Research Articles

De novo Design and in-silico Studies of Coumarin Derivatives as Inhibitors of Cyclin Dependent Kinase-2

Vol. 4 No. 4 (2017) 46-56 Published October 31, 2017

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Abstract

In the present study, around sixty-two novel coumarin derivatives were designed as CDK-2 inhibitors based on essential pharmacophoric requirements. All the designed compounds were subjected to docking study using AutoDock 4.2 against CDK-2 protein (PDB ID: 1HCK). Molinspiration and Osiris property explorer were used to predict Lipinski’s rule of five and toxicity profile. The Structure Activity Relationship study revealed that, the substitution at R1 and R4 of coumarin nucleus enhances the binding energy and inhibitory constant values from nanomolar to picomolar range. Among the designed analogues, compound 15, 28, 43 and 59 showed significant binding energy and inhibitory constant values as compared to the standard drug Olomoucine and Deschloroflavopiridol. Most of the designed analogues showed similar binding mode and orientation inside the active site of the protein as that of the standard drug, which strongly indicates that the designed molecules may emerge as potent inhibitors of CDK-2. Next, molecular dynamics study of the significantly active molecule 15 was studied for 10 ns, in order to determine the stability of the coumarin molecules inside the binding cavity of the protein. In-silico investigations suggest that the de novo designed coumarin derivatives were potentially in-silico bioactive and need to be synthesized and tested further.

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Author information

  • Ashok Sharma

    Birla Institute of Technology & Science

  • Badvel Pallavi

    Birla Institute of Technology & Science

  • Riddhidev Banerjee

    Birla Institute of Technology & Science

  • Mariasoosai Ramya Chandar Charles

    Pondicherry University image/svg+xml

  • Mohane Selvaraj Coumar

    Pondicherry University image/svg+xml

  • Subhash Chander

    Birla Institute of Technology & Science

  • Murugesan Sankaran

    Birla Institute of Technology & Science

  • Paritosh Shukla

    Birla Institute of Technology & Science, Vidya Vihar, Pilani-333031. Rajasthan

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Sharma, A.; Pallavi, B.; Banerjee, R.; Charles, M. R. C.; Coumar, M. S.; Chander, S.; Sankaran, M.; Shukla, P. De Novo Design and in-Silico Studies of Coumarin Derivatives As Inhibitors of Cyclin Dependent Kinase-2. J Pharm Chem 2017, 4 (4), 46-56. https://doi.org/10.14805/jphchem.2017.art78.
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Received
May 26, 2017
Published
October 31, 2017
Section
Research Articles
Pages
46-56

Keywords

  • Coumarine
  • CDK-2
  • anticancer
  • molecular docking
  • molecular dynamics

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