Development of Novel Therapeutics for Schizophrenia Treatment Based on a Selective Positive Allosteric Modulation of α1-Containing GABAARs—In Silico Approach
For the development of atypical antipsychotics, the selective positive allosteric modulation of the ionotropic GABAA receptor (GABAAR) has emerged as a promising approach. In the presented research, two unrelated methods were used for the development of QSAR models for selective positive allosteric...
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| Format: | Article |
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MDPI AG
2022-07-01
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| Series: | Current Issues in Molecular Biology |
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| Online Access: | https://www.mdpi.com/1467-3045/44/8/234 |
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| author | Vladimir Đorđević Milan Petković Jelena Živković Goran M. Nikolić Aleksandar M. Veselinović |
| author_facet | Vladimir Đorđević Milan Petković Jelena Živković Goran M. Nikolić Aleksandar M. Veselinović |
| author_sort | Vladimir Đorđević |
| collection | DOAJ |
| description | For the development of atypical antipsychotics, the selective positive allosteric modulation of the ionotropic GABAA receptor (GABAAR) has emerged as a promising approach. In the presented research, two unrelated methods were used for the development of QSAR models for selective positive allosteric modulation of 1-containing GABAARs with derivatives of imidazo [1,2-a]-pyridine. The development of conformation-independent QSAR models, based on descriptors derived from local molecular graph invariants and SMILES notation, was achieved with the Monte Carlo optimization method. From the vast pool of 0D, 1D, and 2D molecule descriptors, the GA-MLR method developed additional QSAR models. Various statistical methods were utilised for the determination of the developed models’ robustness, predictability, and overall quality, and according to the obtained results, all QSAR models are considered good. The molecular fragments that have a positive or negative impact on the studied activity were obtained from the studied molecules’ SMILES notations, and according to the obtained results, nine novel compounds were designed. The binding affinities to GABAAR of designed compounds were assessed with the application of molecular docking studies and the obtained results showed a high correlation with results obtained from QSAR modeling. To assess all designed molecules’ “drug-likeness”, their physicochemical descriptors were computed and utilised for the prediction of medicinal chemistry friendliness, pharmacokinetic properties, ADME parameters, and druglike nature. |
| first_indexed | 2024-03-09T04:35:24Z |
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| id | doaj.art-eceb014741c3424381d8ec2b87fec39c |
| institution | Directory Open Access Journal |
| issn | 1467-3037 1467-3045 |
| language | English |
| last_indexed | 2024-03-09T04:35:24Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Current Issues in Molecular Biology |
| spelling | doaj.art-eceb014741c3424381d8ec2b87fec39c2023-12-03T13:29:00ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452022-07-014483398341210.3390/cimb44080234Development of Novel Therapeutics for Schizophrenia Treatment Based on a Selective Positive Allosteric Modulation of α1-Containing GABAARs—In Silico ApproachVladimir Đorđević0Milan Petković1Jelena Živković2Goran M. Nikolić3Aleksandar M. Veselinović4Department of Psychiatry with Medical Psychology, Faculty of Medicine, University of Niš, 18000 Niš, SerbiaDepartment of Physiology, Faculty of Medicine, University of Niš, 18000 Niš, SerbiaDepartment of Chemistry, Faculty of Medicine, University of Niš, 18000 Niš, SerbiaDepartment of Chemistry, Faculty of Medicine, University of Niš, 18000 Niš, SerbiaDepartment of Chemistry, Faculty of Medicine, University of Niš, 18000 Niš, SerbiaFor the development of atypical antipsychotics, the selective positive allosteric modulation of the ionotropic GABAA receptor (GABAAR) has emerged as a promising approach. In the presented research, two unrelated methods were used for the development of QSAR models for selective positive allosteric modulation of 1-containing GABAARs with derivatives of imidazo [1,2-a]-pyridine. The development of conformation-independent QSAR models, based on descriptors derived from local molecular graph invariants and SMILES notation, was achieved with the Monte Carlo optimization method. From the vast pool of 0D, 1D, and 2D molecule descriptors, the GA-MLR method developed additional QSAR models. Various statistical methods were utilised for the determination of the developed models’ robustness, predictability, and overall quality, and according to the obtained results, all QSAR models are considered good. The molecular fragments that have a positive or negative impact on the studied activity were obtained from the studied molecules’ SMILES notations, and according to the obtained results, nine novel compounds were designed. The binding affinities to GABAAR of designed compounds were assessed with the application of molecular docking studies and the obtained results showed a high correlation with results obtained from QSAR modeling. To assess all designed molecules’ “drug-likeness”, their physicochemical descriptors were computed and utilised for the prediction of medicinal chemistry friendliness, pharmacokinetic properties, ADME parameters, and druglike nature.https://www.mdpi.com/1467-3045/44/8/234GABAA receptorschizophreniaQSARmolecular modelingdrug design |
| spellingShingle | Vladimir Đorđević Milan Petković Jelena Živković Goran M. Nikolić Aleksandar M. Veselinović Development of Novel Therapeutics for Schizophrenia Treatment Based on a Selective Positive Allosteric Modulation of α1-Containing GABAARs—In Silico Approach Current Issues in Molecular Biology GABAA receptor schizophrenia QSAR molecular modeling drug design |
| title | Development of Novel Therapeutics for Schizophrenia Treatment Based on a Selective Positive Allosteric Modulation of α1-Containing GABAARs—In Silico Approach |
| title_full | Development of Novel Therapeutics for Schizophrenia Treatment Based on a Selective Positive Allosteric Modulation of α1-Containing GABAARs—In Silico Approach |
| title_fullStr | Development of Novel Therapeutics for Schizophrenia Treatment Based on a Selective Positive Allosteric Modulation of α1-Containing GABAARs—In Silico Approach |
| title_full_unstemmed | Development of Novel Therapeutics for Schizophrenia Treatment Based on a Selective Positive Allosteric Modulation of α1-Containing GABAARs—In Silico Approach |
| title_short | Development of Novel Therapeutics for Schizophrenia Treatment Based on a Selective Positive Allosteric Modulation of α1-Containing GABAARs—In Silico Approach |
| title_sort | development of novel therapeutics for schizophrenia treatment based on a selective positive allosteric modulation of α1 containing gabaars in silico approach |
| topic | GABAA receptor schizophrenia QSAR molecular modeling drug design |
| url | https://www.mdpi.com/1467-3045/44/8/234 |
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