5znl
From Proteopedia
Crystal structure of PDE10A catalytic domain complexed with LHB-6
Structural highlights
FunctionPDE10_HUMAN Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.[1] Publication Abstract from PubMedAccurate prediction of absolute protein-ligand binding free energy could considerably enhance the success rate of structure-based drug design but is extremely challenging and time-consuming. Free energy perturbation (FEP) has been proven reliable but is limited to prediction of relative binding free energies of similar ligands (with only minor structural differences) in binding with a same drug target in practical drug design applications. Herein, a Gaussian algorithm-enhanced FEP (GA-FEP) protocol has been developed to enhance the FEP simulation performance, enabling to efficiently carry out the FEP simulations on vanishing the whole ligand and, thus, predict the absolute binding free energies (ABFEs). Using the GA-FEP protocol, the FEP simulations for the ABFE calculation (denoted as GA-FEP/ABFE) can achieve a satisfactory accuracy for both structurally similar and diverse ligands in a dataset of more than 100 receptor-ligand systems. Further, our GA-FEP/ABFE-guided lead optimization against phosphodiesterase-10 led to the discovery of a subnanomolar inhibitor (IC50 = 0.87 nM, approximately 2000-fold improvement in potency) with cocrystal confirmation. Absolute Binding Free Energy Calculation and Design of a Subnanomolar Inhibitor of Phosphodiesterase-10.,Li Z, Huang Y, Wu Y, Chen J, Wu D, Zhan CG, Luo HB J Med Chem. 2019 Feb 12. doi: 10.1021/acs.jmedchem.8b01763. PMID:30689375[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Huang Y | Li Z | Luo HB | Zhan CG