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

Area of Science:

• Medicinal Chemistry
• Computational Biology
• Virology

Background:

• Human immunodeficiency virus type 1 (HIV-1) remains a global health threat, causing severe immune damage and susceptibility to opportunistic infections.
• Current treatments cannot eradicate HIV-1 from the body, necessitating the development of novel therapeutic strategies.
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a crucial class of antiretroviral drugs, but drug resistance remains a challenge.

Purpose of the Study:

• To identify novel natural compounds with bioactivity similar to existing NNRTIs for potential HIV-1 treatment.
• To screen a large library of natural products using in silico methods to predict anti-HIV-1 activity.
• To prioritize compounds based on predicted efficacy, safety, and drug-like properties.

Main Methods:

• In silico screening of 224,205 natural compounds from the ZINC15 database.
• Utilized 3D-similarity search, ADMETox prediction, HIV protein-inhibitor interaction analysis, molecular docking, and MM-GBSA free-binding energy calculations.
• Employed FDA-approved NNRTIs (efavirenz, etravirine, rilpivirine, doravirine) as reference queries.

Main Results:

• Four natural compounds demonstrated promising profiles comparable to established NNRTIs.
• Detailed analysis of binding interactions with HIV-1 reverse transcriptase (RT) residues (Lys101, Tyr181, Tyr188, Trp229, Tyr318) confirmed stable ligand binding.
• ZINC2103242 exhibited the most favorable drug metabolism and safety profile, showing significant potential as an anti-HIV candidate.

Conclusions:

• The study successfully identified novel natural product-based candidates for HIV-1 therapy.
• In silico approaches are effective for discovering potential NNRTIs from large compound libraries.
• ZINC2103242 represents a promising lead compound for further development of new anti-HIV-1 drugs.