3DRS

HIV reverse transcriptase K103N mutant in complex with inhibitor R8D

Summary for 3DRS

• Entry DOI: 10.2210/pdb3drs/pdb
• Related: 3DRP 3DRR
• Descriptor: Reverse transcriptase/ribonuclease H, p66 RT, 3-chloro-5-[2-chloro-5-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenoxy]benzonitrile (3 entities in total)
• Functional Keywords: hiv-1 reverse transcriptase, non-nucleoside inhibition, nucleotidyltrasferase, hydrolase, 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: 117007.82

Authors

Yan, Y.,Prasad, S. (deposition date: 2008-07-11, release date: 2008-10-14, Last modification date: 2023-08-30)

Primary citation

Tucker, T.J.,Sisko, J.T.,Tynebor, R.M.,Williams, T.M.,Felock, P.J.,Flynn, J.A.,Lai, M.T.,Liang, Y.,McGaughey, G.,Liu, M.,Miller, M.,Moyer, G.,Munshi, V.,Perlow-Poehnelt, R.,Prasad, S.,Reid, J.C.,Sanchez, R.,Torrent, M.,Vacca, J.P.,Wan, B.L.,Yan, Y.
Discovery of 3-{5-[(6-Amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): A Potent, Orally Bioavailable HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor with Improved Potency against Key Mutant Viruses.
J.Med.Chem., 51:6503-6511, 2008

PubMed Abstract: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chemistry/SAR analyses, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (MK-4965), which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.

PubMed: 18826204
DOI: 10.1021/jm800856c

Experimental method

X-RAY DIFFRACTION (3.15 Å)