5K14

HIV-1 Reverse Transcriptase in complex with a 2,6-difluorophenyl DAPY analog

Summary for 5K14

• Entry DOI: 10.2210/pdb5k14/pdb
• Descriptor: HIV-1 reverse transcriptase(isolate HXB2), HIV-1 reverse transcriptase (isolate LW123), 4-{[4-(2,6-difluoro-4-methoxybenzene-1-carbonyl)pyrimidin-2-yl]amino}benzonitrile, ... (4 entities in total)
• Functional Keywords: hiv-1, reverse transcriptase, nnrti, inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Human immunodeficiency virus type 1 group M subtype B (isolate HXB2) (HIV-1); More
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor . Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P04585 P0C6F2
• Total number of polymer chains: 2
• Total formula weight: 116328.32

Authors

Lansdon, E.B. (deposition date: 2016-05-17, release date: 2016-06-29, Last modification date: 2024-03-06)

Primary citation

Simon, P.,Baszczynski, O.,Saman, D.,Stepan, G.,Hu, E.,Lansdon, E.B.,Jansa, P.,Janeba, Z.
Novel (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones with restricted conformation as potent non-nucleoside reverse transcriptase inhibitors against HIV-1.
Eur.J.Med.Chem., 122:185-195, 2016

PubMed Abstract: To elucidate the structure-geometry-activity relationship in diarylpyrimidine family (DAPYs) containing carbonyl linker between the central pyrimidine core and phenyl type B-arm, a series of (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones was designed, prepared and tested for their anti-HIV-1 activity. The carbonyl linker bearing B phenyl arm was successfully attached at both C-2 and C-4 positions of the central pyrimidine ring using a new synthetic approach. Further modifications of target compounds are present at C-5 position of the pyrimidine ring. In vitro anti-HIV-1 activity study performed on a series of 22 compounds confirmed the crucial importance of both conformational rigidity between phenyl B arm and the pyrimidine core linked through the carbonyl bridge, as well as presence of fluoro substituents in ortho-positions of phenyl B moiety. The most potent derivative of the series, compound 17, having almost perpendicular angle within the two planes made from the B aromatic arm and the pyrimidine ring, exhibited low nanomolar anti-HIV-1 activity (EC50 = 4 nM) with no significant toxicity (CC50 > 57.1 μM).

PubMed: 27371922
DOI: 10.1016/j.ejmech.2016.06.026

Experimental method

X-RAY DIFFRACTION (2.402 Å)