In silico Study toward Electronic Structures of Bioactive Compounds Benzoquinone and its Derivatives: Toxicity and Molecular Docking against Cyclin-Dependent Kinase

Background

Cyclin-Dependent Kinase is one of the important part the cell cycle control systems and normally active in breast cancer. DFT calculations, ADMET predictions and molecular docking on ligands such as compound 1 (benzoquinone), compound 2 (naphthalene-1,4-dione) and compound 3 (2-isopropyl-5-methylcyclohexa-2,5-diene-1,4-dione) assess their potential as CDK4 inhibitors.

Purpose

The purpose of this study was to assess benzoquinone and two derivatives as probable CDK4 inhibitors using an integrated DFT, ADMET, and docking. It aimed to relate electronic reactivity and pharmacokinetic/toxicity profiles to binding affinity against CDK4 Cyclin D3 (CDK4 Cyclin D3) to line up the most hopeful prime compound.

Materials and Methods

Here we optimized three drugs benzoquinone, naphthalene-1,4-dione, and 2-isopropyl-5-methylcyclohexa-2,5-diene-1,4-dione using software Gaussian16 and functional B3LYP with basis set 6-311G(d,p). Molecular Docking and Pharmokinetics are studied using AutoDock Vina Discovery Studio Visualizer 4.0 and ADMETlab 2.0.

Results

Frontier molecular orbital and DOS analyses showed that compound 3 with the smallest energy gap (3.71 eV) is predicted as the most reactive while compound 2 is more stable. MEP maps show that carbonyl oxygens are key reactive sites with compound 3 exhibiting the highest electronegative potential. ADMET analysis shows that compound 1 is found to be more soluble with strong BBB penetration, compound 2 displays strong CYP inhibition but higher toxicity risks, and compound 3 is more lipophilic with wider tissue distribution but poor CNS penetration. Docking studies against CDK4-Cyclin D3 (PDB ID: 7SJ3) showed compound 2 has the strongest binding affinity (-7.4 kcal/mol) while compound 3 displayed moderate binding and compound 1 the weakest.

Conclusion

Molecular docking against the protein CDK4-Cyclin D3 predicted that compound 2 as the most promising candidate and also supported by the other studied results.