FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4223553248> ?p ?o ?g. }

• W4223553248 endingPage "128732" @default.
• W4223553248 startingPage "128732" @default.
• W4223553248 abstract "In the past two years, the COVID-19 pandemic has caused over 5 million deaths and 250 million infections worldwide. Despite successful vaccination efforts and emergency approval of small molecule therapies, a diverse range of antivirals is still needed to combat the inevitable resistance that will arise from new SARS-CoV-2 variants. The main protease of SARS-CoV-2 (Mpro) is an attractive drug target due to the clinical success of protease inhibitors against other viruses, such as HIV and HCV. However, in order to combat resistance, various chemical scaffolds need to be identified that have the potential to be developed into potent inhibitors. To this end, we screened a high-content protease inhibitor library against Mproin vitro, in order to identify structurally diverse compounds that could be further developed into antiviral leads. Our high-content screening efforts retrieved 27 hits each with > 50% inhibition in our Mpro FRET assay. Of these, four of the top inhibitor compounds were chosen for follow-up due to their potency and drugability (Lipinski's rules of five criteria): anacardic acid, aloesin, aloeresin D, and TCID. Further analysis via dose response curves revealed IC50 values of 6.8 μM, 38.9 μM, 125.3 μM, and 138.0 μM for each compound, respectively. Molecular docking studies demonstrated that the four inhibitors bound at the catalytic active site of Mpro with varying binding energies (-7.5 to -5.6 kcal/mol). Furthermore, Mpro FRET assay kinetic studies demonstrated that Mpro catalysis is better represented by a sigmoidal Hill model than the standard Michaelis-Menten hyperbola, indicating substantial cooperativity of the active enzyme dimer. This result suggests that the dimerization interface could be an attractive target for allosteric inhibitors. In conclusion, we identified two closely-related natural product compounds from the Aloe plant (aloesin and aloeresin D) that may serve as novel scaffolds for Mpro inhibitor design and additionally confirmed the strongly cooperative kinetics of Mpro proteolysis. These results further advance our knowledge of structure-function relationships in Mpro and offer new molecular scaffolds for inhibitor design." @default.
• W4223553248 created "2022-04-15" @default.
• W4223553248 creator A5010372937 @default.
• W4223553248 creator A5030811964 @default.
• W4223553248 creator A5068700897 @default.
• W4223553248 date "2022-06-01" @default.
• W4223553248 modified "2023-09-23" @default.
• W4223553248 title "Identification of Aloe-derived natural products as prospective lead scaffolds for SARS-CoV-2 main protease (Mpro) inhibitors" @default.
• W4223553248 cites W1905435458 @default.
• W4223553248 cites W1968841418 @default.
• W4223553248 cites W1971557089 @default.
• W4223553248 cites W1981737096 @default.
• W4223553248 cites W1991001144 @default.
• W4223553248 cites W2005712012 @default.
• W4223553248 cites W2014529290 @default.
• W4223553248 cites W2019625094 @default.
• W4223553248 cites W2042208119 @default.
• W4223553248 cites W2097136937 @default.
• W4223553248 cites W2131253204 @default.
• W4223553248 cites W2134967712 @default.
• W4223553248 cites W2135732933 @default.
• W4223553248 cites W2142635246 @default.
• W4223553248 cites W2153849867 @default.
• W4223553248 cites W2533210615 @default.
• W4223553248 cites W2797867047 @default.
• W4223553248 cites W2883674917 @default.
• W4223553248 cites W2934863540 @default.
• W4223553248 cites W2999626804 @default.
• W4223553248 cites W3011701533 @default.
• W4223553248 cites W3014684532 @default.
• W4223553248 cites W3021356535 @default.
• W4223553248 cites W3022685474 @default.
• W4223553248 cites W3023894494 @default.
• W4223553248 cites W3026635350 @default.
• W4223553248 cites W3027018705 @default.
• W4223553248 cites W3040116040 @default.
• W4223553248 cites W3041875805 @default.
• W4223553248 cites W3045598552 @default.
• W4223553248 cites W3114991116 @default.
• W4223553248 cites W3127530919 @default.
• W4223553248 cites W3133506477 @default.
• W4223553248 cites W3136968130 @default.
• W4223553248 cites W3141176229 @default.
• W4223553248 cites W3153687839 @default.
• W4223553248 cites W3157429049 @default.
• W4223553248 cites W3158093618 @default.
• W4223553248 cites W3184172540 @default.
• W4223553248 cites W3185558975 @default.
• W4223553248 cites W3194795147 @default.
• W4223553248 cites W3201920406 @default.
• W4223553248 cites W3202496125 @default.
• W4223553248 cites W3204891203 @default.
• W4223553248 cites W3205127490 @default.
• W4223553248 cites W3208802464 @default.
• W4223553248 cites W3209351766 @default.
• W4223553248 cites W3210250692 @default.
• W4223553248 cites W3210498507 @default.
• W4223553248 cites W3210621584 @default.
• W4223553248 cites W3210632115 @default.
• W4223553248 cites W3211279811 @default.
• W4223553248 cites W3211990695 @default.
• W4223553248 cites W3212661334 @default.
• W4223553248 cites W3214909952 @default.
• W4223553248 cites W3215187499 @default.
• W4223553248 cites W3215590980 @default.
• W4223553248 cites W3215863449 @default.
• W4223553248 cites W3217193330 @default.
• W4223553248 cites W3217262353 @default.
• W4223553248 cites W4200590114 @default.
• W4223553248 doi "https://doi.org/10.1016/j.bmcl.2022.128732" @default.
• W4223553248 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35427739" @default.
• W4223553248 hasPublicationYear "2022" @default.
• W4223553248 type Work @default.
• W4223553248 citedByCount "3" @default.
• W4223553248 countsByYear W42235532482022 @default.
• W4223553248 countsByYear W42235532482023 @default.
• W4223553248 crossrefType "journal-article" @default.
• W4223553248 hasAuthorship W4223553248A5010372937 @default.
• W4223553248 hasAuthorship W4223553248A5030811964 @default.
• W4223553248 hasAuthorship W4223553248A5068700897 @default.
• W4223553248 hasBestOaLocation W42235532482 @default.
• W4223553248 hasConcept C104317684 @default.
• W4223553248 hasConcept C181199279 @default.
• W4223553248 hasConcept C185592680 @default.
• W4223553248 hasConcept C202751555 @default.
• W4223553248 hasConcept C2775905019 @default.
• W4223553248 hasConcept C2776714187 @default.
• W4223553248 hasConcept C2777752497 @default.
• W4223553248 hasConcept C41847442 @default.
• W4223553248 hasConcept C55493867 @default.
• W4223553248 hasConcept C57992300 @default.
• W4223553248 hasConcept C70721500 @default.
• W4223553248 hasConcept C86803240 @default.
• W4223553248 hasConcept C98274493 @default.
• W4223553248 hasConceptScore W4223553248C104317684 @default.
• W4223553248 hasConceptScore W4223553248C181199279 @default.
• W4223553248 hasConceptScore W4223553248C185592680 @default.
• W4223553248 hasConceptScore W4223553248C202751555 @default.

• next