Design, synthesis, optimization and antiviral activity of a class of hybrid dengue virus E protein inhibitors

Bioorganic & Medicinal Chemistry Letters
Surender Singh JadavVenkatesan Jayaprakash

Abstract

The β-OG pocket is a cavity in the flavivirus envelope (E) protein that was identified by Proc. Natl. Acad. Sci. U.S.A.2003, 100, 6986 as a promising site for the design of antiviral agents that interfere with virus entry into the host cell. The availability of the X-ray crystal structure of the dengue virus (DENV) E protein provided an opportunity for in silico drug design efforts to identify candidate inhibitors. The present study was set up to explore whether it is possible to generate a novel class of molecules that are hybrids between two hit compounds that have been reported previously by ACS. Chem. Biol.2008, 3, 765 following an in silico screening effort against the DENV E protein. First, a library of twenty hybrid molecules were designed and synthesized to explore the feasibility of this strategy. Antiviral evaluation in a virus-cell-based assay for DENV proved this approach to be successful, after which another twenty-four molecules were produced to further explore and optimize the potency of this novel class of hybrid inhibitors. In the end, a molecule was obtained with an EC50 against dengue virus serotype 2 in the low micromolar range (23, 1.32±0.41μM).

References

Jul 25, 2000·European Journal of Medicinal Chemistry·G Turan-ZitouniK Erol
May 22, 2003·Proceedings of the National Academy of Sciences of the United States of America·Yorgo ModisStephen C Harrison
Jan 23, 2004·Nature·Yorgo ModisStephen C Harrison
Aug 28, 2007·European Journal of Medicinal Chemistry·Gülhan Turan-ZitouniGulsen Akalin
Sep 18, 2008·Antiviral Research·Aruna Sampath, R Padmanabhan
Feb 19, 2009·Antimicrobial Agents and Chemotherapy·Qing-Yin WangSubhash G Vasudevan
Feb 26, 2009·Journal of Computer-aided Molecular Design·Ragothaman YennamalliBostjan Kobe
May 8, 2009·European Journal of Medicinal Chemistry·Osama I el-SabbaghAdel A Rashad
Oct 6, 2009·Antiviral Research·Mee Kian PohWouter Schul
Jan 12, 2010·Antiviral Research·Christian G NoblePei-Yong Shi
Mar 2, 2011·Journal of Medicinal Chemistry·Abdelrahman S MayhoubMark Cushman
Oct 1, 2013·Antiviral Research·Siew Pheng LimPei-Yong Shi
Dec 19, 2013·Clinical Epidemiology·Muayad Ali
Jan 1, 2014·Advances in Virus Research·Lauren E Yauch, Sujan Shresta

❮ Previous
Next ❯

Citations

Jan 16, 2016·Journal of Medicinal Chemistry·Mira A M BehnamChristian D Klein
Jan 23, 2016·Neurochemistry International·Mahua BasuNibha Mishra
Mar 12, 2016·Expert Opinion on Drug Discovery·W Mei Kok
Nov 11, 2018·Scientific Reports·Parichat KanyaboonSiwaporn Boonyasuppayakorn
Jun 5, 2020·Scientific Reports·Antonella ZacheoSilke Krol
Apr 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kowit HengphasatpornThanyada Rungrotmongkol
Oct 30, 2020·Phytotherapy Research : PTR·Faraat AliAsad Ali

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.