3E01

HIV-RT with non-nucleoside inhibitor annulated pyrazole 2

Summary for 3E01

• Entry DOI: 10.2210/pdb3e01/pdb
• Related: 3DYA
• Descriptor: Gag-Pol polyprotein, 3-[2-bromo-4-(1H-pyrazolo[3,4-c]pyridazin-3-ylmethyl)phenoxy]-5-methylbenzonitrile (3 entities in total)
• Functional Keywords: transferase
• Biological source: Human immunodeficiency virus type 1 (HIV-1); More
• 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): P04585 P04585
• Total number of polymer chains: 2
• Total formula weight: 116529.43

Authors

Harris, S.F.,Villasenor, A. (deposition date: 2008-07-30, release date: 2008-11-25, Last modification date: 2024-02-21)

Primary citation

Sweeney, Z.K.,Harris, S.F.,Arora, S.F.,Javanbakht, H.,Li, Y.,Fretland, J.,Davidson, J.P.,Billedeau, J.R.,Gleason, S.K.,Hirschfeld, D.,Kennedy-Smith, J.J.,Mirzadegan, T.,Roetz, R.,Smith, M.,Sperry, S.,Suh, J.M.,Wu, J.,Tsing, S.,Villasenor, A.G.,Paul, A.,Su, G.,Heilek, G.,Hang, J.Q.,Zhou, A.S.,Jernelius, J.A.,Zhang, F.J.,Klumpp, K.
Design of annulated pyrazoles as inhibitors of HIV-1 reverse transcriptase
J.Med.Chem., 51:7449-7458, 2008

PubMed Abstract: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of HIV. These regimens are extremely effective in suppressing virus replication. Structure-based optimization of diaryl ether inhibitors led to the discovery of a new series of pyrazolo[3,4-c]pyridazine NNRTIs that bind the reverse transcriptase enzyme of human immunodeficiency virus-1 (HIV-RT) in an expanded volume relative to most other inhibitors in this class.The binding mode maintains the beta13 and beta14 strands bearing Pro236 in a position similar to that in the unliganded reverse transcriptase structure, and the distribution of interactions creates the opportunity for substantial resilience to single point mutations. Several pyrazolopyridazine NNRTIs were found to be highly effective against wild-type and NNRTI-resistant viral strains in cell culture.

PubMed: 19007201
DOI: 10.1021/jm800527x

Experimental method

X-RAY DIFFRACTION (2.95 Å)