High-Throughput Virtual Screening Enables the Identification of Hit Analogs of Efavirenz

Shelley Li, Kavya Pandrangi, Anushree Marimuthu, Anjali Prabhu, Nandika Nambiar, Madi Lloyd, Alice Finkelstein, and Edward Njoo

Aspiring Scholars Directed Research Program


Efavirenz is a synthetic FDA-approved non-nucleoside reverse transcriptase inhibitor (NNRTI) that has been demonstrated to bind to the allosteric binding pocket of reverse transcriptase (RT) of the human immunodeficiency virus (HIV), effectively inhibiting viral replication. However, the emergence of new drug-resistant variants has reduced the effectiveness of NNRTIs, necessitating the synthesis of new compounds with better biological profiles. Analogs of efavirenz hold potential as next-generation NNRTIs and may overcome resistance to the rapidly mutating HIV RT. In this study, we utilize high-throughput virtual screening (HTVS) to evaluate 112 efavirenz analogs in silico with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tert butyl, and methyl groups as well as chlorine, fluorine, methyl, and trifluoromethyl rotated around the 3, 4, 5, 6 positions on the benzene ring in the efavirenz scaffold. Analogs were evaluated against the wild-type (WT) RT as well as 20 efavirenz-resistant mutations in the WT HIV protein to determine novel next-generation NNRTIs. Based on its predicted binding affinity to the allosteric binding pocket in the RT in comparison to efavirenz, our study has identified several hit compounds as potential next-generation NNRTIs.

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