Binding mechanism, conformation, and stability of diflunisal and mycophenolic acid with p300 HAT enzyme using molecular dynamics simulation and binding free energy analysis

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Among all posttranslational modifications in eukaryotic cell, acetylation is an important one it is controlled by histone acetyltransferase (HAT) enzyme. The aberrant function of this enzyme is forefront for the cause of several nefarious diseases like, cancer, neurological disorders, cardiovascular, and lung diseases. Reports outline that blocking the enzymatic action of this enzyme by an inhibitor molecule is the only remedy to cure these diseases. The in vitro analysis shows that highest inhibition rate of salicylic acid and its derivatives acetylsalicylic acid, 4-amino salicylic acid, diflunisal, mycophenolic acid, 5-amino salicylic acid, and repaglinide against p300. The in silico (molecular docking) analysis confirms that the diflunisal (−6.14 kcal/mol), mycophenolic acid (−6.86 kcal/mol), and repaglinide (−6.26 kcal/mol conformer-4) molecules give highest binding energy values compared with other salicylic acid derivatives and they form strong interactions (H-bond) with the Arg1410, Trp1436, Thr1411, Trp1466, and Tyr1467. These interactions stabilize the molecules in the active site; it leads to inhibit the histone acetylation. The mycophenolic acid is retained these key interactions with the active site amino acid residues (Cys1438, Tyr1446, and Tyr1467) compared with the diflunisal molecule in MD simulation; which is stable up to 40 ns. The binding free energy of mycophenolic acid (−26.26 kcal/mol) is relatively high on compared with the diflunisal (−7.86 kcal/mol).

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Histone acetyltransferase


Molecular dynamics


Molecular mechanics/generalized born surface area


CREB binding protein


Root mean square deviation


Radius of gyration


Root mean square fluctuation


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The authors thank to C-DAC Bangalore for providing the computing facility.

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Correspondence to Kumaradhas Poomani.

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Magudeeswaran, S., Poomani, K. Binding mechanism, conformation, and stability of diflunisal and mycophenolic acid with p300 HAT enzyme using molecular dynamics simulation and binding free energy analysis. Med Chem Res (2020).

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  • Quantum chemical calculations
  • Principle component analysis
  • Molecular docking
  • Molecular dynamics simulation
  • Binding free energy
  • Normal mode analysis