Structural and Energetic Analyses of the Effects of the K103N Mutation of HIV-1 Reverse Transcriptase on Efavirenz Analogues

2004 ◽  
Vol 47 (9) ◽  
pp. 2389-2392 ◽  
Author(s):  
Marina Udier-Blagović ◽  
Julian Tirado-Rives ◽  
William L. Jorgensen
Keyword(s):  
Reverse Transcriptase ◽  
K103n Mutation ◽  
Hiv 1

scholarly journals Mechanism of Interaction of Novel Indolylarylsulfone Derivatives with K103N and Y181I Mutant HIV-1 Reverse Transcriptase in Complex with its Substrates

2011 ◽  
Vol 22 (3) ◽  
pp. 107-118 ◽  
Author(s):  
Alberta Samuele ◽  
Sara Bisi ◽  
Alexandra Kataropoulou ◽  
Giuseppe La Regina ◽  
Francesco Piscitelli ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Resistant Mutant ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Specific Effects ◽  
Steady State Kinetic ◽  
Drug Resistant Mutant ◽  
K103n Mutation ◽  
New Generation ◽  
Hiv 1

Background: Novel indolylarylsulfones (lASs), designed through rational structure-based molecular modelling and docking approaches, have been recently characterized as effective inhibitors of the wild-type and drug-resistant mutant HIV-1 reverse transcriptase (RT). Methods: Here, we studied the interaction of selected halo- and nitra-substituted IAS derivatives, with the RT enzyme carrying the single resistance mutations K103N and Y181I through steady-state kinetic experiments. Results: The studied compounds exhibited high selectivity to the mutant RT in complex with its substrates, behaving as uncompetitive inhibitors. The presence of the K103N mutation, and to a lesser extent the Y181I, stabilized the drug interactions with the viral RT, when both its substrates were bound. Conclusions: The characterization of these mutation-specific effects on inhibitor binding might be relevant to the design of more effective new generation non-nucleoside reverse transcriptase inhibitors, with better resilience towards drug resistant mutants.

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