Computational Discovery of Antithrombotic Ferulate Analogs Through QSPR Modeling, Pharmacokinetic Prediction, Molecular Docking, and Dynamic Stability Assessment

Praditapuspa, Ersanda Nurma; Ekowati, Juni; Purwanto, Djoko Agus; Putra, Masteria Yunovilsa; Siswodiharjo, Siswandono; Tejo, Bimo

doi:10.48309/chemm.2026.563470.2055

Computational Discovery of Antithrombotic Ferulate Analogs Through QSPR Modeling, Pharmacokinetic Prediction, Molecular Docking, and Dynamic Stability Assessment

Articles in Press

Document Type : Original Article

Authors

Ersanda Nurma Praditapuspa ¹^{, 2}

Juni Ekowati ³^{, 4}^{, 5}

Djoko Agus Purwanto ³

Masteria Yunovilsa Putra ⁶^{, 7}^{, 8}

Siswandono Siswodiharjo ³^{, 9}

Bimo Tejo ¹⁰

¹ Doctoral Progamme of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia

² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Hang Tuah, Surabaya, Indonesia

³ Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia

⁴ Drug Development Research Group, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia

⁵ Inter-University Center of Excellence (IUCoE) of Health Autonomy-Drug Discovery, Universitas Airlangga, Surabaya, Indonesia

⁶ Research Center for Vaccine and Drugs, Research Organization for Health, National Research and Innovation Agency (BRIN), Bogor, Indonesia

⁷ Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia

⁸ National Metabolomics Collaborative Research Center, Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia

⁹ Research Center and Community Service Center, Institut Ilmu Kesehatan Bhakti Wiyata, Kediri, Indonesia

¹⁰ Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang, Malaysia

10.48309/chemm.2026.563470.2055

Abstract

Stroke remains a major global health burden, motivating the discovery of safer and more effective antithrombotic candidates. Antithrombotic therapy such as aspirin is widely used; yet, its clinical benefit is constrained by gastrointestinal bleeding risk and interindividual variability, highlighting the need for safer and more effective candidates. Ferulic acid exhibits antithrombotic potential, but its potency is generally lower than that of standard therapy. In this study, an integrated in silico workflow Topliss-guided design, drug-likeness/ADMET screening, network pharmacology, structure-based docking and molecular dynamics (MD), as well as QSPR analysis of Log CLtot were implemented to computationally prioritize a ferulate-derived lead for stroke-related thrombosis. The SAR space was intentionally focused on selective modification of the phenolic –OH via o-benzoylation, yielding 33 synthetically accessible analogs while preserving the cinnamate core. Network pharmacology (SEA, SwissTargetPrediction, BindingDB, DisGeNET, OMIM, STRING, Metascape, and KEGG) prioritized the thromboxane A₂ receptor (TXA₂R/TBXA2R) as a key node based on high network centrality and mechanistic relevance to platelet activation. Molecular docking in MOE, validated by redocking (RMSD = 0.7404 Å), highlighted 4-(3-trifluoromethylbenzoyloxy)-3-methoxycinnamic acid as the top-ranked candidate (S-score = −10.0556 kcal/mol). A 100-ns MD simulation supported stable binding in the TXA₂R pocket, and post-MD MM-GBSA estimated a favorable binding free energy (ΔG_bind = −57.65 kcal/mol). QSPR analysis suggested that Log CLtot is associated with aqueous solubility (LogS), with additional contributions from electronic (Etot) and steric (CMR) descriptors; predictive validation and robustness testing are addressed in the revised manuscript to avoid overinterpretation. Overall, this study computationally prioritized a ferulate-based antithrombotic lead to support synthesis and experimental validation.

Graphical Abstract

Keywords

Ferulate analogs

Stroke

Molecular modeling

QSPR

Molecular dynamics

Network pharmacology

Subjects

Medicinal chemistry

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©2026 The author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit: http://creativecommons.org/licenses/by/4.0/

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