In silico structure-based design of allosteric inhibitors targeting the Dengue virus NS3 helicase.

ADLER, NATALIA ; FIDALGO, DANIELA M.; AMREIN, FERNANDO; KAUFMAN, SERGIO; ARRAR, MEHRNOOSH; BOLLINI, MARIELA; CAVASOTTO, CLAUDIO

Taller; Latin American Workshop in structural Bioinformatics of Proteins; 2019

Dengue virus is the most prevalent mosquito-borne viral pathogen and has become a major publichealth concern worldwide in recent years. However, no clinically approved antiviral therapy isavailable, hence the need for safe and effective anti-dengue drugs is of utmost importance.NS3 is a multifunctional enzyme involved in viral replication, host-immune evasion, and processingof the polyprotein precursor. The N-terminal region is classified as a serine protease and theC-terminal region is an RNA helicase (NS3Hel). It has been established that mutations in NS3Helleading to the absence of helicase activity correlated directly with lack of virus replication. Therefore, NS3Hel is an attractive target for the development of antiviral agents. Helicases are nevertheless challenging drug targets because potent inhibitors are often not specific, so we are focused in identifying molecules that could act as allosteric inhibitors.In order to find possible allosteric pathways we performed an in silico study of NS3Hel actionmechanism, concentrating in the hydrolysis products release pathways from the catalytic site. Theresults found in this stage suggest there is a conformational change that would be key to favor product release. We propose the union of small organic molecules in a pocket located in domain 3 would inhibit this conformational change resulting in the decrease of ATPase and, therefore, helicase activity. We performed prospective docking-based virtual screening in this novel site and 15 structurally different compounds were selected and are currently being purchased or synthesized to evaluate their ATPase inhibitory capacity