2AID

STRUCTURE OF A NON-PEPTIDE INHIBITOR COMPLEXED WITH HIV-1 PROTEASE: DEVELOPING A CYCLE OF STRUCTURE-BASED DRUG DESIGN

Summary for 2AID

• Entry DOI: 10.2210/pdb2aid/pdb
• Descriptor: HUMAN IMMUNODEFICIENCY VIRUS PROTEASE, CHLORIDE ION, 4-(4-CHLORO-PHENYL)-1-{3-[2-(4-FLUORO-PHENYL)-[1,3]DITHIOLAN-2-YL]-PROPYL}-PIPERIDIN-4-OL, ... (4 entities in total)
• Functional Keywords: aspartyl protease, hiv, non-peptide inhibitor, drug design
• 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): P03369
• Total number of polymer chains: 2
• Total formula weight: 22578.53

Authors

Rutenber, E.E.,Fauman, E.B.,Keenan, R.J.,Stroud, R.M. (deposition date: 1997-04-17, release date: 1997-10-15, Last modification date: 2024-05-22)

Primary citation

Rutenber, E.,Fauman, E.B.,Keenan, R.J.,Fong, S.,Furth, P.S.,Ortiz de Montellano, P.R.,Meng, E.,Kuntz, I.D.,DeCamp, D.L.,Salto, R.,Rose, J.R.,Craik, C.S.,Stroud, R.M.
Structure of a non-peptide inhibitor complexed with HIV-1 protease. Developing a cycle of structure-based drug design.
J.Biol.Chem., 268:15343-15346, 1993

PubMed Abstract: A stable, non-peptide inhibitor of the protease from type 1 human immunodeficiency virus has been developed, and the stereochemistry of binding defined through crystallographic three-dimensional structure determination. The initial compound, haloperidol, was discovered through computational screening of the Cambridge Structural Database using a shape complementarity algorithm. The subsequent modification is a non-peptidic lateral lead, which belongs to a family of compounds with well characterized pharmacological properties. This thioketal derivative of haloperidol and a halide counterion are bound within the enzyme active site in a mode distinct from the observed for peptide-based inhibitors. A variant of the protease cocrystallized with this inhibitor shows binding in the manner predicted during the initial computer-based search. The structures provide the context for subsequent synthetic modifications of the inhibitor.

PubMed: 8340363

Experimental method

X-RAY DIFFRACTION (1.9 Å)