Dataset Information

Computer Aided Screening of Phytochemicals from Garcinia against the Dengue NS2B/NS3 Protease.

ABSTRACT: Dengue virus NS2/NS3 protease because of its ability to cleave viral proteins is considered as an attractive target to screen antiviral agents. Medicinal plants contain a variety of phytochemicals that can be used as drug against different diseases and infections. Therefore, this study was designed to uncover possible phytochemical of different classes (Aromatic, Carbohydrates, Lignin, Saponins, Steroids, Tannins, Terpenoids, Xanthones) that could be used as inhibitors against the NS2B/NS3 protease of DENV. With the help of molecular docking, Garcinia phytochemicals found to be bound deeply inside the active site of DENV NS2B/NS3 protease among all tested phytochemicals and had interactions with catalytic triad (His51, Asp75, Ser135). Thus, it can be concluded from the study that these Gracinia phytochemicals could serve as important inhibitors to inhibit the viral replication inside the host cell. Further in-vitro investigations require confirming their efficacy.

SUBMITTER: Qamar TU

PROVIDER: S-EPMC3974236 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Computer Aided Screening of Phytochemicals from Garcinia against the Dengue NS2B/NS3 Protease.

Qamar Tahir Ul TU Mumtaz Arooj A Ashfaq Usman Ali UA Azhar Samia S Fatima Tabeer T Hassan Muhammad M Hussain Syed Sajid SS Akram Waheed W Idrees Sobia S

Bioinformation 20140319 3

Dengue virus NS2/NS3 protease because of its ability to cleave viral proteins is considered as an attractive target to screen antiviral agents. Medicinal plants contain a variety of phytochemicals that can be used as drug against different diseases and infections. Therefore, this study was designed to uncover possible phytochemical of different classes (Aromatic, Carbohydrates, Lignin, Saponins, Steroids, Tannins, Terpenoids, Xanthones) that could be used as inhibitors against the NS2B/NS3 prote ...[more]

PMID: 24748749

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Project description:Dengue fever is a virus spread by mosquitoes that has no effective treatment or vaccination. Several dengue cases combined with the current COVID-19 pandemic, exacerbates this problem. Two proteins, NS5 methyltransferase and NS2B/NS3 primary protease complexes, are crucial for dengue viral replication and are the target sites for antiviral development. Thus, this study screened published literature and identified 162 marine fungus-derived compounds with active bioavailability. Following Lipinski's rules and antiviral property prediction, 41 compounds were selected for docking with NS5 methyltransferase and NS2B/NS3 protease (PDB ID: 6IZZ and 2FOM) to evaluate compounds that could stop the action of dengue viral protein complexes. To find the best candidates, computational ADME, toxicity, and drug target prediction were performed to estimate the potential of the multi-targeting fungal-derived natural compounds. Analyzing the result from 41 compounds, Chevalone E (-13.5 kcal/mol), Sterolic acid (-10.3 kcal/mol) showed higher binding energy against dengue NS2B/NS3 protease; meanwhile, Chevalone E (-12.0 kcal/mol), Brevione K (-7.4 kcal/mol), had greater binding affinity against NS5 methyltransferase. Consequently, this study suggests that Chevalone E is an effective inhibitor of NS5 methyltransferase and NS2B/NS3 protease. Ligand-based virtual screening from DrugBank was utilized to predict biologically active small compounds against dengue virus NS2B/NS3 major protease and NS5 methyltransferase. Both licensed medications, estramustine (DB01196) and quinestrol (DB04575), were found to be similar to Chevalone E, with prediction scores of 0.818 and 0.856, respectively. In addition, cholic acid (DB02659), acitretin (DB00459), and mupirocin (DB00410) are similar to Sterolic acid, zidovudine (DB00495), imipenem (DB01598), and nadolol (DB01203) are similar to Brocazine A, and budesonide (DB01222) and colchicine (DB01394) are related to Brevione K. These findings suggest that these could be feasible dengue virus treatment options, meaning that more research is needed.

Project description:The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and subtropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including processing of 8 of the 13 substrate cleavage sites by dengue virus NS2B/NS3 protease. With no available direct-acting antiviral targeting DENV, NS2/NS3 protease is a promising target for inhibitor design. Current design efforts focus on the nonprime side of the DENV protease active site, resulting in highly hydrophilic and nonspecific scaffolds. However, the prime side also significantly modulates DENV protease binding affinity, as revealed by engineering the binding loop of aprotinin, a small protein with high affinity for DENV protease. In this study, we designed a series of cyclic peptides interacting with both sides of the active site as inhibitors of dengue virus protease. The design was based on two aprotinin loops and aimed to leverage both key specific interactions of substrate sequences and the entropic advantage driving aprotinin's high affinity. By optimizing the cyclization linker, length, and amino acid sequence, the tightest cyclic peptide achieved a Ki value of 2.9 ?M against DENV3 wild-type (WT) protease. These inhibitors provide proof of concept that both sides of DENV protease active site can be exploited to potentially achieve specificity and lower hydrophilicity in the design of inhibitors targeting DENV.IMPORTANCE Viruses of the flaviviral family, including DENV and Zika virus transmitted by Aedes aegypti, continue to be a threat to global health by causing major outbreaks in tropical and subtropical regions, with no available direct-acting antivirals for treatment. A better understanding of the molecular requirements for the design of potent and specific inhibitors against flaviviral proteins will contribute to the development of targeted therapies for infections by these viruses. The cyclic peptides reported here as DENV protease inhibitors provide novel scaffolds that enable exploiting the prime side of the protease active site, with the aim of achieving better specificity and lower hydrophilicity than those of current scaffolds in the design of antiflaviviral inhibitors.

Dataset Information

Computer Aided Screening of Phytochemicals from Garcinia against the Dengue NS2B/NS3 Protease.

Publications

Computer Aided Screening of Phytochemicals from Garcinia against the Dengue NS2B/NS3 Protease.

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