“…In general, it was observed that compounds having p -nitro functionality at the benzylidene moiety played an essential role in bonding with the catalytic triad due to its polar nature. The results of the in vitro study are in consistent with our docking studies and the previous findings which confirm the positive influence of the nitro group on the phenyl ring20, 21. The overall results indicate strong inhibitory activities of 3,5-bis(arylidene)-4-piperidones against NS2B-NS3 dengue protease.Figure 4Dose response curves of some selected compounds on NS2B/NS3 proteases.…”
Dengue is a severe mosquito-borne viral infection causing half a million deaths annually. Dengue virus NS2B/NS3 protease is a validated target for anti-dengue drug design. A series of hitherto unreported 3,5-bis(arylidene)-4-piperidones analogues 4a—4j were synthesized and screened in silico against DENV2 NS2B/NS3 protease to elucidate their binding mechanism and orientation around the active sites. Results were validated through an in vitro DENV2 NS2B/NS3 protease assay using a fluorogenic Boc-Gly-Arg-Arg-AMC substrate. Nitro derivatives of 3,5-bis(arylidene)-4-piperidones (4e and 4j) emerged as promising lead molecules for novel protease inhibitors with an IC50 of 15.22 and 16.23 µmol/L, respectively, compared to the standard, panduratin A, having IC50 of 57.28 µmol/L.
“…In general, it was observed that compounds having p -nitro functionality at the benzylidene moiety played an essential role in bonding with the catalytic triad due to its polar nature. The results of the in vitro study are in consistent with our docking studies and the previous findings which confirm the positive influence of the nitro group on the phenyl ring20, 21. The overall results indicate strong inhibitory activities of 3,5-bis(arylidene)-4-piperidones against NS2B-NS3 dengue protease.Figure 4Dose response curves of some selected compounds on NS2B/NS3 proteases.…”
Dengue is a severe mosquito-borne viral infection causing half a million deaths annually. Dengue virus NS2B/NS3 protease is a validated target for anti-dengue drug design. A series of hitherto unreported 3,5-bis(arylidene)-4-piperidones analogues 4a—4j were synthesized and screened in silico against DENV2 NS2B/NS3 protease to elucidate their binding mechanism and orientation around the active sites. Results were validated through an in vitro DENV2 NS2B/NS3 protease assay using a fluorogenic Boc-Gly-Arg-Arg-AMC substrate. Nitro derivatives of 3,5-bis(arylidene)-4-piperidones (4e and 4j) emerged as promising lead molecules for novel protease inhibitors with an IC50 of 15.22 and 16.23 µmol/L, respectively, compared to the standard, panduratin A, having IC50 of 57.28 µmol/L.
“…[77] NMR spectroscopic studies of NS2B-NS3r evealed that bovine pancreatic trypsin inhibitor (BPTI)a nd a p-guanidinobenzoyl group induce ac onformational change in NS2B-NS3 from the inactive "open state" to the active "closed state" form. [3] Amongt hese compounds, 39 was found to be the most potent against DENV-2 NS2B-NS3 (IC 50 = 1.2 mm). [79] This finding suggestst hat ac yclic inhibitorm ay fit well into the binding pocket and block the active site of NS2B-NS3 protease.…”
Section: Imidazolidinones Against Dengue Virusmentioning
confidence: 98%
“…The virus then undergoes maturationv ia post-translational modifications, and finally,r eleaseo fm ature virionso ccurs by exocytosis. [3] Thep yrrolidino [1,2c]imidazolidinone moiety is av ery stable fused bicyclic structure. Hence, it is an attractive target for anti-dengue virus drug development.…”
Section: Imidazolidinones Against Dengue Virusmentioning
confidence: 99%
“…[75] NS2B-NS3 proteasei se ssential for the maturation and pathogenesis of dengue virus. [3] In the low-energy conformation,compound 39 is close to the catalytic pocket (His51, Asp75,a nd Ser135) of NS2B-NS3 protease. [77] NMR spectroscopic studies of NS2B-NS3r evealed that bovine pancreatic trypsin inhibitor (BPTI)a nd a p-guanidinobenzoyl group induce ac onformational change in NS2B-NS3 from the inactive "open state" to the active "closed state" form.…”
Section: Imidazolidinones Against Dengue Virusmentioning
confidence: 99%
“…[78] Wang and co-workersd iscovered that an eight-residue cyclic peptide (compound 36)f ormed by disulfide bond enhances the inhibitory activity against NS2B-NS3. [3] An ew nonpeptide compound for the inhibition of DENV-2 capsid protein was thus discovered. Peptides are susceptible to hydrolysis by proteolytic enzymes.…”
Section: Imidazolidinones Against Dengue Virusmentioning
Imidazolidinones and imidazolidine‐2,4‐diones are important classes of heterocyclic compounds that possess potent activities against several viruses such as dengue virus, enterovirus, hepatitis C virus (HCV), and human immunodeficiency virus (HIV). The first imidazolidinone derivative as an anti‐HIV agent was reported in 1996. Imidazolidinones inhibit HIV aspartic protease activity, and also act as CCR5 co‐receptor antagonists. Significant effort has been devoted to the design of various imidazolidinone analogues that are active against drug‐resistant HIV strains, with fewer side effects. Different scaffolds have been designed through both rational drug design strategies and computer‐aided drug design. Imidazolidinones have been found to be potent against HIV, and preclinical studies are currently in progress. There are some reports of imidazolidinones as having both anti‐HCV and anti‐dengue virus activity, and more research has yet to be done along these lines. These compounds inhibit NS3 serine protease of HCV, and NS2B‐NS3 protease of dengue virus. Pyridyl‐imidazolidinones possess very specific and potent activity against human enterovirus 71 (EV71) by targeting the EV71 capsid protein VP1, and inhibiting viral adsorption and/or viral RNA uncoating.
Dengue fever is a neglected vector‐borne disease and is more prevalent in Asia. Currently, no specific treatment is available. Given the time and cost of de novo drug discovery and development, an alternative option of drug repurposing is becoming an effective tool. We screened a library of 1127 pharmacologically active, metabolically stable, and structurally diverse small anticancer molecules to identify inhibitors of the dengue virus (DENV) NS2B/NS3 protease. Enzyme kinetics and inhibition data revealed four B‐cell lymphoma 2 inhibitors, that is, ABT263, ABT737, AT101, and TW37, as potent inhibitors of DENV NS2B/NS3 protease, with IC50 values of 0.86, 1.15, 0.81, and 0.89 µM, respectively. Mode of inhibition experiments and computational docking analyses indicated that ABT263 and ABT737 are competitive inhibitors, whereas AT101 and TW37 are noncompetitive inhibitors of the protease. With further evaluation, the identified inhibitors of the DENV NS2B/NS3 protease have the potential to be developed into specific anti‐dengue therapeutics.
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