Structure-Based Discovery of Anti-Viral Compounds for Hepatitis B &amp; C, Human Immunodeficiency, and Dengue Viruses

Velmurugan, D.; Selvi, Udhayasuriyan Malar; Udhayakumar, Mythily; Rao, K. R. Ranga; Rajarajeshwari, Ramaiah; Sangeetha, V.

doi:10.2174/157489312800604462

Cited by 10 publications

(6 citation statements)

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“…It was concluded that all the screened triterpenoids displayed hydrogen bonding with NS3pro at the catalytic triad (His51, Asp75, and Ser135 residue), along with some other conserved residues (Phe130, Tyr150, Asn152 and Gly153) which have been reported to play a significant role in substrate binding for DENV protease 43,44 . Besides, some additional residues were also logged for sharing hydrogen bonds with different ligands.…”

Section: Resultsmentioning

confidence: 99%

“…These observations suggest that hydrogen bonds between a ligand and one of the catalytic triad residues of NS3pro can disturb the electron transfer between the carboxyl and imidazole groups of the Asp75 and His51 residues, respectively. Such a disturbance has been reported to lead to an abortive nucleophilic attack of the hydroxyl group (ß-OH) of residue Ser135, which is essential for initiating proteolytic activity 43,44 . Hence, it was concluded that the screened triterpenoids may displayed strong affinity towards the NS3pro domain of DENV through various intermolecular interactions and suggested that they could act as drugs against DENV infection through NS2B-NS3pro inhibition.…”

Section: Resultsmentioning

confidence: 99%

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Discovery of Ganoderma lucidum triterpenoids as potential inhibitors against Dengue virus NS2B-NS3 protease

Bharadwaj

Lee

Dwivedi³

et al. 2019

Sci Rep

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Dengue virus (DENV) infection causes serious health problems in humans for which no drug is currently available. Recently, DENV NS2B-NS3 protease has been proposed as a primary target for anti-dengue drug discovery due to its important role in new virus particle formation by conducting DENV polyprotein cleavage. Triterpenoids from the medicinal fungus Ganoderma lucidum have been suggested as pharmacologically bioactive compounds and tested as anti-viral agents against various viral pathogens including human immunodeficiency virus. However, no reports are available concerning the anti-viral activity of triterpenoids from Ganoderma lucidum against DENV. Therefore, we employed a virtual screening approach to predict the functional triterpenoids from Ganoderma lucidum as potential inhibitors of DENV NS2B-NS3 protease, followed by an in vitro assay. From in silico analysis of twenty-two triterpenoids of Ganoderma lucidum, four triterpenoids, viz. Ganodermanontriol (−6.291 kcal/mol), Lucidumol A (−5.993 kcal/mol), Ganoderic acid C2 (−5.948 kcal/mol) and Ganosporeric acid A (−5.983 kcal/mol) were predicted to be viral protease inhibitors by comparison to reference inhibitor 1,8-Dihydroxy-4,5-dinitroanthraquinone (−5.377 kcal/mol). These results were further studied for binding affinity and stability using the molecular mechanics/generalized Born surface area method and Molecular Dynamics simulations, respectively. Also, in vitro viral infection inhibition suggested that Ganodermanontriol is a potent bioactive triterpenoid.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Discovery of Ganoderma lucidum triterpenoids as potential inhibitors against Dengue virus NS2B-NS3 protease

Bharadwaj

Lee

Dwivedi³

et al. 2019

Sci Rep

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“…Mollugin has been noticed showing anti-Hepatitis C virus (HCV) activity 9 and HCV is known to transfer via transfusion and community-acquired infection. It is also known that 20% of the infected patients develop acute hepatitis and about 80% suffered by chronic hepatitis lead into liver cirrhosis or liver cancer.…”

Section: Resultsmentioning

confidence: 99%

Facile Synthesis of Mollugin by Kinetic Control and anti-HCV (Hepatitis C Virus) Activity of Its Analogues

Kim¹,

Kim²,

Lee³

et al. 2014

Bulletin of the Korean Chemical Society

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Mollugin has been reported to have various biological activities including antineoplastic, antitumor, antiviral against the hepatitis B virus, anti-aging and antimutagenic activities. An effective and concise synthesis of mollugin in two steps including kinetic control from the cheap starting material 1,4-naphthoquinone has been introduced, and mollugin derivatives thus prepared are screened for their inhibition ability against the hepatitis C virus (HCV) and the dihydrobenzochromene structure might be an additional anti-HCV agent as a new leading compound.

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“…The 3D structure of the target protein in complex with the proposed lead molecule is compared with its apo form (PDB ID 4HHJ) [27]. The lead molecule induces several conformational changes in the drug target DV RdRp.…”

Section: Conformational Changes Induced By Lead Moleculesmentioning

confidence: 99%

“…This changes the conformation and by which impairs the enzymatic activity of the protein [27]. NITD-2 and NITD107 were identified as the NNIs of DV RdRp (Niyomrattanakit et Celgosivir is a host alpha-glucosidase inhibitor, and in clinical studies, it was found to be a safe and well tolerated drug.…”

Section: Introductionmentioning

confidence: 99%

Identification of dengue viral RNA-dependent RNA polymerase inhibitor using computational fragment-based approaches and molecular dynamics study

Shanmugam

Velmurugan

Gromiha

2015

Journal of Biomolecular Structure and Dynamics

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Dengue is a major public health concern in tropical and subtropical countries of the world. There are no specific drugs available to treat dengue. Even though several candidates targeted both viral and host proteins to overcome dengue infection, they have not yet entered into the later stages of clinical trials. In order to design a drug for dengue fever, newly emerged fragment-based drug designing technique was applied. RNA-dependent RNA polymerase, which is essential for dengue viral replication is chosen as a drug target for dengue drug discovery. A cascade of methods, fragment screening, fragment growing, and fragment linking revealed the compound [2-(4-carbamoylpiperidin-1-yl)-2-oxoethyl]8-(1,3-benzothiazol-2-yl)naphthalene-1-carboxylate as a potent dengue viral polymerase inhibitor. Both strain energy and binding free energy calculations predicted that this could be a better inhibitor than the existing ones. Molecular dynamics simulation studies showed that the dengue polymerase-lead complex is stable and their interactions are consistent throughout the simulation. The hydrogen-bonded interactions formed by the residues Arg792, Thr794, Ser796, and Asn405 are the primary contributors for the stability and the rigidity of the polymerase-lead complex. This might keep the polymerase in closed conformation and thus inhibits viral replication. Hence, this might be a promising lead molecule for dengue drug designing. Further optimization of this lead molecule would result in a potent drug for dengue.

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Structure-Based Discovery of Anti-Viral Compounds for Hepatitis B & C, Human Immunodeficiency, and Dengue Viruses

Cited by 10 publications

References 0 publications

Discovery of Ganoderma lucidum triterpenoids as potential inhibitors against Dengue virus NS2B-NS3 protease

Discovery of Ganoderma lucidum triterpenoids as potential inhibitors against Dengue virus NS2B-NS3 protease

Facile Synthesis of Mollugin by Kinetic Control and anti-HCV (Hepatitis C Virus) Activity of Its Analogues

Identification of dengue viral RNA-dependent RNA polymerase inhibitor using computational fragment-based approaches and molecular dynamics study

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