Novel Isosteviol-Based FXa Inhibitors: Molecular Modeling, In Silico Design and Docking Simulation

Abstract

Direct oral anticoagulants are an important and relatively new class of synthetic anticoagulant drugs commonly used for the pharmacotherapy of thromboembolic disorders. However, they still have some limitations and serious side effects, which continuously encourage medicinal chemists to search for new active compounds acting as human-activated coagulation factor X (FXa) inhibitors. Isosteviol is a nontoxic hydrolysis product of naturally occurring stevioside and possesses a wide range of therapeutic properties, including anticoagulant activity. The present contribution describes the in silico design of novel oxime ether isosteviol derivatives as well as a molecular modeling approach based on QSAR analysis and a docking simulation for searching for novel isosteviol-based compounds as potential FXa inhibitors. The elaborated ANN model, encompassing topological and geometrical information, exhibited a significant correlation with FXa-inhibitory activity. Moreover, the docking simulation indicated six of the most promising isosteviol-like compounds for further investigation. Analysis showed that the most promising derivatives contain heterocyclic, aromatic, five-membered moieties, with substituents containing chlorine or fluorine atoms. It is anticipated that the findings reported in the present work may provide useful information for designing effective FXa inhibitors as anticoagulant agents.

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.…”