title: Recent advances in DAPYs and related analogues as HIV-1 NNRTIs.
abstract: HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent most promising anti-AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). They have a unique antiviral potency, high specificity and low cytotoxicity. However, to a great extent, the efficacy of HIV-1 NNRTIs is compounded by rapid emergence of drug resistant virus strains, which calls for continuous efforts to develop novel HIV-1 NNRTIs. Diarylpyrimidine (DAPY) derivatives, one family of NNRTIs with superior activity profiles against wild-type HIV-1 and mutant strains, have attracted considerable attention over the past few years. Among the potent lead DAPY compounds, etravirine was approved by FDA in January 2008, and its analogue rilpivirine (TMC278) has advanced to phase III clinical trials. The successful development of DAPYs results from a multidisciplinary approach involving traditional medicinal chemistry, structural biology, crystallography and computational chemistry. Recently, a number of novel characteristics of DAPYs including conformational flexibility, positional adaptability, key hydrogen bonds and specifically targeting conserved residues of RT, have been identified, providing valuable avenues for further optimization and development of new DAPY analogues as promising anti-HIV drug candidates. In this review, we first present a brief historical account of the medicinal chemistry of the DAPY NNRTIs, then focus on the extensive structural modifications, SAR studies, and binding mode analysis based on crystallographic and molecular modeling. Other structural related NNRTI scaffolds will also be reviewed.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China.
authors.forename: Xuwang
authors.initials: X
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.forename: Dongyue
authors.initials: D
authors.lastname: Li
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015658:HIV Infections / Q000188:drug therapy; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011743:Pyrimidines / Q000737:chemistry* / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase