FMO-guided design of darunavir analogs as HIV-1 protease inhibitors
Document Type
Article
Publication Date
2-1-2024
Abstract
The prevalence of HIV-1 infection continues to pose a significant global public health issue, highlighting the need for antiretroviral drugs that target viral proteins to reduce viral replication. One such target is HIV-1 protease (PR), responsible for cleaving viral polyproteins, leading to the maturation of viral proteins. While darunavir (DRV) is a potent HIV-1 PR inhibitor, drug resistance can arise due to mutations in HIV-1 PR. To address this issue, we developed a novel approach using the fragment molecular orbital (FMO) method and structure-based drug design to create DRV analogs. Using combinatorial programming, we generated novel analogs freely accessible via an on-the-cloud mode implemented in Google Colab, Combined Analog generator Tool (CAT). The designed analogs underwent cascade screening through molecular docking with HIV-1 PR wild-type and major mutations at the active site. Molecular dynamics (MD) simulations confirmed the assess ligand binding and susceptibility of screened designed analogs. Our findings indicate that the three designed analogs guided by FMO, 19-0-14-3, 19-8-10-0, and 19-8-14-3, are superior to DRV and have the potential to serve as efficient PR inhibitors. These findings demonstrate the effectiveness of our approach and its potential to be used in further studies for developing new antiretroviral drugs.
Keywords
HIV-1 protease, Darunavir analogs, Structure-based drug design, Fragment molecular orbital (FMO), Combined analog generator tool
Divisions
CHEMISTRY
Funders
Second Century Fund, Chulalongkorn University,Cygnus,Center for Quantum and Information Lifesciences,Tsukuba Basic Research Support Program Type S, University of Tsukuba, Japan
Publication Title
Scientific Reports
Volume
14
Issue
1
Publisher
Nature Research
Publisher Location
HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY