Pharmacophore-based virtual screening and in-silico study of natural products as potential DENV-2 RdRp inhibitors

Abstract

Dengue fever is a significant public health concern throughout the world, causing an estimated 500,000 hospitalizations and 20,000 deaths each year, despite the lack of effective therapies. The DENV-2 RdRp has been identified as a potential target for the development of new and effective dengue therapies. This research’s primary objective was to discover an anti-DENV inhibitor using in silico ligand- and structure-based approaches. To begin, a ligand-based pharmacophore model was developed, and 130 distinct natural products (NPs) were screened. Docking of the pharmacophore-matched compounds were performed to the active site of DENV-2 RdRp protease . Eleven compounds were identified as potential DENV-2 RdRp inhibitors based on docking energy and binding interactions. ADMET and drug-likeness were done to predict their pharmacologic, pharmacokinetic, and drug-likeproperties . Compounds ranked highest in terms of pharmacokinetics and drug-like appearances were then subjected to additional toxicity testing to determine the leading compound. Additionally, MD simulation of the lead compound was performed to confirm the docked complex’s stability and the binding site determined by docking. As a result, the lead compound (compound-108) demonstrated an excellent match to the pharmacophore, a strong binding contact and affinity for the RdRp enzyme, favourable pharmacokinetics, and drug-like characteristics. In summary, the lead compound identified in this study could be a possible DENV-2 RdRp inhibitor that may be further studied on in vitro and in vivo models to develop as a drug candidate.

Communicated by Ramaswamy H. Sarma

Keywords:

• Anti-dengue
• natural products
• pharmacophore
• virtual screening
• molecular docking
• molecular dynamic simulation

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

We acknowledge the financial support awarded by the Ministry of Higher Education Malaysia (FRGS/1/2019/STG01/UMP/02/4) and Lembaga Koko Malaysia (Malaysian Cocoa Board) (Grant number- RDU210710) to Universiti Malaysia Pahang. The authors would also be thankful to the Universiti Kebangsaan Malaysia (UKM) Faculty of Pharmacy for supplying Discovery Studio 3.1 software.