Unveiling novel inhibitors of dopamine transporter via in silico drug design, molecular docking, and bioavailability predictions as potential antischizophrenic agents
Abstract Background The inhibition of dopamine transporter is known to play a significant role in the treatment of schizophrenia-related and other mental disorders. In a continuing from our previous study, computational drug design approach, molecular docking simulation, and pharmacokinetics study w...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2021-03-01
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| Series: | Future Journal of Pharmaceutical Sciences |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s43094-021-00198-3 |
| _version_ | 1818914176212402176 |
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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 | Abstract Background The inhibition of dopamine transporter is known to play a significant role in the treatment of schizophrenia-related and other mental disorders. In a continuing from our previous study, computational drug design approach, molecular docking simulation, and pharmacokinetics study were explored for the identification of novel inhibitors dopamine transporter as potential Antischizophrenic agents. Consequently, thirteen (13) new inhibitors of dopamine transporter were designed by selecting the molecule with serial number 39 from our previous study as the template molecule because it exhibits good pharmacological attributes. Results Molecular docking simulation results revealed excellent molecular interactions between the protein target (PDB: 4m48) and the ligands (designed inhibitors) with major interactions that involved hydrogen bonding and hydrophobic interactions. Also, some of the designed inhibitors displayed a superior binding affinity range from − 10.0 to − 10.7 kcal/mol compared to the referenced drug (Lumateperone) with a binding affinity of − 9.7 kcal/mol. Computed physicochemical parameters showed that none of the designed inhibitors including the referenced drug violate Lipinski’s rule of five indicating that all the designed inhibitors would be orally bioavailable as potential drug candidates. Similarly, the ADMET/pharmacokinetics evaluations of some designed inhibitors revealed that they possessed good absorption, distribution, metabolism and excretion properties and none of the inhibitors is neither carcinogens nor toxic toward human ether-a-go-go related gene (hERG I) inhibitor or skin sensitization. Likewise, the BOILED-Egg graphics unveils that all the designed inhibitors demonstrate a high probability to be absorbed by the human gastrointestinal tract and could permeate into the brain. Besides, the predicted bioactive parameters suggested that all the selected inhibitors would be active as drug candidates. Furthermore, the synthetic accessibility scores for all the selected inhibitors and referenced drug lied within the easy zone (i.e., between 1–4) with their computed values range from 2.55 to 3.92, this implies that all the selected inhibitors would be very easy to synthesize in the laboratory. Conclusions Hence, all the designed inhibitors having shown excellent pharmacokinetics properties and good bioavailabilities attributes with remarkable biochemical interactions could be developed and optimized as novel Antischizophrenic agents after the conclusion of other experimental investigations. |
| first_indexed | 2024-12-19T23:42:13Z |
| format | Article |
| id | doaj.art-5264908e1ff0440285430938cc234221 |
| institution | Directory Open Access Journal |
| issn | 2314-7253 |
| language | English |
| last_indexed | 2024-12-19T23:42:13Z |
| publishDate | 2021-03-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | Future Journal of Pharmaceutical Sciences |
| spelling | doaj.art-5264908e1ff0440285430938cc2342212022-12-21T20:01:23ZengSpringerOpenFuture Journal of Pharmaceutical Sciences2314-72532021-03-017111010.1186/s43094-021-00198-3Unveiling novel inhibitors of dopamine transporter via in silico drug design, molecular docking, and bioavailability predictions as potential antischizophrenic agentsSabitu Babatunde Olasupo0Adamu Uzairu1Gideon Adamu Shallangwa2Sani Uba3National Agency for Food and Drug Administration and Control (NAFDAC)Department of Chemistry, Ahmadu Bello UniversityDepartment of Chemistry, Ahmadu Bello UniversityDepartment of Chemistry, Ahmadu Bello UniversityAbstract Background The inhibition of dopamine transporter is known to play a significant role in the treatment of schizophrenia-related and other mental disorders. In a continuing from our previous study, computational drug design approach, molecular docking simulation, and pharmacokinetics study were explored for the identification of novel inhibitors dopamine transporter as potential Antischizophrenic agents. Consequently, thirteen (13) new inhibitors of dopamine transporter were designed by selecting the molecule with serial number 39 from our previous study as the template molecule because it exhibits good pharmacological attributes. Results Molecular docking simulation results revealed excellent molecular interactions between the protein target (PDB: 4m48) and the ligands (designed inhibitors) with major interactions that involved hydrogen bonding and hydrophobic interactions. Also, some of the designed inhibitors displayed a superior binding affinity range from − 10.0 to − 10.7 kcal/mol compared to the referenced drug (Lumateperone) with a binding affinity of − 9.7 kcal/mol. Computed physicochemical parameters showed that none of the designed inhibitors including the referenced drug violate Lipinski’s rule of five indicating that all the designed inhibitors would be orally bioavailable as potential drug candidates. Similarly, the ADMET/pharmacokinetics evaluations of some designed inhibitors revealed that they possessed good absorption, distribution, metabolism and excretion properties and none of the inhibitors is neither carcinogens nor toxic toward human ether-a-go-go related gene (hERG I) inhibitor or skin sensitization. Likewise, the BOILED-Egg graphics unveils that all the designed inhibitors demonstrate a high probability to be absorbed by the human gastrointestinal tract and could permeate into the brain. Besides, the predicted bioactive parameters suggested that all the selected inhibitors would be active as drug candidates. Furthermore, the synthetic accessibility scores for all the selected inhibitors and referenced drug lied within the easy zone (i.e., between 1–4) with their computed values range from 2.55 to 3.92, this implies that all the selected inhibitors would be very easy to synthesize in the laboratory. Conclusions Hence, all the designed inhibitors having shown excellent pharmacokinetics properties and good bioavailabilities attributes with remarkable biochemical interactions could be developed and optimized as novel Antischizophrenic agents after the conclusion of other experimental investigations.https://doi.org/10.1186/s43094-021-00198-3ADMETInhibitorDopamineReceptorDisorderSchizophrenia |
| spellingShingle | Sabitu Babatunde Olasupo Adamu Uzairu Gideon Adamu Shallangwa Sani Uba Unveiling novel inhibitors of dopamine transporter via in silico drug design, molecular docking, and bioavailability predictions as potential antischizophrenic agents Future Journal of Pharmaceutical Sciences ADMET Inhibitor Dopamine Receptor Disorder Schizophrenia |
| title | Unveiling novel inhibitors of dopamine transporter via in silico drug design, molecular docking, and bioavailability predictions as potential antischizophrenic agents |
| title_full | Unveiling novel inhibitors of dopamine transporter via in silico drug design, molecular docking, and bioavailability predictions as potential antischizophrenic agents |
| title_fullStr | Unveiling novel inhibitors of dopamine transporter via in silico drug design, molecular docking, and bioavailability predictions as potential antischizophrenic agents |
| title_full_unstemmed | Unveiling novel inhibitors of dopamine transporter via in silico drug design, molecular docking, and bioavailability predictions as potential antischizophrenic agents |
| title_short | Unveiling novel inhibitors of dopamine transporter via in silico drug design, molecular docking, and bioavailability predictions as potential antischizophrenic agents |
| title_sort | unveiling novel inhibitors of dopamine transporter via in silico drug design molecular docking and bioavailability predictions as potential antischizophrenic agents |
| topic | ADMET Inhibitor Dopamine Receptor Disorder Schizophrenia |
| url | https://doi.org/10.1186/s43094-021-00198-3 |
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