5K14: Hiv-1 Reverse Transcriptase In Complex With A 2,6-difluorophenyl Dapy Analog

Citation:
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 muM).
PDB ID: 5K14Download
MMDB ID: 140590
PDB Deposition Date: 2016/5/17
Updated in MMDB: 2016/07
Experimental Method:
x-ray diffraction
Resolution: 2.4  Å
Source Organism:
Human immunodeficiency virus type 1 lw12.3 isolate
Similar Structures:
Biological Unit for 5K14: dimeric; determined by author and by software (PISA)
Molecular Components in 5K14
Label Count Molecule
Proteins (2 molecules)
1
Hiv-1 Reverse Transcriptase(isolate Hxb2)(Gene symbol: gag-pol)
Molecule annotation
1
Hiv-1 Reverse Transcriptase (Isolate Lw123)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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