In Silico Mining of the Streptome Database for Hunting Putative Candidates to Allosterically Inhibit the Dengue Virus (Serotype 2) RdRp.

Background/

Objectives

In the last few decades, the dengue virus, a prevalent flavivirus, has demonstrated various epidemiological, economic, and health impacts around the world. Dengue virus serotype 2 (DENV2) plays a vital role in dengue-associated mortality. The RNA-dependent RNA polymerase (RdRp) of DENV2 is a charming druggable target owing to its crucial function in viral reproduction. In recent years, streptomycetes natural products (NPs) have attracted considerable attention as a potential source of antiviral drugs.

Methods

Seeking prospective inhibitors that inhibit the DENV2 RdRp allosteric site, in silico mining of the Streptome database was executed. AutoDock4.2.6 software performance in predicting docking poses of the inspected inhibitors was initially conducted according to existing experimental data. Upon the assessed docking parameters, the Streptome database was virtually screened against DENV2 RdRp allosteric site. The streptomycetes NPs with docking scores less than the positive control (68T; calc. -35.6 kJ.mol-1) were advanced for molecular dynamics simulations (MDS), and their binding affinities were computed by employing the MM/GBSA approach.

Results

SDB9818 and SDB4806 unveiled superior inhibitor activities against DENV2 RdRp upon MM/GBSA//300 ns MDS than 68T with ΔGbinding values of -246.4, -242.3, and -150.6 kJ.mol-1, respectively. A great consistency was found in both the energetic and structural analyses of the identified inhibitors within the DENV2 RdRp allosteric site. Furthermore, the physicochemical characteristics of the identified inhibitors demonstrated good oral bioavailability. Eventually, quantum mechanical computations were carried out to evaluate the chemical reactivity of the identified inhibitors.

Conclusions

As determined by in silico computations, the identified streptomycetes NPs may act as DENV2 RdRp allosteric inhibitors and mandate further experimental assays.