Probing Phytochemicals As Prospective Antiviral Agents Against HIV-1 Protease Through Structure-Based Virtual Screening and Molecular Dynamics Simulations

Abstract

Human Immunodeficiency Virus (HIV) causes enormous morbidity and mortality in subtropical and tropical regions of the world in the form of AIDS (acquired immunodeficiency syndrome), which has been of prime concern to governments and the World Health Organization (WHO). UNAIDS assessment speculates the presence of millions of AIDS patients worldwide at the end of year 2019. However, at present there is no potent antiviral drugs or clinically approved vaccines in specifically effective against HIV; hence controlling this pathogen has been a difficult task. Most of the presently treated HIV-1 protease (HIV-PR) inhibitors have been susceptible to suffer from the mutations assisted drug resistance. Hence, it is essential to explore effective substitutes against the HIV-PR, a potential salutary target for AIDS therapy. Numerous tactics have been followed in probing for HIV antivirals against HIV enzymes. From last decades, scientists have spun their dedication to nature, probing compounds that can be utilized as HIV antivirals. Phytochemicals, the chemical compounds produced by plants, have been used widely to treat a variety of diseases such as dengue, malaria. The current study aims to understand phytochemicals as anti-HIV agents targeting the HIV-PR, with multi-faceted in silico analysis. Initially, virtual screening analysis of library of phytochemicals with target (HIV-PR) was carried out using a molecular modelling and docking approach taking more than 300 phytochemicals from Duke’s phytochemical library by using Autodock tool to dock the ligand databases and selected compounds according to its highest binding affinity. The five top most were found to be Cyanin, Barberine, Maslinic acid, Stigmasterol, and Diadzein with binding energies of -10.5, -8.9, -8.7, -8.3, and -8.0 kcal/mol, respectively. From the finest docked complexes those with HIV-PR were directed to nano-second level Molecular Dynamics (MD) simulations and MM-PBSA based free energy calculations. It was observed that, the binding between the phytochemicals and the HIV-PR with almost same affinity like that of the most potent HIV-PR inhibitor, Darunavir (TMC114). Inquisitively, the important interactions with binding energy more than 1 kcal/mol falls on the flap and active site regions, which helps closing flap-flap and neutralizing the active residues of the HIV-PR. The flap dynamics activities and binding affinity of the studied phytochemicals information can support in design phytochemicals-based HIV-PR inhibitors.

Keywords: HIV-1 Protease, Phytochemicals, Drug Design, Virtual screening, MD simulations