Molecular Docking and Pharmacological In Silico Evaluation of Genistein and Hematoxylin as Promising Ribonucleotide Reductase-targeted Therapies for Cancer
Oun Deli Khudhair, Muhammad Azrul Zabidi, Amirah Mohd Gazzali, Mohd Nadzri Mohd Najib, Taif M. MaryooshBackground:
Ribonucleotide Reductase (RR) is a pivotal enzyme in DNA synthesis and repair, making it a vital target in cancer therapy. While synthetic RR inhibitors such as gemcitabine and hydroxyurea are used clinically, their long-term efficacy is hampered by drug resistance and systemic toxicity. This has prompted growing interest in natural compounds with potential anticancer properties and reduced toxicity. This study aims to evaluate the molecular interactions and pharmacokinetic profiles of two naturally derived compounds traditionally used, genistein (Chinese name: 大豆异黄, derived from Glycine max) and hematoxylin (Chinese name: 木素, extracted from Caesalpinia sappan), against human RR using molecular docking and in silico pharmacological analyses.
Methods:
The three-dimensional structure of human RR (PDB ID: 6L7L) was retrieved and subjected to docking simulations using AutoDock Vina and Chimera. Genistein and hematoxylin were docked into the RR active site, and their interactions were analyzed in comparison to gemcitabine. Molecular dynamics simulations over 100 ns further confirmed the structural stability and binding persistence of both compounds within the RR active site. Pharmacokinetic and drug-likeness properties were evaluated via SwissADME and Molinspiration platforms.
Results:
Both genistein and hematoxylin exhibited strong binding affinities (-8.2 kcal/mol, -8.8 kcal/mol), respectively, to the RR active site, interacting with key catalytic residues in a manner comparable to the standard drug gemcitabine (-7.3 kcal/mol). Molecular dynamics simulations over 100 ns further confirmed the structural stability and binding persistence of both compounds within the RR active site. In silico pharmacokinetic predictions indicated good oral bioavailability, compliance with drug-likeness criteria, and low predicted toxicity
Discussion:
Genistein emerges as a good candidate owing to its strong RRM1 binding, favorable physicochemical attributes, clean medicinal chemistry profile, and low predicted toxicity. Hematoxylin offers superior binding affinity but requires refinement to address solubility and PAINS-related concerns. Gemcitabine, while efficacious clinically, suffers from limited oral bioavailability and potential toxicities.
Conclusion:
Genistein and hematoxylin demonstrate promising molecular interactions and pharmacological profiles as potential natural RR inhibitors. Their dual role in traditional healing and modern molecular pharmacology supports further preclinical development as anticancer agents.