Theoretical justification of a purposeful search of potential neurotropic drugs

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 b...

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Main Authors: Anton Semenets, Marharyta Suleiman, Victoriya Georgiyants, Sergiy Kovalenko, Natalia Kobzar, Lina Grinevich, Mikhail Pokrovskii, Mikhail Korokin, Vladislav Soldatov, Vera Bunyatyan, Lina Perekhoda
Format: Article
Language:English
Published: PC Technology Center 2020-08-01
Series:ScienceRise: Pharmaceutical Science
Subjects:
Online Access:http://journals.uran.ua/sr_pharm/article/view/210042
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author Anton Semenets
Marharyta Suleiman
Victoriya Georgiyants
Sergiy Kovalenko
Natalia Kobzar
Lina Grinevich
Mikhail Pokrovskii
Mikhail Korokin
Vladislav Soldatov
Vera Bunyatyan
Lina Perekhoda
spellingShingle Anton Semenets
Marharyta Suleiman
Victoriya Georgiyants
Sergiy Kovalenko
Natalia Kobzar
Lina Grinevich
Mikhail Pokrovskii
Mikhail Korokin
Vladislav Soldatov
Vera Bunyatyan
Lina Perekhoda
Theoretical justification of a purposeful search of potential neurotropic drugs
ScienceRise: Pharmaceutical Science
1-benzyl-4-pyrrolidin-2-one derivatives
virtual screening
nootropic action
molecular docking
author_facet Anton Semenets
Marharyta Suleiman
Victoriya Georgiyants
Sergiy Kovalenko
Natalia Kobzar
Lina Grinevich
Mikhail Pokrovskii
Mikhail Korokin
Vladislav Soldatov
Vera Bunyatyan
Lina Perekhoda
author_sort Anton Semenets
title Theoretical justification of a purposeful search of potential neurotropic drugs
title_short Theoretical justification of a purposeful search of potential neurotropic drugs
title_full Theoretical justification of a purposeful search of potential neurotropic drugs
title_fullStr Theoretical justification of a purposeful search of potential neurotropic drugs
title_full_unstemmed Theoretical justification of a purposeful search of potential neurotropic drugs
title_sort theoretical justification of a purposeful search of potential neurotropic drugs
publisher PC Technology Center
series ScienceRise: Pharmaceutical Science
issn 2519-4844
2519-4852
publishDate 2020-08-01
description 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
topic 1-benzyl-4-pyrrolidin-2-one derivatives
virtual screening
nootropic action
molecular docking
url http://journals.uran.ua/sr_pharm/article/view/210042
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spelling doaj-7ef6affc052947dcb63119effc9e63732020-11-25T04:06:53ZengPC Technology CenterScienceRise: Pharmaceutical Science2519-48442519-48522020-08-0104 (26)41710.15587/2519-4852.2020.210042210042Theoretical justification of a purposeful search of potential neurotropic drugsAnton Semenets0Marharyta Suleiman1Victoriya Georgiyants2Sergiy Kovalenko3Natalia Kobzar4Lina Grinevich5Mikhail Pokrovskii6Mikhail Korokin7Vladislav Soldatov8Vera Bunyatyan9Lina Perekhoda10National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002V. N. Karazin Kharkiv National University 4 Svobody sq., Kharkiv, Ukraine, 61022National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002Belgorod State University Pobedy str., 85, Belgorod, Russia, 308015Belgorod State University Pobedy str., 85, Belgorod, Russia, 308015Belgorod State University Pobedy str., 85, Belgorod, Russia, 308015M. Sechenov First Moscow State Medical University (Sechenov University) Trubeckaya Str., 8, Moscow, Russia, 119991National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002A 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 studieshttp://journals.uran.ua/sr_pharm/article/view/2100421-benzyl-4-pyrrolidin-2-one derivativesvirtual screeningnootropic actionmolecular docking