4NYF

HIV integrase in complex with inhibitor

Summary for 4NYF

• Entry DOI: 10.2210/pdb4nyf/pdb
• Descriptor: Integrase, (2S)-tert-butoxy[4-(4-chlorophenyl)-2-methylquinolin-3-yl]ethanoic acid, CADMIUM ION, ... (4 entities in total)
• Functional Keywords: allosteric inhibitor, ncini, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Human immunodeficiency virus type 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): P0C6F2
• Total number of polymer chains: 2
• Total formula weight: 37178.85

Authors

Coulombe, R.,Fader, L. (deposition date: 2013-12-10, release date: 2014-06-25, Last modification date: 2023-09-20)

Primary citation

Fader, L.D.,Malenfant, E.,Parisien, M.,Carson, R.,Bilodeau, F.,Landry, S.,Pesant, M.,Brochu, C.,Morin, S.,Chabot, C.,Halmos, T.,Bousquet, Y.,Bailey, M.D.,Kawai, S.H.,Coulombe, R.,LaPlante, S.,Jakalian, A.,Bhardwaj, P.K.,Wernic, D.,Schroeder, P.,Amad, M.,Edwards, P.,Garneau, M.,Duan, J.,Cordingley, M.,Bethell, R.,Mason, S.W.,Bos, M.,Bonneau, P.,Poupart, M.A.,Faucher, A.M.,Simoneau, B.,Fenwick, C.,Yoakim, C.,Tsantrizos, Y.
Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1.
ACS Med Chem Lett, 5:422-427, 2014

PubMed Abstract: An assay recapitulating the 3' processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial.

PubMed: 24900852
DOI: 10.1021/ml500002n

Experimental method

X-RAY DIFFRACTION (1.9 Å)