In silico studies and synthesis of Coumarin derivatives with Promising anticoagulant activity

Abstract

The absorption, distribution, metabolism, and excretion (ADME) properties of coumarin derivatives play a crucial role in their pharmacokinetic profiles and therapeutic efficacy. This study aims to evaluate the ADME properties of a novel coumarin derivative using the computational tool Swiss ADME. Swiss ADME offers a reliable and comprehensive platform for predicting pharmacokinetic parameters, physicochemical properties, and drug-likeness of small molecules. The coumarin derivative was subjected to Swiss ADME analysis to predict its gastrointestinal absorption, blood-brain barrier permeability, metabolic stability, and potential for drug-drug interactions. Key parameters such as water solubility, lipophilicity, bioavailability score, and the presence of structural alerts for toxicity were assessed. Additionally, the molecule's compliance with Lipinski's Rule of Five and other drug-likeness filters were evaluated to determine its potential as an orally active drug.

Objectives: The results indicated that the coumarin derivative possesses favorable ADME properties, including high gastrointestinal absorption and moderate permeability across the blood-brain barrier. The compound demonstrated acceptable metabolic stability and a low risk of cytochrome P450-mediated drug-drug interactions. Furthermore, the molecule adhered to Lipinski's Rule of Five, suggesting good oral bioavailability.

Methods: The Swiss ADME software (available at www.swissadme.ch) developed by the Swiss Institute of Bioinformatics (http://www.sib.swiss) was utilized through a web server. This server provides a submission page that can be accessed via Google, facilitating the estimation of individual ADME behaviours of plant-derived compounds. The input area features a molecular sketcher based on Chem Axon's Marvin JS (http://www.chemaxon.com), enabling users to draw and modify 2D chemical structures. These structures are then listed on the right side of the submission page, which serves as the actual input for computations. The list is formatted to include one molecule per line, with multiple inputs defined by the simplified molecular input line entry system (SMILES). The results for each molecule are displayed in tables, graphs, and also provided in an Excel spreadsheet. The output from SwissADME consists of a panel for each molecule, offering a clear presentation and export option that includes all relevant information about the molecules.

Results Modern drug discovery involves evaluating the efficacy of dynamic molecules and their ability to reach the target site in a bioactive form. This process includes cellular, animal, and human clinical trials, which are costly and fraught with risks (Ndombera et al., 2019; Ranjith & Viswanath, 2019). Currently, computer-aided drug development facilitates the prediction of absorption, distribution, metabolism, and excretion (ADME) properties. These computational tools provide anticipatory and reliable data rapidly, complementing experimental approaches (Sliwoski et al., 2014; Ndombera et al., 2019). Early assessment of ADME properties during the discovery phase significantly reduces the incidence of pharmacokinetic-related failures during clinical trials.

In SwissADME, Lipinski's Rule of 5 plays a crucial role in assessing the drug-likeness of small molecules based on their physicochemical properties. This rule, developed by Christopher Lipinski, outlines four key criteria that predict whether a compound is likely to have good oral bioavailability and permeability.

Conclusions According to Lipinski's Rule of 5, a molecule is considered more likely to be orally bioavailable if it has a molecular weight less than 500 daltons (Da), a partition coefficient (log P) less than 5, no more than 5 hydrogen bond donors, and no more than 10 hydrogen bond acceptors. These parameters reflect the ideal characteristics for small molecules to be efficiently absorbed in the gastrointestinal tract and potentially reach systemic circulation. By applying Lipinski's Rule of 5 within SwissADME, researchers can quickly screen compounds to prioritize those with higher probabilities of being successful drug candidates, thus optimizing the early stages of drug discovery and development processes.