ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

In silico design, docking simulation, and ANN-QSAR model for predicting the anticoagulant activity of thiourea isosteviol compounds as FXa inhibitors

Marcin Gackowski, Burhanuddin Madriwala, and Marcin Koba

Department of Toxicology and Bromatology, Faculty of Pharmacy, L. Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland

E-mail: marcin.gackowski@cm.umk.pl

Received: 23 May 2023  Accepted: 14 July 2023

Abstract:

Novel oral anticoagulants are frequently used for the pharmacotherapy of thromboembolic disorders but still have drawbacks and side effects. While numerous synthetic and semisynthetic derivatives of nontoxic isosteviol possess potential therapeutic properties, including anticoagulant activity. Besides, thiourea is recognized in medicinal chemistry research as a component of a common framework of many drugs or bioactive compounds. The present work combines molecular modeling and docking approach for searching and designing novel thiourea isosteviol-based compounds as potential FXa inhibitors. Elaborated regression model well reflects the relationships between experimentally determined anticoagulant activity and molecular descriptors and may be used for the prediction of FXa inhibitory activity of novel thiourea isosteviol compounds. Among 20 descriptors incorporated into the ANN model, 60% are 2D topological descriptors, 25% describe three-dimensional molecular structure, and remaining 15% belong to constitutional descriptors. Additionally, docking simulation confirms the prominent binding of the newly in silico designed molecules with the active sites of the protein, which may be the lead molecules and can be further optimized for the efficient pharmacodynamic and pharmacokinetic profiles. Based on the results obtained, thiourea derivatives of isosteviol with 3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl or 4-(oxazol-5-yl)phenyl substituent may be promising FXa inhibitors. Findings reported in the present work can be used as valuable information for the development of anticoagulants.

Keywords: Thiourea isosteviol derivatives; Anticoagulant activity; Factor X inhibitor; Molecular modeling; Docking simulation; Artificial neural networks; QSAR

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-023-02994-y

Chemical Papers 77 (11) 7027–7044 (2023)