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

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

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Abstract

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.

Item Type: Article (Journal)
Additional Information: 5956/47962
Uncontrolled Keywords: Thioguanine-based DENV-2 NS2B/NS3, molecular modelling
Subjects: R Medicine > RS Pharmacy and materia medica
R Medicine > RS Pharmacy and materia medica > RS403 Materia Medica-Pharmaceutical Chemistry
Kulliyyahs/Centres/Divisions/Institutes: Kulliyyah of Pharmacy
Kulliyyah of Pharmacy > Department of Pharmaceutical Chemistry
Depositing User: Dr Mohamed Sufian Mohd Nawi
Date Deposited: 08 Mar 2019 11:13
Last Modified: 12 Jul 2019 15:49
URI: http://irep.iium.edu.my/id/eprint/47962

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