Virtual and experimental screening of new melatonin bioisosteres for the treatment of glaucoma

Background. Melatonin is an endogenous regulator of intraocular pressure (IOP), but its effectiveness as a drug for glaucoma treatment is limited.The  aim of  the  study. To develop and  to  validate a  virtual screening method to identify bioisosteric analogs of melatonin that are promising for study as agents that reduce intraocular pressure.Results. A database containing structural and experimental affinity information for 48 individual reference compounds was created. Risk assessments for mutagenic, carcinogenic, irritant and reproductive toxicity were performed in DataWarrior based on substructural analysis and identification of fragments that are markers of relevant toxicity. A virtual screening of 2457 structures was carried out and 25 compounds from the selected ones were experimentally studied for their effect on intraocular pressure (IOP) in intact rats. 10 of the 25 prioritized compounds were found to significantly reduce IOP; compound RU-398 reduced IOP by 40 %, K-165 – by 40.9 %, and RU-615 reduced glaucoma by 33.3 %.Conclusion. The  effectiveness of  virtual screening after experimental validation was 40 %. The identified active compounds are promising for further study and development as the agents for the treatment of glaucoma.