Academic Journal
Integrated structure-based and fragment-guided design of isonicotinic acid derivatives as potential KDM4A inhibitors: an in silico study.
| Title: | Integrated structure-based and fragment-guided design of isonicotinic acid derivatives as potential KDM4A inhibitors: an in silico study. |
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| Authors: | 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. |
| Source: | Journal of computer-aided molecular design [J Comput Aided Mol Des] 2026 Jun 29; Vol. 40 (1). Date of Electronic Publication: 2026 Jun 29. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | 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- |
| MeSH Terms: | 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 |
| Abstract: | 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 (ΔG (© 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: 20260711 |
| Update Code: | 20260711 |
| DOI: | 10.1007/s10822-026-00865-8 |
| PMID: | 42371179 |
| Database: | MEDLINE |
| ISSN: | 1573-4951 |
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| DOI: | 10.1007/s10822-026-00865-8 |