Matches in SemOpenAlex for { <https://semopenalex.org/work/W4293793251> ?p ?o ?g. }
- W4293793251 endingPage "4094" @default.
- W4293793251 startingPage "4083" @default.
- W4293793251 abstract "We have used molecular dynamics (MD) simulations with hybrid quantum mechanics/molecular mechanics (QM/MM) potentials to investigate the reaction mechanism for covalent inhibition of cathepsin K and assess the reversibility of inhibition. The computed free energy profiles suggest that a nucleophilic attack by the catalytic cysteine on the inhibitor warhead and proton transfer from the catalytic histidine occur in a concerted manner. The results indicate that the reaction is more strongly exergonic for the alkyne-based inhibitors, which bind irreversibly to cathepsin K, than for the nitrile-based inhibitor odanacatib, which binds reversibly. Gas-phase energies were also calculated for the addition of methanethiol to structural prototypes for a number of warheads of interest in cysteine protease inhibitor design in order to assess electrophilicity. The approaches presented in this study are particularly applicable to assessment of novel warheads, and computed transition state geometries can be incorporated into molecular models for covalent docking." @default.
- W4293793251 created "2022-08-31" @default.
- W4293793251 creator A5005482561 @default.
- W4293793251 creator A5028159090 @default.
- W4293793251 creator A5031776530 @default.
- W4293793251 creator A5039642161 @default.
- W4293793251 creator A5068283947 @default.
- W4293793251 creator A5087137334 @default.
- W4293793251 creator A5091501010 @default.
- W4293793251 date "2022-08-31" @default.
- W4293793251 modified "2023-10-17" @default.
- W4293793251 title "Assessment of Reversibility for Covalent Cysteine Protease Inhibitors Using Quantum Mechanics/Molecular Mechanics Free Energy Surfaces" @default.
- W4293793251 cites W1625910593 @default.
- W4293793251 cites W1976499671 @default.
- W4293793251 cites W1977334898 @default.
- W4293793251 cites W1978363938 @default.
- W4293793251 cites W1984075743 @default.
- W4293793251 cites W1993287695 @default.
- W4293793251 cites W2000401583 @default.
- W4293793251 cites W2004303971 @default.
- W4293793251 cites W2005236619 @default.
- W4293793251 cites W2010654750 @default.
- W4293793251 cites W2010993054 @default.
- W4293793251 cites W2020642787 @default.
- W4293793251 cites W2022558488 @default.
- W4293793251 cites W2029079594 @default.
- W4293793251 cites W2030971294 @default.
- W4293793251 cites W2035495099 @default.
- W4293793251 cites W2039485335 @default.
- W4293793251 cites W2058848030 @default.
- W4293793251 cites W2061532598 @default.
- W4293793251 cites W2064975811 @default.
- W4293793251 cites W2076638844 @default.
- W4293793251 cites W2084257914 @default.
- W4293793251 cites W2093217911 @default.
- W4293793251 cites W2095145098 @default.
- W4293793251 cites W2109154308 @default.
- W4293793251 cites W2111066407 @default.
- W4293793251 cites W2117518744 @default.
- W4293793251 cites W2118233996 @default.
- W4293793251 cites W2124137657 @default.
- W4293793251 cites W2128339707 @default.
- W4293793251 cites W2130752141 @default.
- W4293793251 cites W2162376148 @default.
- W4293793251 cites W2287686703 @default.
- W4293793251 cites W2316509125 @default.
- W4293793251 cites W2322310184 @default.
- W4293793251 cites W2322586343 @default.
- W4293793251 cites W2327581403 @default.
- W4293793251 cites W2330799739 @default.
- W4293793251 cites W2410141289 @default.
- W4293793251 cites W2511955955 @default.
- W4293793251 cites W2518235065 @default.
- W4293793251 cites W2527718275 @default.
- W4293793251 cites W2556724632 @default.
- W4293793251 cites W2566502318 @default.
- W4293793251 cites W2622009965 @default.
- W4293793251 cites W2742611687 @default.
- W4293793251 cites W2748708601 @default.
- W4293793251 cites W2763673935 @default.
- W4293793251 cites W2767459967 @default.
- W4293793251 cites W2769901316 @default.
- W4293793251 cites W2796108867 @default.
- W4293793251 cites W2801332174 @default.
- W4293793251 cites W280973946 @default.
- W4293793251 cites W2889785065 @default.
- W4293793251 cites W2904506792 @default.
- W4293793251 cites W2911268412 @default.
- W4293793251 cites W2914871918 @default.
- W4293793251 cites W2932449756 @default.
- W4293793251 cites W2942419925 @default.
- W4293793251 cites W2964899800 @default.
- W4293793251 cites W2969628133 @default.
- W4293793251 cites W2973195589 @default.
- W4293793251 cites W2981994760 @default.
- W4293793251 cites W2987941122 @default.
- W4293793251 cites W3000643563 @default.
- W4293793251 cites W3009264613 @default.
- W4293793251 cites W3011701533 @default.
- W4293793251 cites W3040116040 @default.
- W4293793251 cites W3090894484 @default.
- W4293793251 cites W3105360998 @default.
- W4293793251 cites W3111742605 @default.
- W4293793251 cites W3127215132 @default.
- W4293793251 cites W3127766909 @default.
- W4293793251 cites W3130333735 @default.
- W4293793251 cites W3154863304 @default.
- W4293793251 cites W3189646261 @default.
- W4293793251 cites W3197312055 @default.
- W4293793251 cites W3204146108 @default.
- W4293793251 cites W4280544645 @default.
- W4293793251 doi "https://doi.org/10.1021/acs.jcim.2c00466" @default.
- W4293793251 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36044342" @default.
- W4293793251 hasPublicationYear "2022" @default.
- W4293793251 type Work @default.
- W4293793251 citedByCount "5" @default.
- W4293793251 countsByYear W42937932512022 @default.
- W4293793251 countsByYear W42937932512023 @default.