Identification of EPAC (Exchange Protein Activated by cAMP) bioinformatically as a potential signalling biomarker in Cardiovascular Disease (CVD) and its molecular docking by a lead molecule

  • Bala S
  • Pathak R
  • Mishra V
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Abstract

The present work delineates the combinatorial approach of firstly, creation of a centralized data-set comprising signalling proteins identified on the basis of altered expression, such as over-expression or repression of a set of signalling protein(s) leading to the cause of the disease, which is based on published reports screened through Pubmed and secondly, in the in silico creation of novel lead (drug) molecules and docking of identified signalling biomarkers using such drugs to investigate possibility of their future application in the model systems eventually. EPAC (Exchange Protein Activated by cAMP) emerges as a signalling biomarker in cases studied presently. Brefeldin, the known inhibitor of EPAC, though the mechanism yet unexplored, has been the molecule used as the pharmacophore for creation of lead drug molecule. Various modifications have been incorporated into the pharmacophore to increase the hydrophobic interactions for increasing the binding efficiency of the generated lead molecule. Side-chain modifications of the pharmacophore and refinement of data through firedock upon docking of EPAC with the modified pharmacophore yielded best results on the bases of atomic contact energy, van der Waal and partial electrostatic interactions as well as additional estimations of the binding free energy. Modifications of CH3 at C15 with COOH and H at C2 with OH in brefeldin showed the best docking results on the basis of protein-drug interaction parameters. The present work provides a clue in rational design of EPAC inhibitors which could be developed as drug lead in combating CVD.

Figures

  • Figure 2: The criteria adopted for curating the signalling molecules.
  • Figure 3: PDB ID: 3CF6, Epac protein (Shown in Green is Epac2) is activated by binding of the second messenger cAMP (Shown in Red,It is an analogue of cAMP) and then act as guanine nucleotide exchange factors for Rap proteins (Shown in Blue,It is Rap1B) [21].
  • Figure 4(A): Structure of unmodified brefeldin; 4(B): Interactions between unmodified Brefeldin and residues of Chain E of EPAC. Fewer groups are found to be involved in hydrophobic interaction and no H-bond is observed; 4(C): Structure of modified brefeldin (BR2); 4(D): The interactions between BR2 (modified brefeldin) and residues of Chain E of EPAC are shown. Of the 12 different modifications involving C2, C10 and C15 of brefeldin pharmacophore, the replacement of -CH3 at C15 and -H at C2 with – COOH and –OH, respectively yielded H- bond interactions between BR2 and Ala 407 (E) [highlighted as boxed area], which in turn induced additional H-bond formation between –OH at C1 and C7 and Ala 416 and Cys 395, respectively. These interactions induce further stability in the complex by improved hydrophobic interactions.

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APA

Bala, S., Pathak, R. K., & Mishra, V. (2011). Identification of EPAC (Exchange Protein Activated by cAMP) bioinformatically as a potential signalling biomarker in Cardiovascular Disease (CVD) and its molecular docking by a lead molecule. Bioinformation, 6(5), 176–178. https://doi.org/10.6026/97320630006176

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