Novel piperidinylamino-diarylpyrimidine derivatives with dual structural conformations as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.
A series of novel piperidinylamino-diarylpyrimidine (pDAPY) derivatives with dual structural conformations was designed through a molecular hybridization strategy and expected to bind into the non-nucleoside inhibitor binding pocket (NNIBP) of HIV-1 RT in a flexible manner. A cell-based antiviral screening assay showed that some compounds were active against both wild-type and drug-resistant mutant virus strains (K103N+Y181C RT) of HIV-1 (compound 10b3 with EC50 = 0.047 and 4.6 μM, selectivity index = 2145 and 22, respectively). Molecular simulation studies indicated that compound 10b3 could maintain the key hydrophobic interaction and hydrogen bonds with the NNIBP of two RT/ligand complexes. In particular, it could simultaneously occupy the protein/solvent interface and the entrance channel. Exploring these hybrid molecules with dual binding conformations might provide optional chemical scaffolds as novel HIV-1 reverse transcriptase inhibitors (HIV-1 NNRTIs).
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Ji'nan, Shandong, PR China.
Xuwang
X
Chen
Xin
X
Liu
Qing
Q
Meng
Ding
D
Wang
Huiqing
H
Liu
Erik
E
De Clercq
Christophe
C
Pannecouque
Jan
J
Balzarini
Xinyong
X
Liu
D001665:Binding Sites; D024882:Drug Resistance, Viral; D004789:Enzyme Activation / Q000187:drug effects; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C030986:pyrimidine
DAPY; Dual conformations; HIV-1 NNRTIs; Molecular hybridization; Piperidin-4-yl-aminopyrimidines