Computational Modelling of 4-Substituted Coumarins as Polymerization Inhibitors: A Combined 3D-QSAR, Pharmacophore, ADMET, Docking, MM-GBSA, and Molecular Simulations Study

Abstract:

Using computational approaches, this study aimed to assess the potential efficacy and specificity of 4-substituted coumarins as tubulin polymerization inhibitors, which will aid in rational drug design for cancer therapy. According to the most recent IARC reports, there were 10.3 million cancer deaths and 19.3 million cancer diagnoses worldwide in 2020. A broad class of naturally occurring substances known as substituted coumarins serves as a flexible scaffold for the synthesis of compounds with therapeutic effects. Many essential oils, including those from lavender, cassia leaf, and cinnamon bark, contain coumarins, which are widely distributed among higher plant groups, including Rutaceae and Umbelliferae. Naturally occurring coumarins and their synthetic derivatives have been shown to exhibit a wide range of biological activities, including antitumor, antibacterial, antifungal, anticancer, anticoagulant, antimalarial, antiviral, anti-HIV, and antiinflammatory properties. Increasing the potency and specificity of tubulin polymerization inhibitors requires a combination of docking, structure-activity correlations, pharmacophore models, and molecular dynamics. Providing a structural feature will help researchers develop new molecular entities using a three-dimensional quantitative structure-activity relationship, molecular docking, and absorption, distribution, metabolism, and excretion evaluation. In this study, the PHASE module (Schrodinger) was used to perform pharmacophorebased virtual screening, including pharmacophore creation, 3D-QSAR modelling, ADMET prediction, and docking, for the identification of potent tubulin polymerization inhibitors with possible anticancer activity based on previously synthesized compounds. The PHASE program was used to generate pharmacophore hypotheses. Based on high survival scores, site scores, optimal alignment, and the number of matched features, the hypothesis labeled AHHRR_1 was selected. The resulting pharmacophore was validated using a 3D-QSAR model, which demonstrated strong statistical significance and predictive capacity, with R2= 0.9663 and Q2= 0.8683.This hypothesis model, AHHRR_1, underwent ligand-based virtual screening using molecules from the Asinex database. The screened compounds were further refined through ADMET property prediction and molecular docking analyses. The 3D-QSAR models also enabled correlations between specific chemical groups or substituents at various molecular sites of interest and their biological activities, providing insights for potential structural modifications. From the screened compounds, eight exhibited improved docking interactions with the protein structure corresponding to PDB code: 4O2B compared to the standard molecule, colchicine. Subsequently, two compounds were selected for molecular dynamics (MD) simulation studies based on their docking scores. Additionally, the free binding energies of these compounds were predicted using post-MD MM-GBSA analysis. This research facilitates a deeper understanding of the critical interactions that novel derivatives have with the tubulin polymerization protein, which is essential for developing new lead compounds for cancer treatment. This study presents novel findings for the development of 4- substituted coumarins as potential tubulin polymerization inhibitors for cancer therapy. Utilizing the PHASE module from Schrodinger, a validated pharmacophore model (AHHRR_1) was created, demonstrating strong predictive capacity (R² = 0.9663, Q² = 0.8683). Eight compounds were identified through virtual screening that showed improved docking interactions with tubulin (PDB Code: 4O2B) compared to the standard colchicine, with two compounds selected for molecular dynamics simulations to assess their stability and interactions. Additionally, comprehensive ADMET property predictions were conducted, enhancing the understanding of pharmacokinetic profiles. This research establishes critical structure-activity relationships and highlights the potential of these coumarin derivatives as promising leads for developing new anticancer agents targeting tubulin polymerization. After a thorough literature search using SciFinder, Scopus, and other abstracting of indexed journal searches, we firmly state that the present work, the interpreted results, and the outcomes of this project have not been reported to date. Hence, the current study represents a novel contribution to the field.