1G2K

HIV-1 PROTEASE WITH CYCLIC SULFAMIDE INHIBITOR, AHA047

Summary for 1G2K

• Entry DOI: 10.2210/pdb1g2k/pdb
• Related: 1ajv 1ajx
• Descriptor: PROTEASE RETROPEPSIN, 3-(7-BENZYL-4,5-DIHYDROXY-1,1-DIOXO-3,6-BIS-PHENOXYMETHYL-1L6-[1,2,7]THIADIAZEPAN-2-YLMETHYL)-N-METHYL-BENZAMIDE (3 entities in total)
• Functional Keywords: hiv, protease inhibitors, hydrolase
• Biological source: Human immunodeficiency virus 1
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P04587
• Total number of polymer chains: 2
• Total formula weight: 22239.25

Authors

Lindberg, J.,Unge, T. (deposition date: 2000-10-20, release date: 2001-06-01, Last modification date: 2023-08-09)

Primary citation

Schaal, W.,Karlsson, A.,Ahlsen, G.,Lindberg, J.,Andersson, H.O.,Danielson, U.H.,Classon, B.,Unge, T.,Samuelsson, B.,Hulten, J.,Hallberg, A.,Karlen, A.
Synthesis and comparative molecular field analysis (CoMFA) of symmetric and nonsymmetric cyclic sulfamide HIV-1 protease inhibitors.
J.Med.Chem., 44:155-169, 2001

PubMed Abstract: 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.

PubMed: 11170625
DOI: 10.1021/jm001024j

Experimental method

X-RAY DIFFRACTION (1.95 Å)