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Integrated structure-based and fragment-guided design of isonicotinic acid derivatives as potential KDM4A inhibitors: an in silico study.

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Τίτλος: Integrated structure-based and fragment-guided design of isonicotinic acid derivatives as potential KDM4A inhibitors: an in silico study.
Συγγραφείς: Eslami K; Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran., Sirous H; Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran. h_sirous@pharm.mui.ac.ir., Cursaro I; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy., Milioni L; Department of Medical Biotechnologies, University of Siena, Viale Mario Bracci 16, 53100, Siena, Italy., Shafiee F; Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran.; Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran., Carullo G; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy., Gemma S; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy., Rajabi S; Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran., Campiani G; Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran.; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy., Calderone V; Department of Pharmacy, University of Pisa, Via Bonanno 6, I-56126, Pisa, Italy., Brogi S; Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran. simone.brogi@unipi.it.; Department of Pharmacy, University of Pisa, Via Bonanno 6, I-56126, Pisa, Italy. simone.brogi@unipi.it.
Πηγή: Journal of computer-aided molecular design [J Comput Aided Mol Des] 2026 Jun 29; Vol. 40 (1). Date of Electronic Publication: 2026 Jun 29.
Τύπος έκδοσης: Journal Article; Research Support, Non-U.S. Gov't
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Springer Country of Publication: Netherlands NLM ID: 8710425 Publication Model: Electronic Cited Medium: Internet ISSN: 1573-4951 (Electronic) Linking ISSN: 0920654X NLM ISO Abbreviation: J Comput Aided Mol Des Subsets: MEDLINE
Imprint Name(s): Publication: Amsterdam : Springer
Original Publication: Leiden, The Netherlands : ESCOM, [c1987-
Ιατρικοί όροι (MeSH): Jumonji Domain-Containing Histone Demethylases*/antagonists & inhibitors , Jumonji Domain-Containing Histone Demethylases*/chemistry , Isonicotinic Acids*/chemistry , Isonicotinic Acids*/pharmacology , Enzyme Inhibitors*/chemistry , Enzyme Inhibitors*/pharmacology , Drug Design*, Molecular Dynamics Simulation ; Molecular Docking Simulation ; Humans ; Structure-Activity Relationship ; Catalytic Domain
Περίληψη: Lysine-specific demethylase 4 A (KDM4A) is an Fe2+-dependent epigenetic regulator implicated in various cancers, representing an emerging target for anticancer drug development. However, the high polarity of its catalytic pocket poses a significant challenge in designing potent small-molecule inhibitors. In this study, a structure-based virtual screening workflow was implemented to optimize the known KDM4A inhibitor QC6352 and design novel isonicotinic acid derivatives with improved predicted binding affinity and dynamic stability. Two Python-based workflows employing fragment replacement and molecular breeding strategies were developed to generate virtual libraries while retaining the isonicotinic acid core. A total of 135,000 derivatives were produced and subjected to a hierarchical screening protocol involving molecular docking, ADMET-based filtering, induced fit docking (IFD), molecular dynamics (MD) simulations, and MM-GBSA rescoring. ADMET filtering was based on standard QikProp drug-likeness and pharmacokinetic criteria to prioritize compounds with acceptable predicted physicochemical, absorption, distribution, and safety-related profiles. Among the screened derivatives, QC-L1A and QC-L2B showed the most favorable overall profiles compared with the reference compound QC6352 across multiple computational parameters. QC-L1A exhibited the most favorable binding free energy (ΔGbind = - 30.96 kcal/mol), representing a 3.12 kcal/mol improvement over QC6352 (- 27.84 kcal/mol), along with the lowest mean RMSD (0.807 Å), indicating marked conformational stability. QC-L2B achieved the most favorable IFD score (- 751.02 kcal/mol), surpassing QC6352 by 7.64 kcal/mol, and yielded a ΔGbind of - 29.62 kcal/mol. MD simulations revealed stable coordination between the conserved isonicotinic acid core and the catalytic Fe2+ ion, together with persistent interactions with key active-site residues. Selectivity analysis, performed by IFD-based profiling against KDM4 isoforms and other related JmjC demethylases, indicated a preferential binding profile toward KDM4 family members, particularly KDM4A and KDM4D. Retrosynthetic feasibility was assessed using the Spaya CASP platform, with both lead compounds showing favorable RScore values and practical synthetic routes. Accordingly, these findings highlight the effectiveness of a fragment-guided computational workflow for rational inhibitor optimization and introduce promising scaffolds for KDM4A-targeted drug design.
(© 2026. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest.
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Grant Information: 240375 Bioinformatics Research Center, Isfahan University of Medical Sciences
Contributed Indexing: Keywords: Epigenetics; Fragment-based design; Isonicotinic acid derivatives; KDM4A inhibitors; MM-GBSA; Molecular dynamics (MD) simulation
Substance Nomenclature: EC 1.14.11.- (Jumonji Domain-Containing Histone Demethylases)
0 (Isonicotinic Acids)
EC 1.5.- (KDM4A protein, human)
0 (Enzyme Inhibitors)
Entry Date(s): Date Created: 20260629 Date Completed: 20260629 Latest Revision: 20261010
Update Code: 20261010
DOI: 10.1007/s10822-026-00865-8
PMID: 42371179
Βάση Δεδομένων: MEDLINE
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