5ZNL

Crystal structure of PDE10A catalytic domain complexed with LHB-6

Summary for 5ZNL

• Entry DOI: 10.2210/pdb5znl/pdb
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: pde10a inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 75896.71

Authors

Li, Z.,Huang, Y.,Zhan, C.G.,Luo, H.B. (deposition date: 2018-04-09, release date: 2019-02-20, Last modification date: 2023-11-22)

Primary citation

Li, Z.,Huang, Y.,Wu, Y.,Chen, J.,Wu, D.,Zhan, C.G.,Luo, H.B.
Absolute Binding Free Energy Calculation and Design of a Subnanomolar Inhibitor of Phosphodiesterase-10.
J. Med. Chem., 62:2099-2111, 2019

PubMed Abstract: Accurate 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 (IC = 0.87 nM, ∼2000-fold improvement in potency) with cocrystal confirmation.

PubMed: 30689375
DOI: 10.1021/acs.jmedchem.8b01763

Experimental method

X-RAY DIFFRACTION (2.8 Å)