Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent an important component of current HIV treatment, and work via allosteric inhibition of the viral polymerase reverse transcriptase (RT). Clinical NNRTIs, while potent, can select for resistant mutations and cause harmful side effects, highlighting a need for new compounds. Despite the availability of >125 NNRTI-bound RT PDB structures, structure-based design of new compounds remains challenging because of their broad chemical diversity and the fact that the drugs bind to RT via an induced fit mechanism, resulting in large variations in binding modes. To address this problem we have created an automated workflow using multiple molecular descriptors to select appropriate receptors for novel compound docking based on similarity to NNRTIs with solved conformations and including biological vectors based on resistance patterns. We demonstrate this application for the rapid generation of hypothetical structure activity relationships for NNRTI drug discovery programs.

Automated docking receptor selection workflow for non-nucleoside reverse transcriptase drug discovery

245th National Meeting (2013)

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