Staff View: FMO-guided design of darunavir analogs as HIV-1 protease inhibitors

FMO-guided design of darunavir analogs as HIV-1 protease inhibitors

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 mat...

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Main Authors:	Chuntakaruk, Hathaichanok, Hengphasatporn, Kowit, Shigeta, Yasuteru, Aonbangkhen, Chanat, Lee, Vannajan Sanghiran, Khotavivattana, Tanatorn, Rungrotmongkol, Thanyada, Hannongbua, Supot
Format:	Article
Published:	Nature Research 2024
Subjects:	Q Science (General) QD Chemistry
Online Access:	http://eprints.um.edu.my/45628/ https://doi.org/10.1038/s41598-024-53940-1
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spelling	my.um.eprints.456282024-11-06T08:44:45Z http://eprints.um.edu.my/45628/ FMO-guided design of darunavir analogs as HIV-1 protease inhibitors Chuntakaruk, Hathaichanok Hengphasatporn, Kowit Shigeta, Yasuteru Aonbangkhen, Chanat Lee, Vannajan Sanghiran Khotavivattana, Tanatorn Rungrotmongkol, Thanyada Hannongbua, Supot Q Science (General) QD Chemistry 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. Nature Research 2024-02 Article PeerReviewed Chuntakaruk, Hathaichanok and Hengphasatporn, Kowit and Shigeta, Yasuteru and Aonbangkhen, Chanat and Lee, Vannajan Sanghiran and Khotavivattana, Tanatorn and Rungrotmongkol, Thanyada and Hannongbua, Supot (2024) FMO-guided design of darunavir analogs as HIV-1 protease inhibitors. Scientific Reports, 14 (1). p. 3639. ISSN 2045-2322, DOI https://doi.org/10.1038/s41598-024-53940-1 <https://doi.org/10.1038/s41598-024-53940-1>. https://doi.org/10.1038/s41598-024-53940-1 10.1038/s41598-024-53940-1
institution	Universiti Malaya
building	UM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Universiti Malaya
content_source	UM Research Repository
url_provider	http://eprints.um.edu.my/
topic	Q Science (General) QD Chemistry
spellingShingle	Q Science (General) QD Chemistry Chuntakaruk, Hathaichanok Hengphasatporn, Kowit Shigeta, Yasuteru Aonbangkhen, Chanat Lee, Vannajan Sanghiran Khotavivattana, Tanatorn Rungrotmongkol, Thanyada Hannongbua, Supot FMO-guided design of darunavir analogs as HIV-1 protease inhibitors
description	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.
format	Article
author	Chuntakaruk, Hathaichanok Hengphasatporn, Kowit Shigeta, Yasuteru Aonbangkhen, Chanat Lee, Vannajan Sanghiran Khotavivattana, Tanatorn Rungrotmongkol, Thanyada Hannongbua, Supot
author_facet	Chuntakaruk, Hathaichanok Hengphasatporn, Kowit Shigeta, Yasuteru Aonbangkhen, Chanat Lee, Vannajan Sanghiran Khotavivattana, Tanatorn Rungrotmongkol, Thanyada Hannongbua, Supot
author_sort	Chuntakaruk, Hathaichanok
title	FMO-guided design of darunavir analogs as HIV-1 protease inhibitors
title_short	FMO-guided design of darunavir analogs as HIV-1 protease inhibitors
title_full	FMO-guided design of darunavir analogs as HIV-1 protease inhibitors
title_fullStr	FMO-guided design of darunavir analogs as HIV-1 protease inhibitors
title_full_unstemmed	FMO-guided design of darunavir analogs as HIV-1 protease inhibitors
title_sort	fmo-guided design of darunavir analogs as hiv-1 protease inhibitors
publisher	Nature Research
publishDate	2024
url	http://eprints.um.edu.my/45628/ https://doi.org/10.1038/s41598-024-53940-1
_version_	1816130429578641408
score	13.223943

FMO-guided design of darunavir analogs as HIV-1 protease inhibitors

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