Structure-based evaluation of non-nucleoside inhibitors with improved potency and solubility that target HIV reverse transcriptase variants.

摘要: The development of novel non-nucleoside inhibitors (NNRTIs) with activity against variants HIV reverse transcriptase (RT) is crucial for overcoming treatment failure. NNRTIs bind in an allosteric pocket RT ∼10 A away from the active site. Earlier analogues catechol diether compound series have picomolar strains wild-type but lose potency single Y181C and double K103N/Y181C mutations. As guided by structure-based computational studies, removal 5-Cl substitution 1 on aryl ring system led to a new analogue 2 that maintains greater better solubility (510 μg/mL). Crystal structures were determined wild-type, Y181C, complex both compounds understand structural basis these findings. Comparison reveals mutation destabilizes binding mode disrupts the...