Fig 1.
Two-dimensional chemical structures of Allium sativum L.-derived compounds investigated for their inhibitory potential and physicochemical properties.
Fig 2.
Co-crystallized ligands of the selected macromolecular targets.
The ligand-receptor pairs include CDK2/DTQ, CDK6/FSE, Topoisomerase I/EDH, Topoisomerase II/ANP, G-Quadruplex/PYN, Bcl-2/LIO, and XIAP-Bir2/1RH. These ligands are established inhibitors of their respective targets and were used to validate docking protocols.
Fig 3.
Conformational clustering of co-crystal ligands used to validate molecular docking parameters.
The RMSD was calculated between the original co-crystal ligand positions (green-colored aromatic carbons) and their docked poses (cyan-colored aromatic carbons). A cut-off RMSD value of 2.0 Å was applied to identify closely related conformers, indicating acceptable docking accuracy.
Table 1.
Binding energy (ΔG, kcal/mol) and inhibition constant (Ki, μM) of organosulfur compounds from Allium sativum L. docked against selected macromolecular targets.
Fig 4.
Binding modes and LigPlot+ molecular interactions of the best-docked investigational ligands with their molecular targets.
Bond lengths shown in Å and hydrogen bonding angles between the ligands and key amino acid or nucleotide residues of the receptors are annotated on the LigPlot+ and binding mode images respectively. Z-ajoene (cpd1) showed notable binding with Bcl-2 (Panel 4a), CDK2 (Panel 4b), and Topoisomerase II (Panel 4f) through a combination of hydrogen bonding and hydrophobic interactions. S-allyl-L-cysteine (cpd6) demonstrated strong interactions with G-Quadruplex (Panel 4d), Topoisomerase I (Fig 4e), VEGFR2 (Panel 4g), XIAP-Bir2 (Panel 4h), and CDK-6 (Panel 4c), involving hydrogen bonds and multiple hydrophobic contacts. Specific interacting residues and bond types are highlighted in each panel (Panel 4a-4h).
Fig 5.
Post-docking energy minimization using OpenBabel tool.
Energy values showed that ligand-receptor complexes have lower energy post-docking minimization (Panel 5a). An RMSD value of 2.0 Å was considered as cut-off for ligands that remain in similar poses after aligning pre-energy minimization complexes (green colored carbon backbone) with post-docking energy minimization complexes (cyan colored carbon backbone) (Panel 5b-j). Complexes: Cpd1/Bcl2 (Panel 5c), Cpd1/Cdk2 (Panel 5d), Cpd6/Cdk6 (Panel 5e), Cpd6/G-Quadruplex (Panel 5f), Cpd6/Topoisomerase II (Panel 5g), Cpd1/Topoisomerase I (Fig 5h), Cpd6/VEGFR2 (Panel 5i) and Cpd6/XIAP Bir2 (Panel 5j).
Table 2.
Predicted physicochemical properties of the investigational bioactive compounds calculated using the Molinspiration web server.
Table 3.
Physicochemical properties of the investigational compounds calculated using DataWarrior software.
Table 4.
Oral bioavailability of the selected compounds based on Veber and Egan Rules as predicted by the SwissADME server.
Table 5.
Absorption, distribution, elimination, and toxicity profiles of the bioactive compounds assessed using PreADME; CYP2C19 and CYP2C9 inhibition predicted by SwissADME.