Computer-aided drug design and in silico pharmacokinetics predictions of some potential antipsychotic agents
The target of many drugs for the treatment of psychiatric disorders and other related neurological conditions are majorly relied on monoaminergic systems. In continuation of our previous study, computer-aided drug design approach was employed to design some new inhibitors of norepinephrine transport...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | Scientific African |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468227621000387 |
| _version_ | 1818718554683342848 |
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| author | Sabitu Babatunde Olasupo Adamu Uzairu Gideon Adamu Shallangwa Sani Uba |
| author_facet | Sabitu Babatunde Olasupo Adamu Uzairu Gideon Adamu Shallangwa Sani Uba |
| author_sort | Sabitu Babatunde Olasupo |
| collection | DOAJ |
| description | The target of many drugs for the treatment of psychiatric disorders and other related neurological conditions are majorly relied on monoaminergic systems. In continuation of our previous study, computer-aided drug design approach was employed to design some new inhibitors of norepinephrine transporter as potential antipsychotic agents. The significant contribution of some descriptors (AlogP, AATS7i and ATSC3p) in the developed QSAR model and the result of molecular docking simulations from our previous study informed the selection of compound 2 as the lead compound for the design of some new inhibitors in the present study. Subsequently, ten (10) hypothetical inhibitors were designed that showed better pharmacological properties as potential antipsychotic agents when compared the results with an FDA approved antispychotic drug (Atomoxetine). The molecular docking analysis of the designed inhibitors revealed good biochemical interactions toward the active site of the biological target (receptor) with better binding affinities ranges from -7.2 to -7.6 kcal/mol compared to the binding affinity of the lead compound and the referenced drug (Atomoxetine) which were found to be 7.1 kcal/mol and 6.5 kcal/mol, respectively. An appreciable number of hydrogen bonds were associated between the amino acid residues of the protein target and all the designed inhibitors when compared the result to that of the lead compound. Likewise, the computed numerical values of all the descriptors in the designed inhibitors were significantly increased. These remarkable properties observed in the designed inhibitors could be ascribed to the structural modification via electrophilic substitutions (NH2, -OH, –OCH3, -CH3, NO2, -CF3, -F and Cl) at different positions of the lead compound owing to the influence of heteroatoms in the substituents as revealed by the descriptors in the developed QSAR model of our previous study. Similarly, drug-likeness and bioavailability evaluation showed that none of the designed inhibitors violates Lipinski's rule of five. The ADMET properties also revealed that all the designed inhibitors possessed excellent pharmacological attributes. Furthermore, toxicity risk assessments of some selected designed inhibitors showed that most of the selected inhibitors are non-AMES mutagenicity and none of these inhibitors is carcinogens. Against this background, the hypothetical designed inhibitors could be subjected to further experimental investigations and in vitro evaluations before it could be developed and optimized as novel antipsychotic agents/ drug candidates. |
| first_indexed | 2024-12-17T19:52:54Z |
| format | Article |
| id | doaj.art-e061986db7ea443da222ab64014b9869 |
| institution | Directory Open Access Journal |
| issn | 2468-2276 |
| language | English |
| last_indexed | 2024-12-17T19:52:54Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Scientific African |
| spelling | doaj.art-e061986db7ea443da222ab64014b98692022-12-21T21:34:41ZengElsevierScientific African2468-22762021-07-0112e00734Computer-aided drug design and in silico pharmacokinetics predictions of some potential antipsychotic agentsSabitu Babatunde Olasupo0Adamu Uzairu1Gideon Adamu Shallangwa2Sani Uba3National Agency for Food and Drug Administration and Control (NAFDAC), Abuja, Nigeria; Corresponding author.Department of Chemistry, Ahmadu Bello University Zaria, NigeriaDepartment of Chemistry, Ahmadu Bello University Zaria, NigeriaDepartment of Chemistry, Ahmadu Bello University Zaria, NigeriaThe target of many drugs for the treatment of psychiatric disorders and other related neurological conditions are majorly relied on monoaminergic systems. In continuation of our previous study, computer-aided drug design approach was employed to design some new inhibitors of norepinephrine transporter as potential antipsychotic agents. The significant contribution of some descriptors (AlogP, AATS7i and ATSC3p) in the developed QSAR model and the result of molecular docking simulations from our previous study informed the selection of compound 2 as the lead compound for the design of some new inhibitors in the present study. Subsequently, ten (10) hypothetical inhibitors were designed that showed better pharmacological properties as potential antipsychotic agents when compared the results with an FDA approved antispychotic drug (Atomoxetine). The molecular docking analysis of the designed inhibitors revealed good biochemical interactions toward the active site of the biological target (receptor) with better binding affinities ranges from -7.2 to -7.6 kcal/mol compared to the binding affinity of the lead compound and the referenced drug (Atomoxetine) which were found to be 7.1 kcal/mol and 6.5 kcal/mol, respectively. An appreciable number of hydrogen bonds were associated between the amino acid residues of the protein target and all the designed inhibitors when compared the result to that of the lead compound. Likewise, the computed numerical values of all the descriptors in the designed inhibitors were significantly increased. These remarkable properties observed in the designed inhibitors could be ascribed to the structural modification via electrophilic substitutions (NH2, -OH, –OCH3, -CH3, NO2, -CF3, -F and Cl) at different positions of the lead compound owing to the influence of heteroatoms in the substituents as revealed by the descriptors in the developed QSAR model of our previous study. Similarly, drug-likeness and bioavailability evaluation showed that none of the designed inhibitors violates Lipinski's rule of five. The ADMET properties also revealed that all the designed inhibitors possessed excellent pharmacological attributes. Furthermore, toxicity risk assessments of some selected designed inhibitors showed that most of the selected inhibitors are non-AMES mutagenicity and none of these inhibitors is carcinogens. Against this background, the hypothetical designed inhibitors could be subjected to further experimental investigations and in vitro evaluations before it could be developed and optimized as novel antipsychotic agents/ drug candidates.http://www.sciencedirect.com/science/article/pii/S2468227621000387AntipsychoticADMETPharmacokineticsDesignDrugQSAR |
| spellingShingle | Sabitu Babatunde Olasupo Adamu Uzairu Gideon Adamu Shallangwa Sani Uba Computer-aided drug design and in silico pharmacokinetics predictions of some potential antipsychotic agents Scientific African Antipsychotic ADMET Pharmacokinetics Design Drug QSAR |
| title | Computer-aided drug design and in silico pharmacokinetics predictions of some potential antipsychotic agents |
| title_full | Computer-aided drug design and in silico pharmacokinetics predictions of some potential antipsychotic agents |
| title_fullStr | Computer-aided drug design and in silico pharmacokinetics predictions of some potential antipsychotic agents |
| title_full_unstemmed | Computer-aided drug design and in silico pharmacokinetics predictions of some potential antipsychotic agents |
| title_short | Computer-aided drug design and in silico pharmacokinetics predictions of some potential antipsychotic agents |
| title_sort | computer aided drug design and in silico pharmacokinetics predictions of some potential antipsychotic agents |
| topic | Antipsychotic ADMET Pharmacokinetics Design Drug QSAR |
| url | http://www.sciencedirect.com/science/article/pii/S2468227621000387 |
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