New strategy for identifying potential natural HIV-1 non-nucleoside reverse transcriptase inhibitors against drug-resistance: an in silico study

Non-nucleosides reverse transcriptase inhibitors (NNRTIs), specifically targeting the HIV-1 reverse transcriptase (RT), play a unique role in anti-AIDS agents due to their high antiviral potency, structural diversity, and low toxicity in antiretroviral combination therapies used to treat HIV. However, due to the emergence of new drug-resistant strains, the development of novel NNRTIs with adequate potency, improved resistance profiles and less toxicity is highly required. In this work, a novel virtual screening strategy combined with structure-based drug design was proposed to discover the potential inhibitors against drug-resistant HIV strains. Seven structure-variant RTs, ranging from the wild type to a hypothetical multi-mutant were regarded as target proteins to perform structure-based virtual screening. Totally 23 small molecules with good binding affinity were identified from the Traditional Chinese Medicine database (TCM) as potential NNRTIs candidates. Among these hits, (+)-Hinokinin has confirmed anti-HIV activity, and some hits are structurally identical with anti-HIV compounds. Almost all these hits are consistent with external experimental results. Molecular simulations analysis revealed that top 2 hits (Pallidisetin A and Pallidisetin B) bind stably and in high affinity to HIV-RT, which are ready to be experimental confirmed. These results suggested that the strategy we proposed is feasible, trustworthy and effective. Our finding might be helpful in the identification of novel NNRTIs against drug-resistant, and also provide a new clue for the discovery of HIV drugs in natural products. Communicated by Ramaswamy H. Sarma.