Theoretical justification of a purposeful search of potential neurotropic drugs

Authors

DOI:

https://doi.org/10.15587/2519-4852.2020.210042

Keywords:

1-benzyl-4-pyrrolidin-2-one derivatives, virtual screening, nootropic action, molecular docking

Abstract

A targeted search for potential drugs of neurotropic action involves the choice of a basic “pharmacophore”, which is advisable to carry out on the basis of the achieved principle among the classes of chemical compounds where active pharmaceutical substances with high targeted activity have already been identified. Therefore, the pyrrolidine core, which is the basic fragment of nootropics of the racetam group, is promising for the rational design of biologically active compounds of nootropic action. Its combination with other heterocyclic fragments, in particular, the 1,2,4-triazole ring, allows for these “hybrid” molecules to expect a permanent change in the magnitude of the pharmacological effects. Creation of a virtual library of compounds, 3D-pharmacophore screening and molecular docking is a promising way to optimize a targeted search for substances with a given pharmacological activity.

The aim. To optimize targeted search for new nootropic compounds.

Materials and methods. The base generation for the virtual screening was carried out using the Marvin Sketch 20.5 software. For receptor-oriented flexible docking, the Autodock 4.2 software package was used.

Results. New derivatives of 1-benzyl-4-pyrrolidin-2-one were selected as the object of the study. Based on the results of the 3D pharmacophore screening and molecular docking to nootropic targets of the virtual base compounds, scoring functions were calculated. A detailed analysis of the geometrical arrangement of “hit compounds” at the active sites of nootropic receptors (PDB ID: 5UOW, 5CXV, 6PV7) made it possible to formulate hypotheses regarding possible ways of interaction of “hybrid” compounds with biotargets.

The activity of promising molecules with respect to the studied receptors can be realized by creating complexes between them, the stability of which is ensured mainly due to the energetically favourable geometric arrangement of ligands in the active center of these acceptors, the formation of hydrogen bonds between them, and intermolecular electrostatic and donor-acceptor interactions.

Conclusions. Structural modification of the pyrrolidine ring by combining with 1,2,4-triazole scaffold containing substituents of various electronic nature has been proposed. Using 3D-pharmacophore screening, the virtual base of 1-benzyl-4-pyrrolidin-2-one derivatives was analyzed in order to search among them for new molecules of nootropic action. Docking studies have identified a promising group of derivatives of 1-benzyl-4 (4-R-5-sulfanylidene-4,5 dihydro-1H-1,2,4-triazol-3-yl) pyrrolidin-2-one, which have affinity for nootropic biotargets and are promising for further synthetic and pharmacological studies

Author Biographies

Anton Semenets, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

Postgraduate Student

Department of Medicinal Chemistry

Marharyta Suleiman, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

PhD, Assistant

Department of Medicinal Chemistry

Victoriya Georgiyants, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

Doctor of Pharmaceutical Sciences, Professor, Head of Department

Department of Pharmaceutical Chemistry

Sergiy Kovalenko, V. N. Karazin Kharkiv National University 4 Svobody sq., Kharkiv, Ukraine, 61022

Doctor of Chemical Sciences, Professor

Department of Organic Chemistry

Natalia Kobzar, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

PhD, Associate Professor

Department of Pharmaceutical Chemistry

Lina Grinevich, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

PhD, Associate Professor

Department of Pharmaceutical Chemistry

Mikhail Pokrovskii, Belgorod State University Pobedy str., 85, Belgorod, Russia, 308015

MD, Professor, Head of Department

Department of Pharmacology and Clinical Pharmacology

Mikhail Korokin, Belgorod State University Pobedy str., 85, Belgorod, Russia, 308015

MD, Associate Professor

Department of Pharmacology and Clinical Pharmacology

Vladislav Soldatov, Belgorod State University Pobedy str., 85, Belgorod, Russia, 308015

Assistant

Department of Pharmacology and Clinical Pharmacology

Vera Bunyatyan, M. Sechenov First Moscow State Medical University (Sechenov University) Trubeckaya Str., 8, Moscow, Russia, 119991

PhD, Associate Professor

Department of Pharmaceutical Technology and Pharmacology

Lina Perekhoda, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

Doctor of Pharmaceutical Sciences, Professor, Head of Department

Department of Medicinal Chemistry

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Published

2020-08-31

How to Cite

Semenets, A., Suleiman, M., Georgiyants, V., Kovalenko, S., Kobzar, N., Grinevich, L., Pokrovskii, M., Korokin, M., Soldatov, V., Bunyatyan, V., & Perekhoda, L. (2020). Theoretical justification of a purposeful search of potential neurotropic drugs. ScienceRise: Pharmaceutical Science, (4 (26), 4–17. https://doi.org/10.15587/2519-4852.2020.210042

Issue

No. 4 (26) (2020)

Section

Pharmaceutical Science

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Copyright (c) 2020 Anton Semenets, Marharyta Suleiman, Victoriya Georgiyants, Sergiy Kovalenko, Natalia Kobzar, Lina Grinevich, Mikhail Pokrovskii, Mikhail Korokin, Vladislav Soldatov, Vera Bunyatyan, Lina Perekhoda

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