In-silico design of novel myocilin inhibitors for glaucoma therapy

Min Tang,Zhi Zheng,Ying Fan,Xun Xu,Yang Fu,Ming-Shui Fu

doi:10.4314/tjpr.v16i10.29

Abstract

Purpose: To explore newer computational approaches in the design of novel myocilin inhibitors for the treatment of glaucoma.Methods: An in-silico virtual screening technique based on simulation of molecular docking was utilised to design a novel myocilin inhibitors for the treatment of glaucoma. The designed novel molecules were theoretically evaluated to predict their pharmacokinetic properties and toxic effects. Lead molecules were screened out in virtual screening technique on the basis of low binding energies obtained in AutoDock based molecular docking simulation.Results: Out of ten top lead compounds screened, ZINC01729523 and ZINC04692015 were promising, having shown potent inhibition of myocilin, good pharmacokinetic properties and absence of any toxic effects.Conclusion: In-silico virtual screening of molecular libraries containing a large number of ligands is very useful for short-listing of potential lead molecules for further structure-based discovery of antiglaucoma-drugs.Keywords: Glaucoma, Myocilin, Docking, Virtual-screening, Autodock, Ligand, Drug design

Highlights

Glaucoma is the loss of visual sensitivity and field because of optic neuropathy associated with damage to the optic nerve heads
These results clearly suggest that the ligand binding mode obtained by molecular docking technique simulated exactly the binding mode observed within the human body
The molecular docking simulation process is validated by using re-docking of already bound ligand on the basis of its binding energy and overlay methods, which confirmed the similarity in binding patterns obtained by molecular docking simulation studies with that was occurring inside the human body [11]

Summary

INTRODUCTION

Glaucoma is the loss of visual sensitivity and field because of optic neuropathy associated with damage to the optic nerve heads. The receptor protein myocilin was prepared for molecular docking by removing ligand and from active site, removal of water molecules which are not interacting with the ligand, and addition of polar hydrogen’s. Lamarckian genetic algorithm (LGA) is the primary conformational search approach in AutoDock [11] In this search, a trail population is created for various possible conformations, and mutations and exchange of conformational parameters take place to compete in a similar manner to that of the successive generations for biological evolution by the selection of the final individuals with minimum binding energy. The results obtained from molecular docking simulation were evaluated on the basis of hydrophobic and polar interactions obtained between ligand and the binding residues present in the active ligand binding site of the macromolecule.

RESULTS

DISCUSSION

CONCLUSION

Conflict of Interest

Vision 2020