Identification of novel flavonoid inhibitor of Catechol-O-Methyltransferase enzyme by molecular screening, quantum mechanics/molecular mechanics and molecular dynamics simulations

Abstract

The low level of dopamine at substantia nigra (mid-brain) has been considered to be one of the reasons for Parkinson’s disease (PD). This dopamine deficit is due to the influence of Catechol-O-Methyltransferase (COMT). A recent report outline that the flavonoid family of molecules are able to inhibit the COMT enzyme. To identify a potential molecule from the flavonoid family, we performed molecular screening over a group of flavonoid molecules using glide method. Among the screened molecules, morin molecule shows, relatively larger binding affinity (−7.90 kcal/mol) towards COMT enzyme. Further, an Induced Fit Docking (IFD) has been carried out for morin with COMT enzyme; the corresponding docking score value is −8.17 kcal/mol. To understand the conformational flexibility of morin in the active site of COMT, its conformation has been compared with the corresponding gas phase conformation. Further, molecular dynamics (MD) simulation has been performed to understand the dynamical behavior and the stability of morin molecule in the active site of COMT enzyme. The morin strongly binds with the catalytic triad and gatekeeper residues and these interactions have been maintained during the 50 ns MD simulation. Notably, the O(1) atom of morin forms interaction with Glu198, Mg ion and catalytic residue Asn169; in which, Glu198 is more stable during the simulation. The O(11) atom blocks the ionization process through the interaction with Lys143. Both of these interactions are essential to inhibit the enzymatic function of COMT enzyme. The binding free energy study shows morin molecule exhibit good binding towards COMT enzyme.

Communicated by Ramaswamy H. Sarma

Keywords:

• Parkinson’s disease
• morin
• virtual screening
• molecular docking
• molecular dynamics simulation

Acknowledgements

The authors thank to Schrödinger, Bangalore, India allow us to use the software for the docking study and C-DAC Bangalore for providing the GARUDA, supercomputing facility.

Disclosure statement

No potential conflict of interest was reported by the authors.