Inhibitory potential of furanocoumarins against cyclin dependent kinase 4 using integrated docking, molecular
Srutishree Sarma1, Dikshita Dowerah1, Moumita Basumatary1
1CMML-Catalysis and Molecular Modelling Lab, Department of Chemical Sciences, Tezpur University, Sonitpur, Assam, India.
Abstract:
Cyclin Dependent Kinase 4 (CDK4) is vital in the process of cell-cycle and serves as a G1 phase checkpoint in cell division. Selective antagonists of CDK4 which are in use as clinical chemotherapeutics cause various side-effects in patients. Furanocoumarins induce anti-cancerous effects in a range of human tumours. Therefore, targeting these compounds against CDK4 is anticipated to enhance therapeutic effectiveness. This work intended to explore the CDK4 inhibitory potential of 50 furanocoumarin molecules, using a comprehensive approach that integrates the processes of docking, drug-likeness, pharmacokinetic analysis, molecular dynamics simulations and ONIOM (Our own N-layered Integrated molecular Orbital and Molecular mechanics) methods. The top five best docked compounds obtained from docking studies were screened for subsequent analysis. The molecules displayed good pharmacokinetic properties and no toxicity. Epoxybergamottin, dihydroxybergamottin and notopterol were found to inhabit the ATP-binding zone of CDK4 with substantial stability and negative binding free energy forming hydrogen bonds with key catalytic residues of the protein. Notopterol exhibiting the highest binding energy was subjected to ONIOM calculations wherein the hydrogen bonding interactions were retained with significant negative interaction energy. Hence, through these series of computerised methods, notopterol was screened as a potent CDK4 inhibitor and can act as a starting point in successive processes of drug design.
Insights
This study screened 50 furanocoumarins for Cyclin Dependent Kinase 4 (CDK4) inhibition. Notopterol emerged as a potent CDK4 inhibitor, offering a promising starting point for new cancer drug design.
Area of Science:
- Medicinal Chemistry
- Computational Biology
- Pharmacology
Background:
- Cyclin Dependent Kinase 4 (CDK4) regulates the cell cycle G1 checkpoint, and its inhibition is a cancer therapy target.
- Current CDK4 antagonists cause significant patient side-effects.
- Furanocoumarins exhibit anti-cancer properties and are explored for CDK4 targeting.
Purpose of the Study:
- To investigate the CDK4 inhibitory potential of 50 furanocoumarin compounds.
- To identify novel furanocoumarin-based CDK4 inhibitors using computational methods.
- To evaluate the drug-likeness and pharmacokinetic properties of potential inhibitors.
Main Methods:
- Molecular docking to predict binding affinity.
- Drug-likeness and pharmacokinetic analyses.
- Molecular dynamics simulations and ONIOM calculations to assess stability and interactions.
- Screening of 50 furanocoumarin derivatives.
Main Results:
- Five furanocoumarins showed promising docking scores and favorable pharmacokinetic profiles.
- Epoxybergamottin, dihydroxybergamottin, and notopterol demonstrated stable binding within the CDK4 ATP-binding site.
- Notopterol exhibited the strongest binding energy and maintained key hydrogen bonding interactions, confirmed by ONIOM calculations.
Conclusions:
- Notopterol is identified as a potent CDK4 inhibitor through comprehensive computational analysis.
- This study provides a strong foundation for developing notopterol-based therapeutics.
- Furanocoumarins represent a promising class of compounds for targeted CDK4 inhibition in cancer therapy.
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