Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling

Dengue virus Type 2 (DENV-2) is predominant serotype causing major dengue epidemics. There are a number of studies carried out to find its effective antiviral, however to date, there is still no molecule either from peptide or small molecules released as a drug. The present study aims to identify sm...

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Main Authors:	Hariono, Maywan, Choi, Sy Bing, Roslim, Ros Fatihah, Mohd. Nawi, Mohamed Sufian, Tan, Mei Lan, Kamarulzaman, Ezatul Ezleen, Mohamed, Nornisah, Yusof, Rohana, Othman, Shatrah, Abd Rahman, Noorsaadah, Othman, Rozana, A. Wahab, Habibah
Format:	Article
Language:	English English English
Published:	Public Library of Science 2019
Subjects:	RS Pharmacy and materia medica RS403 Materia Medica-Pharmaceutical Chemistry
Online Access:	http://irep.iium.edu.my/47962/ http://irep.iium.edu.my/47962/ http://irep.iium.edu.my/47962/ http://irep.iium.edu.my/47962/1/47962_Thioguanine-based%20DENV-2%20NS2B-NS3.pdf http://irep.iium.edu.my/47962/2/47962_Thioguanine-based%20DENV-2%20NS2B-NS3_SCOPUS.pdf http://irep.iium.edu.my/47962/3/47962_Thioguanine-based%20DENV-2%20NS2B-NS3_WOS.pdf

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recordtype	eprints
spelling	iium-479622019-07-12T07:49:42Z http://irep.iium.edu.my/47962/ Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling Hariono, Maywan Choi, Sy Bing Roslim, Ros Fatihah Mohd. Nawi, Mohamed Sufian Tan, Mei Lan Kamarulzaman, Ezatul Ezleen Mohamed, Nornisah Yusof, Rohana Othman, Shatrah Abd Rahman, Noorsaadah Othman, Rozana A. Wahab, Habibah RS Pharmacy and materia medica RS403 Materia Medica-Pharmaceutical Chemistry Dengue virus Type 2 (DENV-2) is predominant serotype causing major dengue epidemics. There are a number of studies carried out to find its effective antiviral, however to date, there is still no molecule either from peptide or small molecules released as a drug. The present study aims to identify small molecules inhibitor from National Cancer Institute database through virtual screening. One of the hits, D0713 (IC50 = 62 μM) bearing thioguanine scaffold was derivatised into 21 compounds and evaluated for DENV-2 NS2B/NS3 protease inhibitory activity. Compounds 18 and 21 demonstrated the most potent activity with IC50 of 0.38 μM and 16 μM, respectively. Molecular dynamics and MM/PBSA free energy of binding calculation were conducted to study the interaction mechanism of these compounds with the protease. The free energy of binding of 18 calculated by MM/PBSA is -16.10 kcal/mol compared to the known inhibitor, panduratin A (-11.27 kcal/mol), which corroborates well with the experimental observation. Results from molecular dynamics simulations also showed that both 18 and 21 bind in the active site and stabilised by the formation of hydrogen bonds with Asn174. Public Library of Science 2019-01 Article PeerReviewed application/pdf en http://irep.iium.edu.my/47962/1/47962_Thioguanine-based%20DENV-2%20NS2B-NS3.pdf application/pdf en http://irep.iium.edu.my/47962/2/47962_Thioguanine-based%20DENV-2%20NS2B-NS3_SCOPUS.pdf application/pdf en http://irep.iium.edu.my/47962/3/47962_Thioguanine-based%20DENV-2%20NS2B-NS3_WOS.pdf Hariono, Maywan and Choi, Sy Bing and Roslim, Ros Fatihah and Mohd. Nawi, Mohamed Sufian and Tan, Mei Lan and Kamarulzaman, Ezatul Ezleen and Mohamed, Nornisah and Yusof, Rohana and Othman, Shatrah and Abd Rahman, Noorsaadah and Othman, Rozana and A. Wahab, Habibah (2019) Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling. PLoS ONE, 14 (1). pp. 1-21. ISSN 1932-6203 https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0210869&type=printable 10.1371/journal.pone.0210869
repository_type	Digital Repository
institution_category	Local University
institution	International Islamic University Malaysia
building	IIUM Repository
collection	Online Access
language	English English English
topic	RS Pharmacy and materia medica RS403 Materia Medica-Pharmaceutical Chemistry
spellingShingle	RS Pharmacy and materia medica RS403 Materia Medica-Pharmaceutical Chemistry Hariono, Maywan Choi, Sy Bing Roslim, Ros Fatihah Mohd. Nawi, Mohamed Sufian Tan, Mei Lan Kamarulzaman, Ezatul Ezleen Mohamed, Nornisah Yusof, Rohana Othman, Shatrah Abd Rahman, Noorsaadah Othman, Rozana A. Wahab, Habibah Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling
description	Dengue virus Type 2 (DENV-2) is predominant serotype causing major dengue epidemics. There are a number of studies carried out to find its effective antiviral, however to date, there is still no molecule either from peptide or small molecules released as a drug. The present study aims to identify small molecules inhibitor from National Cancer Institute database through virtual screening. One of the hits, D0713 (IC50 = 62 μM) bearing thioguanine scaffold was derivatised into 21 compounds and evaluated for DENV-2 NS2B/NS3 protease inhibitory activity. Compounds 18 and 21 demonstrated the most potent activity with IC50 of 0.38 μM and 16 μM, respectively. Molecular dynamics and MM/PBSA free energy of binding calculation were conducted to study the interaction mechanism of these compounds with the protease. The free energy of binding of 18 calculated by MM/PBSA is -16.10 kcal/mol compared to the known inhibitor, panduratin A (-11.27 kcal/mol), which corroborates well with the experimental observation. Results from molecular dynamics simulations also showed that both 18 and 21 bind in the active site and stabilised by the formation of hydrogen bonds with Asn174.
format	Article
author	Hariono, Maywan Choi, Sy Bing Roslim, Ros Fatihah Mohd. Nawi, Mohamed Sufian Tan, Mei Lan Kamarulzaman, Ezatul Ezleen Mohamed, Nornisah Yusof, Rohana Othman, Shatrah Abd Rahman, Noorsaadah Othman, Rozana A. Wahab, Habibah
author_facet	Hariono, Maywan Choi, Sy Bing Roslim, Ros Fatihah Mohd. Nawi, Mohamed Sufian Tan, Mei Lan Kamarulzaman, Ezatul Ezleen Mohamed, Nornisah Yusof, Rohana Othman, Shatrah Abd Rahman, Noorsaadah Othman, Rozana A. Wahab, Habibah
author_sort	Hariono, Maywan
title	Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling
title_short	Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling
title_full	Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling
title_fullStr	Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling
title_full_unstemmed	Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling
title_sort	thioguanine-based denv-2 ns2b/ns3 protease inhibitors: virtual screening, synthesis, biological evaluation and molecular modelling
publisher	Public Library of Science
publishDate	2019
url	http://irep.iium.edu.my/47962/ http://irep.iium.edu.my/47962/ http://irep.iium.edu.my/47962/ http://irep.iium.edu.my/47962/1/47962_Thioguanine-based%20DENV-2%20NS2B-NS3.pdf http://irep.iium.edu.my/47962/2/47962_Thioguanine-based%20DENV-2%20NS2B-NS3_SCOPUS.pdf http://irep.iium.edu.my/47962/3/47962_Thioguanine-based%20DENV-2%20NS2B-NS3_WOS.pdf
first_indexed	2023-09-18T21:08:09Z
last_indexed	2023-09-18T21:08:09Z
_version_	1777411072725090304

Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling

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