Targeting the DENV NS2B-NS3 protease with active antiviral phytocompounds: structure-based virtual screening, molecular docking and molecular dynamics simulation studies

Abstract

Dengue fever has been a global health concern. Mitigation is a challenging problem due to non-availability of workable treatments. The most difficult objective is to design a perfect anti-dengue agent capable of inhibiting infections caused by all four serotypes. Various tactics have been employed in the past to discover dengue antivirals, including screening of chemical compounds against dengue virus enzymes. The objective of the current study is to investigate phytocompounds as anti-dengue remedies that target the non-structural 2B and non-structural 3 protease (NS2B-NS3 pro ), a possible therapeutic target for dengue fever. Initially, 300 + antiviral phytocompounds were collected from Duke’s phytochemical and ethnobotanical database and 30 phytocompounds with anti-dengue properties were identified from previously reported studies, which were virtually screened against NS2B-NS3 pro using molecular docking and toxicity evaluation. The top five most screened ligands were naringin, hesperidin, gossypol, maslinic acid and rhodiolin with binding affinities of − 8.7 kcal/mol, − 8.5 kcal/mol, − 8.5 kcal/mol, − 8.5 kcal/mol and − 8.1 kcal/mol, respectively. The finest docked compounds complexed with NS2B-NS3 pro were subjected for molecular dynamics (MD) simulations and binding free energy estimations through molecular mechanics generalized born surface area–based calculations. The results of the study are intriguing in the context of computer-aided screening and the binding affinities of the phytocompounds, proposing maslinic acid (MAS) as a potent bioactive antiviral for the development of phytocompound-based anti-dengue agent. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00894-022-05355-w.

Identification of Antiviral Phytocompounds as Potential Anti‐Dengue Agents against DENV NS2B/NS3 Protease: An Integrated Molecular Modelling and Dynamics Approach

“…Al. [17,26] Our additional research shows that among the phytocompounds listed in Table 6, Glabridin has the highest binding affinity for NS2B/NS3 protease (À 120.122 kJ/ mol). Except this, phytocompounds like Gallocatechin (À 111.168 kJ/mol) and Isorhamnetin (À 105.312 kJ/mol) may play a significant role in the development of rational treatments against DENV NS2B/NS3pro.…”

“…Many phytochemicals can be used to treat viral diseases and infections since they have few or no side effects. [14][15][16][17][18][19] From a detailed literature study, eight medicinal plants as shown in S_ Figure : 1 (Vernonia cinerea, Tridax procumbens, Cassia angustifolia, Lawsonia inermis, Dryobalanops aromatic, Punica granatum, Zingiber zerumbet and Zizyphus-jujuba) constituting 82 phytocompounds, which possesses effective antiviral activity against DENV2 have been selected. The effect of V. cinerea leaf extract against DENV NS2B/NS3 protease was investigated through an in vitro viral inhibition assay against Vero cells.…”

“…[25] In our previous studies targeting the DENV-2 NS2B/NS3pro with active antiviral phytocompounds, we found compounds like Isorhamnetin, Gallocatechin, FlavokwainÀ C, Maslinic acid, Hesperidin, Naringin, Rhodiolin and Gossypol can inhibit the enzymatic properties of which Maslinic acid and Isorhamnetin to be most effective against the target protein with binding affinities of À 29.20 kcal/mol and À 25.17 kcal/mol, respectively. [17,26] The current study is designed to explore novel phytocompounds as a potential inhibitor for NS2B/NS3pro of DENV through various computational approaches like molecular docking, molecular dynamic simulation studies, and free energy calculations for complexes with NS2B/NS3pro and five different selected phytocompounds.…”

“…The compound in question is known as (3E,5E)‐ 3,5‐bis(4‐methoxybenzylidene)‐ 1‐(phenylsulfonyl) piperidin‐4‐one [25] . In our previous studies targeting the DENV‐2 NS2B/NS3pro with active antiviral phytocompounds, we found compounds like Isorhamnetin, Gallocatechin, Flavokwain−C, Maslinic acid, Hesperidin, Naringin, Rhodiolin and Gossypol can inhibit the enzymatic properties of which Maslinic acid and Isorhamnetin to be most effective against the target protein with binding affinities of −29.20 kcal/mol and −25.17 kcal/mol, respectively [17,26] …”

Evaluating the Antiviral Potential of Phytocompounds from Mesua ferrea against SARS‐CoV‐2 Main Protease: Structure‐Based Virtual Screening and Molecular Dynamics Simulation Investigations

“…[38] Moreover, the traditional methods of studying binding affinities using MM/PBSA have been largely replaced by the more modern MM/GBSA due to its faster computation speed and slightly higher accuracy. [39] We previously used the MM-PB/GBSA technique to study the SARS-CoV-2 M Pro , [40,41] HIV-1 protease, [42] and DENV NS2B-NS3 protease [43,44] systems. AMBER18's MM-PBSA.py algorithm [45] was used to determine the binding free energies.…”