Studies of molecular mechanism of tenofovir against 3TC- and AZT-resistance mutant HIV-1 reverse transcriptase.
Molecular modeling study shows that conformational flexibility of acyclic nature of TFV provides energetically indistinguishable multiple conformations, which do not experience the cross-resistance conferred by mutant RTs. TFV-DP is located far away from the bulky side chain of Val184 in M184V RT and tenofovir is readily translocated without steric hindrance with Asp185 after incorporation into the growing primer chain complexed with AZT-resistant RT.
Chong
Youhoon
Y
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, GA 30602, USA.
Akula
Nagaraju
N
Chu
Chung K
CK
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000595:Amino Acid Sequence; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000068698:Tenofovir; D015215:Zidovudine / Q000494:pharmacology*
D063065:Organophosphonates; D009943:Organophosphorus Compounds; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000225:Adenine