Karlsson A, Ahlsen G, Lindberg J, Andersson HO, Danielson UH, Classon B, Unge T, Samuelsson B, Hulten J, Hallberg A, Karlen A, J Med Chem. 2001 Jan 18;44(2):155-69. PMID:11170625

Page seeded by OCA on Thu Nov 8 14:03:45 2007