Virtual and experimental screening of new melatonin bioisosteres for the treatment of glaucoma
D. A. Babkov,
A. S. Taran,
A. A. Shevchenko,
L. V. Naumenko,
O. N. Zhukovskaya,
A. M. Efremov,
E. N. Bezsonova,
N. A. Lozinskaya,
A. A. Spasov https://doi.org/10.29413/ABS.2024-9.1.12
Abstract
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.
About the Authors
D. A. Babkov
Volgograd State Medical University
Russian Federation
Russian Federation
Denis A. Babkov – Cand. Sc. (Chem.), Senior Research Officer at the Laboratory of Metabotropic Agents of the Scientific Сentre for Innovative Drugs,
Pavshikh Bortsov square 1, Volgograd 400131
A. S. Taran
Volgograd State Medical University;
Volgograd Medical Scientific Center
Russian Federation
Russian Federation
Alena S. Taran – Cand. Sc. (Med.), Senior Research Officer at the Laboratory of Toxicology of the Scientific Сentre for Innovative Drugs;
Junior Research Officer at the Laboratory of Experimental Pharmacology,
Pavshikh Bortsov square 1, Volgograd 400131
A. A. Shevchenko
Volgograd Medical Scientific Center
Russian Federation
Russian Federation
Alina A. Shevchenko – Postgraduate at the Department of Pharmacology and Bioinformatics,
Pavshikh Bortsov square 1, Volgograd 400131
L. V. Naumenko
Volgograd State Medical University
Russian Federation
Russian Federation
Lyudmila V. Naumenko – Dr. Sc. (Med.), Professor at the Department of Pharmacology and Bioinformatics,
Pavshikh Bortsov square 1, Volgograd 400131
O. N. Zhukovskaya
Research Scientific Institute of Physical and Organic Chemistry, Southern Federal University
Russian Federation
Russian Federation
Olga N. Zhukovskaya – Cand. Sc. (Chem.), Senior Research Officer at the Laboratory of Organic Synthesis,
Stachki Ave. 194/2, Rostov-on-Don 344090
A. M. Efremov
Lomonosov Moscow State University
Russian Federation
Russian Federation
Alexander M. Efremov – Postgraduate at the Department of Medicinal Chemistry and Fine Organic Synthesis,
Leninskie Gory 1, Moscow 119991
E. N. Bezsonova
Lomonosov Moscow State University
Russian Federation
Russian Federation
Elena N. Bezsonova – Postgraduate at the Department of Medicinal Chemistry and Fine Organic Synthesis,
Leninskie Gory 1, Moscow 119991
N. A. Lozinskaya
Lomonosov Moscow State University
Russian Federation
Russian Federation
Natalia A. Lozinskaya – Cand. Sc. (Chem.), Associate Professor at the Department of Medicinal Chemistry and Fine Organic Synthesis,
Leninskie Gory 1, Moscow 119991
A. A. Spasov
Volgograd State Medical University;
Volgograd Medical Scientific Center
Russian Federation
Russian Federation
Alexander A. Spasov – Dr. Sc. (Med.), Head of the Department of Pharmacology and Bioinformatics,
Head of the Department of Pharmacology, Head of the Laboratory of Experimental Pharmacology,
Pavshikh Bortsov square 1, Volgograd 400131
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Review
For citations:
Babkov D.A., Taran A.S., Shevchenko A.A., Naumenko L.V., Zhukovskaya O.N., Efremov A.M., Bezsonova E.N., Lozinskaya N.A., Spasov A.A. Virtual and experimental screening of new melatonin bioisosteres for the treatment of glaucoma. Acta Biomedica Scientifica. 2024;9(1):116-128. (In Russ.) https://doi.org/10.29413/ABS.2024-9.1.12
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