Design of novel HIV-1 protease inhibitors with favorable oral properties using a virtual screening and lead optimization approach

Abstract

Abstract Acquired Immunodeficiency Syndrome (AIDS) is a chronic and potentially fatal transmissible disease caused by the Human Immunodeficiency Virus (HIV). Since its discovery in 1981, an estimated 85 million cases and 40 million AIDS related deaths have occurred worldwide. Among the two types of HIV, HIV-1 accounts for over 90% of reported cases. Throughout the years, multiple drugs have been approved for the treatment of AIDS. However, these drugs face many drawbacks such as toxic side effects, non-optimal pharmacokinetic profile and drug resistance due to virus mutation. This study aims to design novel potent HIV-1 protease inhibitors that overcome these drawbacks through molecular modelling methods. Pubchem database was screened for potential lead compounds. Results were filtered through two phases of ADMET and docking studies. Finally, the chosen lead compound was optimized through fragment replacement to obtain the novel inhibitors. Scientific contribution: This study aims to employ an in-silico virtual screening and lead optimization workflow, in order to design potential HIV-1 protease inhibitors which build upon the strengths, and overcome some of the most prominent obstacles facing current approved anti-HIV medication, including drug resistance, toxic side effects and low reachability to viral reservoirs such as the central nervous system.