Paper Contents
Abstract
Cyclin D1, a key regulator of the G1S phase transition in the cell cycle, is frequently overexpressed in various cancers, including breast, colon, and non-small cell lung cancer (NSCLC), promoting uncontrolled cell proliferation and tumor progression. This makes it an attractive therapeutic target for anticancer drug development. Natural compounds, such as gingerol derivatives from Zingiber officinale, have shown promising anticancer activities by inhibiting cell proliferation, inducing apoptosis, and modulating key signaling pathways. In this study, we evaluated the ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties and molecular docking potential of a novel gingerol derivative, (E)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-6-methyloct-1-en-3-one (Molecule 1), against Cyclin D1. The ADMET analysis was conducted using the ADMET-AI online tool, a machine learning-based platform that predicts 41 ADMET endpoints from molecular SMILES input. Molecule 1 exhibited favorable pharmacokinetic profiles, including a molecular weight of 278.348 Da, LogP of 2.7802, and high human intestinal absorption (HIA) probability of 0.9999. It showed low probabilities for toxicities such as AMES mutagenicity (0.3027), carcinogenicity (0.0895), and clinical toxicity (0.0599), with moderate inhibition potentials for cytochrome P450 enzymes. Percentile rankings against DrugBank-approved drugs indicated competitive drug-likeness, with QED (Quantitative Estimate of Drug-likeness) at 82.59%ile. Molecular docking was performed using CB-Dock2, an advanced blind docking tool integrating cavity detection, AutoDock Vina scoring, and template fitting. The Cyclin D1 structure (PDB ID: 2W96) was used, revealing the highest binding affinity in cavity C1 with a Vina score of -7.4 kcalmol. Residue interactions involved hydrophobic contacts with Leu80 and Ile196, hydrogen bonding with Arg57 and Thr156, and -stacking with Phe195, suggesting stable binding at the active site. Results indicate that Molecule 1 possesses drug-like ADMET properties and strong binding potential to Cyclin D1, potentially disrupting CDK4-Cyclin D1 complex formation and halting cell cycle progression. This in silico study supports further in vitro and in vivo validation of Molecule 1 as a lead compound for Cyclin D1-targeted cancer therapy, highlighting the efficacy of computational tools in accelerating natural product-based drug discovery.
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Copyright © 2025 Aasma Anjum. This is an open access article distributed under the Creative Commons Attribution License.
