Graph theoretical analysis, pharmacoinformatics and molecular docking investigation of Chalcone-Schiff base hybrids as Cyclin-Dependent kinase inhibitors

Abstract

One of the promising classes of compounds in medicinal chemistry and drug design is those with azomethine linkages. The Chalcone-Schiff base hybrids contain this linkage and some heteroatoms, which are versatile molecules, play a vital role in drug discovery and development with enormous therapeutic applications. In this view, the present work deals with the investigation of the in silico biological potential of the Chalcone-Schiff base hybrids based on the network pharmacology approach. From the results obtained from network pharmacology, the Cyclin-dependent kinase (CDK) isoforms were identified as the potential targets and the CDK inhibitory activity of the compounds was investigated using molecular docking studies. The in silico pharmacokinetic, metabolic and theoretical studies at DFT level were performed. Molecular docking studies revealed that the compounds have better CDK inhibitory potential with better binding affinity and interaction profile. Among the tested compounds, (Z)-2-((4,6-diphenyl-5,6-dihydro-4H-1,3-thiazin-2-yl)imino)-2,3-dihydro-1H-inden-1-one was found to be the most active compound than the standards, palbociclib and dinaciclib against the CDK isoforms (CDK1, CDK2 and CDK4) with the binding energies of -9.9, -10.3 and -10 Kcal/Mol, respectively. Also, this compound exhibited better pharmacokinetic and metabolic properties along with better solubility. The theoretical studies at the DFT level also indicate that the compound has better metabolic stability and the electron transfer from HOMO to LUMO was observed. Thus, the tested Chalcone-Schiff base hybrids can be used effectively for the inhibition of CDK isoforms.