Crystallographic study of a novel subnanomolar inhibitor provides insight on the binding interactions of alkenyldiarylmethanes with human immunodeficiency virus-1 reverse transcriptase.
Two crystal structures have been solved for separate complexes of alkenyldiarylmethane (ADAM) nonnucleoside reverse transcriptase inhibitors (NNRTI) 3 and 4 with HIV-1 reverse transcriptase (RT). The structures reveal inhibitor binding is exclusively hydrophobic in nature and the shape of the inhibitor-bound NNRTI binding pocket is unique among other reported inhibitor-RT crystal structures. Primarily, ADAMs 3 and 4 protrude from a large gap in the back side of the binding pocket, placing portions of the inhibitors unusually close to the polymerase active site and allowing 3 to form a weak hydrogen bond with Lys223. The lack of additional stabilizing interactions, beyond the observed hydrophobic surface contacts, between 4 and RT is quite perplexing given the extreme potency of the compound (IC(50) </= 1 nM). ADAM 4 was designed to be hydrolytically stable in blood plasma, and an investigation of its hydrolysis in rat plasma demonstrated it has a significantly prolonged half-life in comparison to ADAM lead compounds 1 and 2.
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA.
Matthew D
MD
Cullen
William C
WC
Ho
Joseph D
JD
Bauman
Kalyan
K
Das
Eddy
E
Arnold
Tracy L
TL
Hartman
Karen M
KM
Watson
Robert W
RW
Buckheit
Christophe
C
Pannecouque
Erik
E
De Clercq
Mark
M
Cushman
D000818:Animals; D018360:Crystallography, X-Ray; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D008697:Methane / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D008697:Methane