Fan H
Recent Advances in Structure, Function, and Pharmacology of Class A Lipid GPCRs: Opportunities and Challenges for Drug Discovery
Keywords: lipid GPCR; ligand access; orthosteric and allosteric binding sites; drug discovery; antibody; computational methods; prostaglandin receptor; platelet-activating factor receptor; sphingosine-1-phosphate receptor; lysophosphatidic acid receptor; leukotriene receptor; free fatty acid receptor; cannabinoid receptor
ReadMolecular basis for lipid recognition by the prostaglandin D2 receptor CRTH2
Prostaglandin D2 (PGD2) signals through the G protein-coupled receptor (GPCR) CRTH2 to mediate various inflammatory responses. CRTH2 is the only member of the prostanoid receptor family that is phylogenetically distant from others, implying a nonconserved mechanism of lipid action on CRTH2.
ReadInfigratinib is a Reversible Inhibitor and Mechanism-based Inactivator of Cytochrome P450 3A4
Infigratinib (INF) is a promising selective inhibitor of fibroblast growth factor receptors 1-3 that has recently been accorded both orphan drug designation and priority review status by the U.S Food and Drug Administration for the treatment of advanced cholangiocarcinoma.
ReadDifferential Reversible and Irreversible Interactions between Benzbromarone and Human Cytochrome P450s 3A4 and 3A5
Mounting evidence have revealed that despite the high degree of sequence homology between cytochrome P450 3A isoforms (i.e. CYP3A4 and CYP3A5), they have the propensities to exhibit vastly different irreversible and reversible interactions with a single substrate. We have previously established that benzbromarone (BBR), a potent uricosuric agent utilized in the management of gout, irreversibly inhibits CYP3A4 via mechanism-based inactivation (MBI).
ReadStructure-based virtual screening of CYP1A1 inhibitors: towards rapid tier-one assessment of potential developmental toxicants
Cytochrome P450 1A1 (CYP1A1) metabolizes estrogens, melatonin, and other key endogenous signaling molecules critical for embryonic/fetal development. The enzyme has increasing expression during pregnancy, and its inhibition or knockout increases embryonic/fetal lethality and/or developmental problems.
ReadThe Stability of R-spine Defines RAF Inhibitor Resistance: A Comprehensive Analysis of Oncogenic BRAF Mutants with In-frame Insertion of αC-β4 loop
Although targeting BRAF mutants with RAF inhibitors has achieved promising outcomes in cancer therapy, drug resistance remains a remarkable challenge, and underlying molecular mechanisms are not fully understood. Here, we characterized a previously unknown group of oncogenic BRAF mutants with in-frame insertions (LLRins506 or VLRins506) of αC-β4 loop.
ReadAtypical kinetics of cytochrome P450 2J2: epoxidation of arachidonic acid and reversible inhibition by xenobiotic inhibitors
Extrahepatic CYP2J2 metabolism of arachidonic acid (AA) to bioactive regioisomeric epoxyeicosatrienoic acids (EETs) is implicated in both physiological and pathological conditions. Here, we aimed to characterize atypical substrate inhibition kinetics of this endogenous metabolic pathway and its reversible inhibition by xenobiotic inhibitors when AA is used as the physiologically-relevant substrate vis-à-vis conventional probe substrate astemizole (AST).
ReadMolecular docking-aided identification of novel small molecule inhibitors targeting the β-catenin-TCF4 interaction
Here we report a molecular docking-based approach to identify small molecules that can target the β-catenin (β-cat)-TCF4 protein-protein interaction (PPI), a key effector complex for nuclear Wnt signaling activity.
Read