Small Molecules of Natural Origin as Potential Anti-HIV Agents: A Computational Approach

Abstract

The human immunodeficiency virus type 1 (HIV-1), one of the leading causes of infectious death globally, generates severe damages to people’s immune systems and makes them susceptible to serious diseases. To date, there are no drugs that completely remove HIV from the body. This paper focuses on screening 224,205 natural compounds of ZINC15 NPs subset to identify those with bioactivity similar to non-nucleoside reverse transcriptase inhibitors (NNRTIs) as promising candidates to treat HIV-1. To reach the goal, an in silico approach involving 3D-similarity search, ADMETox, HIV protein-inhibitor prediction, docking, and MM-GBSA free-binding energies was trained. The FDA-approved HIV drugs, efavirenz, etravirine, rilpivirine, and doravirine, were used as queries. The prioritized compounds were subjected to ADMETox, docking, and MM-GBSA studies against HIV-1 reverse transcriptase (RT). Lys101, Tyr181, Tyr188, Trp229, and Tyr318 residues and free-binding energies have proved that ligands can stably bind to HIV-1 RT. Three natural products (ZINC37538901, ZINC38321654, and ZINC67912677) containing oxan and oxolan rings with hydroxyl substituents and one (ZINC2103242) having 3,6,7,8-tetrahydro-2H-pyrido[1 ,2-a]pyrazine-1,4-dione core exhibited comparable profiles to etravirine and doravirine, with ZINC2103242 being the most promising anti-HIV candidate in terms of drug metabolism and safety profile. These findings may open new avenues to guide the rational design of novel HIV-1 NNRTIs.

Discovery of Novel HIV Protease Inhibitors Using Modern Computational Techniques

“…T. pyriformis is a protozoa bacterium with its toxicity measured in log μg/L often used as a toxic endpoint. If the value is <−0.5 log μg/L for any compound, it is considered to be toxic [ 47 ]. None of the hit molecules and the reference drugs showed toxicity against T. pyriformis .…”

A computational overview of integrase strand transfer inhibitors (INSTIs) against emerging and evolving drug-resistant HIV-1 integrase mutants

“…Some of the IN inhibitor-based HAARTs have revealed antiviral potency against Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), and viruses associated with COVID-19 (Rameshrad et al 2020 ; Makoti and Fielding 2020 ). However, no clinical improvements beyond standard care were noticed, when administered to severe COVID-19 patients (Crisan and Bora 2021 ).…”

“…A personalized cocktail of diverse classes of drugs commonly referred to as the HAART exists to manage the disease. At present, about 26 antiretroviral drugs are FDA approved, which do not eradicate HIV infection but suppress its activity (Crisan and Bora 2021 ), as depicted in Fig. 2 .…”

“…These aid in predicting the significance of mutations involved in making the strain resistant, elucidating the molecular mechanisms of resistance associated to IN-ligand complex, and lastly, disclosing precise insights vital to designing new potent INSTIs, refer to Fig. 4 for major INSTI resistance-associated mutations (RAMs) (Islam and Pillay 2016 ; Han et al 2016 ; Zhou et al 2021 ; Crisan and Bora 2021 ). Consequently, the approved anti-HIV agents can be employed either as reference molecules to guide the design of novel ones or can be scrutinized for their re-application to other viruses or non-virus diseases using computational as well as experimental methods (like in the case of COVID-19) (Rameshrad et al 2020 ; Indu et al 2020 ; Alavian et al 2021 ; Crisan and Bora 2021 ).…”

“…Both serotypes of the virus, HIV-1 and HIV-2 (comparatively less virulent), lead to acquired immunodeficiency syndrome (AIDS), which is the most advanced stage of HIV infection, in which an immunodeficient state is reached (Notario-Pérez et al 2017 ). HIV uses the bloodstream as a means to spread (Evans et al 2021 ); it destroys or impairs the functionality of the host’s cell-mediated immunity by specifically attacking the CD4 + cells from the monocyte–macrophage lineage, dendritic, microglial, and resting T-cells via gp120 (Wallet et al 2019 ; Kruize and Kootstra 2019 ; Crisan and Bora 2021 ). Ultimately, it establishes a provirus reservoir causing a progressive deterioration of immunity and making the host’s body easily accessible to be attacked by a myriad of opportunistic infections, disorders, and cancers (Putim et al 2018 ; Siwe-Noundou et al 2019 ; Gong et al 2020 ), further allowing them to persist in multiple organs, even while on ART (Evans et al 2021 ).…”