Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery [PDF]
Pharmaceuticals, 2022 Fragment based drug discovery has long been used for the identification of new ligands and interest in targeted covalent inhibitors has continued to grow in recent years, with high profile drugs such as osimertinib and sotorasib gaining FDA approval.
Kirsten McAulay +2 more
doaj +7 more sources
Exploration of a 14-3-3 PPI Pocket by Covalent Fragments as Stabilizers [PDF]
ACS Medicinal Chemistry Letters, 2021 The systematic discovery of functional fragments binding to the composite interface of protein complexes is a first critical step for the development of orthosteric stabilizers of protein–protein interactions (PPIs).
Luc Brunsveld +2 more
exaly +8 more sources
Discovery of covalent enzyme inhibitors using virtual docking of covalent fragments [PDF]
Bioorganic and Medicinal Chemistry Letters, 2019 Here we present a virtual docking screen of 1648 commercially available covalent fragments, and identified covalent inhibitors of cysteine protease cathepsin L. These inhibitors did not inhibit closely related protease cathepsin B.
Alexander Statsyuk +2 more
exaly +6 more sources
Functionalized Scout Fragments for Site-Specific Covalent Ligand Discovery and Optimization [PDF]
ACS Central Science, 2021 Covalent ligands are a versatile class of chemical probes and drugs that can target noncanonical sites on proteins and display differentiated pharmacodynamic properties.
Vincent M. Crowley +2 more
doaj +5 more sources
The effective fragment molecular orbital method for fragments connected by covalent bonds. [PDF]
PLoS ONE, 2012 We extend the effective fragment molecular orbital method (EFMO) into treating fragments connected by covalent bonds. The accuracy of EFMO is compared to FMO and conventional ab initio electronic structure methods for polypeptides including proteins ...
Casper Steinmann +2 more
doaj +10 more sources
Covalent tethering of fragments for covalent probe discovery [PDF]
MedChemComm, 2016 Covalent probes and drugs have found widespread use as research tools and clinical agents. Covalent probes are useful because of their increased intracellular potency and because covalent labeling of cellular proteins can be tracked using click chemistry.
Alexander Statsyuk, Stefan Kathman
exaly +4 more sources
Probing the Protein Kinases′ Cysteinome by Covalent Fragments
Angewandte Chemie - International EditionProtein kinases are important drug targets, yet specific inhibitors have been developed for only a fraction of the more than 500 human kinases. A major challenge in designing inhibitors for highly related kinases is selectivity. Unlike their non-covalent
Stefan Knapp +2 more
exaly +5 more sources
A practical method for determining the rate of covalent modification of fragments and leads [PDF]
Nature CommunicationsThe clinical success of covalent drugs such as sotorasib has renewed interest in covalency for rational drug design. The most rigorous potency metric for covalent modifiers is the second-order rate constant k inact /K I.
Janice Jeon +5 more
doaj +4 more sources
Assessment of Tractable Cysteines for Covalent Targeting by Screening Covalent Fragments [PDF]
ChemBioChem, 2020 Targeted covalent inhibition and the use of irreversible chemical probes are important strategies in chemical biology and drug discovery. To date, the availability and reactivity of cysteine residues amenable for covalent targeting have been evaluated by
L. Petri +19 more
semanticscholar +4 more sources
Covalent Fragments Acting as Tyrosine Mimics for Mutant p53-Y220C Rescue by Nucleophilic Aromatic Substitution. [PDF]
ACS Pharmacol Transl SciThe tumor suppressor p53 is frequently mutated in human cancers. The Y220C mutant is the ninth most common p53 cancer mutant and is classified as a structural mutant, as it leads to strong thermal destabilization and degradation by creating a solvent ...
Klett T +8 more
europepmc +2 more sources