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

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.

Novel Thiourea and Oxime Ether Isosteviol-Based Anticoagulants: MD Simulation and ADMET Prediction

“…To examine the stability of FXa complexes with designed ISV derivatives, 100 ns MD simulations were carried out. The structures obtained from docking studies, previously published, were utilized as the initial structures for the MD simulations ( Figure 2 ) [ 9 , 10 ]. The stability of the complex was assessed by calculating the RMSD of the protein main chain and the RMSD of the ligand, with the initial structure from the MD simulation serving as the reference structure.…”

“…These are, for example, five-membered heterocyclic rings present both in most of the designed compounds and the commercial drugs, e.g., thiophen and oxazole rings (as in rivaroxaban and apixaban) and phenyl rings (as in rivaroxaban, apixaban, and betrixaban). Molecular modeling shows that they are important for the interaction of the ligand with the active site [ 9 , 10 ]. The presence of halogen atoms attached to aromatic rings in most of the described relationships, as in rivaroxaban, edoxaban, and betrixaban molecules, is also important.…”

“…All the MD simulations were done using the GROMACS 2023.2 package [ 26 ] with an AMBER ff99-SB-ILDN force field [ 27 ]. Structures obtained from previously published docking studies served as starting geometries for complexes of ISV derivatives with FXa [ 9 , 10 ]. Ligand parameterization was conducted using the Acpype 2022.6.6 [ 28 ], employing the GAFF2 force field and the BCC charge method.…”

“…Recently almost forty isosteviol(ISV) analogs bearing two different moieties, i.e., thiourea [ 9 ] and oxime ether [ 10 ] isosteviol derivatives as FXa inhibitors, were designed based on structural knowledge derived from quantitative structure–activity relationship (QSAR) studies and molecular docking simulation. For both groups of ISV-like compounds, promising predicted FXa inhibitory activity was described, and also, interactions with the active site of FXa were revealed.…”

“…The objective of this study was to use an in silico pharmacoinformatics approach to validate and prioritize potentially active candidate compounds from newly designed thiourea and oxime ether ISV derivatives. MD simulations were conducted for 100 ns as a continuation of previous molecular docking studies [ 9 , 10 ] to evaluate the validity of the FXa–ligand binding pose predictions and to furnish additional information. Subsequently, the compounds were screened for ADME/drug-likeness properties.…”