Crystal-guided computational profiling of dichlorophenyl-piperazine ligands as JNK3 binders: Hydrophobic interaction-driven design for neurodegenerative therapy

Harish, Keshav Kumar and Swamynayaka, Ananda and Nagaraja, Omantheswara and Haruvegowda, Doreswamy B. and Vahini M, Vindu and Vishwanath, Divakar and Basappa, Basappa and Dukanya, Dukanya and Madegowda, Mahendra (2026) Crystal-guided computational profiling of dichlorophenyl-piperazine ligands as JNK3 binders: Hydrophobic interaction-driven design for neurodegenerative therapy. Journal of Molecular Structure, 1351. p. 144361. ISSN 0022-2860

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Abstract

The present work reported a comprehensive structural, electronic, and biological evaluation of two novel heterocyclic compounds, KDM1 and KDM2, featuring a 2,3-dichlorophenyl piperazine moiety, as c-Jun N-terminal kinase 3 (JNK3) binders with potential applications in treating neurodegenerative and neuroinflammatory disorders. Single-crystal X-ray diffraction confirmed the crystallization of KDM1 in the orthorhombic Pbca space group and KDM2 in the monoclinic C2/c space group. Both structures exhibited prominent hydrogen-bonding and halogen-mediated supramolecular networks. Quantum Theory of Atoms in Molecules (QTAIM) and Non-Covalent Interaction (NCI) analyses revealed that weak van der Waals forces. Density Functional Theory (DFT) computations provided insights into the electronic properties, highlighting the chemical stability and intramolecular delocalization within each compound. Molecular docking studies indicated strong binding affinity of KDM1 and KDM2 to the JNK3 active site, largely driven by hydrophobic and van der Waals interactions within the ATP-binding cleft. Molecular dynamics (MD) simulations further validated the stability of the ligand–JNK3 complexes, with root mean square deviation (RMSD), root mean square fluctuation (RMSF), solvent-accessible surface area (SASA), and radius of gyration analyses confirming minimal structural deviation. MM-GBSA free energy calculations supported the thermodynamic favorability of ligand binding. Comparative MD simulations with apo-JNK3 reinforced the role of the ligands in stabilizing the enzyme structure. ADME profiling indicated favorable pharmacokinetic properties for both compounds. Overall, this multistage investigation underscores the therapeutic potential of KDM1 and KDM2 as JNK3 binders and offers molecular-level insights into their supramolecular behavior, guiding the design of next-generation neuro-protective agents.

Item Type:	Article
Uncontrolled Keywords:	Crystal structure, Piperazine, Neurodegeneration, Density functional theory, simulations, MM-GBSA, Non-covalent interactions
Subjects:	C Chemical Science > Chemistry
Divisions:	Department of > Chemistry
Depositing User:	C Swapna Library Assistant
Date Deposited:	12 Nov 2025 05:17
Last Modified:	12 Nov 2025 05:17
URI:	http://eprints.uni-mysore.ac.in/id/eprint/17909

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