Chemo-informatics guided study of natural inhibitors targeting rho GTPase: a lead for treatment of glaucoma

Sumit Kumar Rai; Rajesh Kumar Pathak; Dev Bukhsh Singh; Arun Bhatt; Mamta Baunthiyal

doi:10.1007/s40203-020-00061-y

Chemo-informatics guided study of natural inhibitors targeting rho GTPase: a lead for treatment of glaucoma

In Silico Pharmacol. 2021 Jan 3;9(1):4. doi: 10.1007/s40203-020-00061-y. eCollection 2021.

Authors

Sumit Kumar Rai¹, Rajesh Kumar Pathak¹, Dev Bukhsh Singh², Arun Bhatt¹, Mamta Baunthiyal¹

Affiliations

¹ Department of Biotechnology, Govind Ballabh Pant Institute of Engineering and Technology, Pauri Garhwal, Uttarakhand 246194 India.
² Department of Biotechnology, Institute of Biosciences and Biotechnology, Chhatrapati Shahu Ji Maharaj University, Kanpur, 208024 India.

Abstract

Glaucoma, the most perilous disease leading to blindness is a result of optical neuropathy. Accumulation of aqueous humor in the posterior chamber due to a large difference in the rate of formation and its drainage in the anterior chamber causes an increase in intraocular pressure (IOP) leading to damage of nerve cells. A literature survey has revealed that inhibition of the Rho guanosine triphosphatases (rho GTPase) pathway by specific inhibitors leads to the relaxation of contractile cells involved in the aqueous outflow pathway. Relaxation of the strained contractile cells results in increased outflow thereby releasing IOP. In the present study molecular docking has been used to screen twenty seven bioactive (17 natural compounds and 10 conventional drugs) compounds that may play a significant role in relaxing contractile cells by inhibiting rho-GTPase protein. Docking results showed that among all-natural bioactive compounds Cyanidin and Delphinidine have a good binding affinity (- 8.4 kcal/mol) than the top screened conventional drug molecule Mitomycin, (- 6.3 kcal/mol) when docked with rho-GTPase protein. Cyanidin and Delphinidin belong to anthocyanidin, a glycoside form of anthocyanins from Vaccinium myrtillus L. and Punica granatum. The resembling potential of Cyanidin and Delphinidin concerning the drug Mitomycin was confirmed through simulation analysis. Molecular dynamics study (MDS) for 100 ns, showed that the rho GTPase-Delphinidine complex structure was energetically more stable than rho GTPase-Cyaniding complex in comparison to rho GTPase-Mitomycin complex. The comparative study of both the selected hits (Cyanidin and Delphinidin) was assessed by RMSD, RMSF, Rg, SASA, H-bond, PCA MM/PBSA analysis. The analysis revealed that Delphinidine is more potent to inhibit the rho GTPase as compare to Cyaniding and available conventional drugs in terms of stability and binding free energy. Based on the results, these molecules have good pharmacokinetic and pharmacodynamics properties and will prove to be a promising lead compound as a future drug for Glaucoma.

Keywords: Docking interaction; Glaucoma disease; Molecular dynamics; Rho-GTPase pathway; Toxicity prediction.