FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3196353982> ?p ?o ?g. }

• W3196353982 abstract "The phosphatidylinostitol-3-kinase (PI3K)/AKT/mammalian target of rapamycin signaling pathway is a vital regulator of cell proliferation, growth, and survival, which is frequently overactivated in many human cancers. To this effect, PI3K, which is an important mediator of this pathway, has been pinpointed as a crucial target in cancer therapy and hence the importance of PI3K inhibitors. It was recently reported that defluorination and pyridine-to-pyrimidine ring interconversion increase the potency of specific small-molecule inhibitors of PI3K. Compound 4, an inhibitor with the difluorinated pyrimidine motif, was found to be eight times more potent against PI3K than compound 1, an inhibitor with the trifluorinated pyridine motif. This observation presents the need to rationally resolve the differential inhibitory mechanisms exhibited by both compounds. In this present work, we employed multiple computational approaches to investigate and distinguish the binding modes of 1 and 4 in addition to the effects they mediate on the secondary structure of PI3K. Likewise, we evaluated two other derivatives, compounds 2 with the difluorinated pyridine motif and 3 with the trifluorinated pyrimidine motif, to investigate the cooperativity effect between the defluorination of CF3 and pyridine-to-pyrimidine ring interconversion. Findings revealed that PI3K, upon interaction with 4, exhibited a series of structural changes that favored the binding of the inhibitor at the active-site region. Furthermore, a positive (synergistic) cooperativity effect was observed between CF3 defluorination and pyridine-to-pyrimidine ring interconversion. Moreover, there was a good correlation between the binding free energy estimated and the biological activity reported experimentally. Energy decomposition analysis revealed that the major contributing force to binding affinity variations between 1 and 4 is the electrostatic energy. Per-residue energy-based hierarchical clustering analysis further identified four hot-spot residues ASP841, TYR867, ASP964, and LYS833 and four warm-spot residues ASP836, SER806, ASP837, and LYS808, which essentially mediate the optimal and higher-affinity binding of compound 4 to PI3K relative to 1. This study therefore provides rational insights into the mechanisms by which 4 exhibited superior PI3K-inhibitory activities over 1, which is vital for future structure-based drug discovery efforts in PI3K targeting." @default.
• W3196353982 created "2021-09-13" @default.
• W3196353982 creator A5001213347 @default.
• W3196353982 creator A5042702055 @default.
• W3196353982 creator A5088017580 @default.
• W3196353982 date "2021-09-02" @default.
• W3196353982 modified "2023-09-23" @default.
• W3196353982 title "Molecular Mechanism Exploration of Potent Fluorinated PI3K Inhibitors with a Triazine Scaffold: Unveiling the Unusual Synergistic Effect of Pyridine-to-Pyrimidine Ring Interconversion and CF3 Defluorination" @default.
• W3196353982 cites W1587176568 @default.
• W3196353982 cites W1973266090 @default.
• W3196353982 cites W1976499671 @default.
• W3196353982 cites W1977267072 @default.
• W3196353982 cites W1978981032 @default.
• W3196353982 cites W1979309900 @default.
• W3196353982 cites W1979915001 @default.
• W3196353982 cites W1981711832 @default.
• W3196353982 cites W1985915253 @default.
• W3196353982 cites W1991741354 @default.
• W3196353982 cites W1999800992 @default.
• W3196353982 cites W2006771504 @default.
• W3196353982 cites W2016381774 @default.
• W3196353982 cites W2024553805 @default.
• W3196353982 cites W2029161305 @default.
• W3196353982 cites W2035266068 @default.
• W3196353982 cites W2037535298 @default.
• W3196353982 cites W2042464370 @default.
• W3196353982 cites W2043666236 @default.
• W3196353982 cites W2057370954 @default.
• W3196353982 cites W2065283382 @default.
• W3196353982 cites W2072683434 @default.
• W3196353982 cites W2090033012 @default.
• W3196353982 cites W2093381148 @default.
• W3196353982 cites W2094860818 @default.
• W3196353982 cites W2100251789 @default.
• W3196353982 cites W2105103540 @default.
• W3196353982 cites W2106140689 @default.
• W3196353982 cites W2107063279 @default.
• W3196353982 cites W2109027353 @default.
• W3196353982 cites W2124967403 @default.
• W3196353982 cites W2129172946 @default.
• W3196353982 cites W2132629607 @default.
• W3196353982 cites W2144288821 @default.
• W3196353982 cites W2147993766 @default.
• W3196353982 cites W2148181778 @default.
• W3196353982 cites W2148267502 @default.
• W3196353982 cites W2158534713 @default.
• W3196353982 cites W2159367911 @default.
• W3196353982 cites W2208895751 @default.
• W3196353982 cites W2313116527 @default.
• W3196353982 cites W2321766973 @default.
• W3196353982 cites W2332712348 @default.
• W3196353982 cites W2334483166 @default.
• W3196353982 cites W2550870820 @default.
• W3196353982 cites W2594226370 @default.
• W3196353982 cites W2600623446 @default.
• W3196353982 cites W2618283547 @default.
• W3196353982 cites W2744377419 @default.
• W3196353982 cites W2750423398 @default.
• W3196353982 cites W2782438044 @default.
• W3196353982 cites W2785390464 @default.
• W3196353982 cites W2793665794 @default.
• W3196353982 cites W2801026274 @default.
• W3196353982 cites W2906375925 @default.
• W3196353982 cites W2906821479 @default.
• W3196353982 cites W2917344804 @default.
• W3196353982 cites W2923057410 @default.
• W3196353982 cites W2954094311 @default.
• W3196353982 cites W2955490639 @default.
• W3196353982 cites W2971466226 @default.
• W3196353982 cites W2972166846 @default.
• W3196353982 cites W2976922696 @default.
• W3196353982 cites W2980063489 @default.
• W3196353982 cites W3040407283 @default.
• W3196353982 cites W3047584373 @default.
• W3196353982 cites W641802818 @default.
• W3196353982 doi "https://doi.org/10.1021/acs.jpcb.1c03242" @default.
• W3196353982 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34473499" @default.
• W3196353982 hasPublicationYear "2021" @default.
• W3196353982 type Work @default.
• W3196353982 sameAs 3196353982 @default.
• W3196353982 citedByCount "3" @default.
• W3196353982 countsByYear W31963539822023 @default.
• W3196353982 crossrefType "journal-article" @default.
• W3196353982 hasAuthorship W3196353982A5001213347 @default.
• W3196353982 hasAuthorship W3196353982A5042702055 @default.
• W3196353982 hasAuthorship W3196353982A5088017580 @default.
• W3196353982 hasConcept C107824862 @default.
• W3196353982 hasConcept C155647269 @default.
• W3196353982 hasConcept C166014724 @default.
• W3196353982 hasConcept C185592680 @default.
• W3196353982 hasConcept C187250156 @default.
• W3196353982 hasConcept C21951064 @default.
• W3196353982 hasConcept C2779321679 @default.
• W3196353982 hasConcept C2779485729 @default.
• W3196353982 hasConcept C55493867 @default.
• W3196353982 hasConcept C62478195 @default.
• W3196353982 hasConcept C71240020 @default.
• W3196353982 hasConcept C86554907 @default.
• W3196353982 hasConceptScore W3196353982C107824862 @default.
• W3196353982 hasConceptScore W3196353982C155647269 @default.

• next