Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Structural and Computational Insights into the Mechanism of the Superior Pharmacological Activity of Crisugabalin: A Third-Generation Cavαδ1 Ligand.
Journal, issue, pages	J Chem Inf Model, Vol. 66, Issue 1, Page 632-641, Year 2026
Publish date	Dec 24, 2025
Authors	Zhaoqiang Chen / Xiaoli Gou / Qingyuan Meng / He Li / Yao Li / Zongjun Shi / Xinxin Li / Ju Wang /
PubMed Abstract	Crisugabalin, a recently approved third-generation GABA analogue with a unique cage-like tricyclic scaffold, shows superior efficacy and safety over pregabalin and mirogabalin for treating ...Crisugabalin, a recently approved third-generation GABA analogue with a unique cage-like tricyclic scaffold, shows superior efficacy and safety over pregabalin and mirogabalin for treating neuropathic pain. Through integrated biophysical, structural, and computational approaches, we elucidate the molecular basis of its enhanced pharmacological profile. Dissociation kinetic studies revealed that crisugabalin exhibited the slowest dissociation kinetics from the αδ1 subunit (τ = 32.05, 80.00, 111.11 min for pregabalin, mirogabalin, and crisugabalin) but the fastest dissociation from the αδ2 subunit (τ = 8.70, 16.39, 5.78 min for pregabalin, mirogabalin, and crisugabalin). Cryo-EM structures demonstrated crisugabalin's superior binding affinity for αδ1 over gabapentin and l-leucine, driven by enhanced hydrogen bonding and hydrophobic contacts, alongside volumetric expansion of the l-leucine binding pocket. Molecular dynamics (MD) simulations identified significantly more persistent hydrogen bonding by crisugabalin (66.3% average occupancy) relative to pregabalin (28.3%). Random Acceleration Molecular Dynamics (RAMD) simulations revealed that ligand dissociation primarily proceeds via Pathway A (along the β2, β3, and β1 segments), and τRAMD calculations correctly ranked the ligand residence times, yielding values of 0.18 ns for pregabalin and 2.88 ns for crisugabalin. Furthermore, the binding free energies for pregabalin, mirogabalin, and crisugabalin were -21.64, -31.30, and -34.99 kcal/mol, calculated by MM/GBSA. The decomposition of the binding free energy components revealed that crisugabalin exhibits a dual-action mechanism characterized by enhanced hydrophobic interactions (-28.46 kcal/mol) and favorable entropic contributions (3.03 kcal/mol). This unique binding behavior stems from its cage-like tricyclic scaffold, an unprecedented substructure in drug molecules. These findings establish the cage-like tricyclic motif as a novel pharmacophore that simultaneously optimizes binding entropy and enthalpy, providing a blueprint for next-generation voltage-gated calcium channel modulators. MD, τRAMD, and MM-GBSA used in this study are powerful computational tools for rational drug design, particularly for optimizing compounds with prolonged target residence times.
External links	J Chem Inf Model / PubMed:41439594 / PubMed Central
Methods	EM (single particle)
Resolution	3.01 Å
Structure data	65160 9vlg EMDB-65160, PDB-9vlg: Structure of human alpha-2/delta-1 with crisugabalin Method: EM (single particle) / Resolution: 3.01 Å
Chemicals	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose PDB-1esq: CRYSTAL STRUCTURE OF THIAZOLE KINASE MUTANT (C198S) WITH ATP AND THIAZOLE PHOSPHATE.
Source	homo sapiens (human)
Keywords	MEMBRANE PROTEIN / Complex / Alpha-2/delta-1 / Crisugabalin