Theoretical activity prediction, structure-based design, molecular docking and pharmacokinetic studies of some maleimides against Leishmania donovani for the treatment of leishmaniasis
Abstract Background Leishmaniasis is a neglected tropical disease caused by a group of protozoan of the genus Leishmania and transmitted to humans majorly through the bite of the female sand fly. It is prevalent in the tropical regions of the world especially in Africa and estimated to affect a popu...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2022-04-01
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| Series: | Bulletin of the National Research Centre |
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| Online Access: | https://doi.org/10.1186/s42269-022-00779-z |
| _version_ | 1811272644817846272 |
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| author | Fabian Audu Ugbe Gideon Adamu Shallangwa Adamu Uzairu Ibrahim Abdulkadir |
| author_facet | Fabian Audu Ugbe Gideon Adamu Shallangwa Adamu Uzairu Ibrahim Abdulkadir |
| author_sort | Fabian Audu Ugbe |
| collection | DOAJ |
| description | Abstract Background Leishmaniasis is a neglected tropical disease caused by a group of protozoan of the genus Leishmania and transmitted to humans majorly through the bite of the female sand fly. It is prevalent in the tropical regions of the world especially in Africa and estimated to affect a population of about 12 million people annually. This theoretical study was therefore conducted in support of the search for more effective drug candidates for the treatment of leishmaniasis. This study focuses on the in silico activity prediction of twenty-eight (28) maleimides, structure-based design, molecular docking study and pharmacokinetics analysis of the newly designed maleimides. All the studied compounds were drawn using ChemDraw Ultra and optimized by the density functional theory (DFT) approach using B3LYP with 6-31G⁄ basis set. Results The built QSAR model was found to satisfy the requirement of both internal and external validation tests for an acceptable QSAR model with R 2 = 0.801, R 2 adj = 0.748, Q 2 cv = 0.710, R 2 test = 0.892 and cR p 2 = 0.664 and has shown excellent prediction of the studied compounds. Among the five (5) protein receptors utilized for the virtual docking screening, pyridoxal kinase (PdxK) receptor (Pdb id = 6k91) showed the strongest binding interactions with compounds 14, 21 and 24 with the highest binding affinities of − 7.7, − 7.7 and − 7.8 kcal/mol, respectively. The selected templates (14, 21 and 24) were used to design twelve (12) new compounds (N1–N12) with higher docking scores than the templates. N7 (affinity = − 8.9 kcal/mol) and N12 (− 8.5 kcal/mol) showed higher binding scores than the reference drug pentamidine (− 8.10 kcal/mol), while N3 and N7–N12 showed higher predicted pIC50 than the templates. Also, the pharmacokinetics properties prediction revealed that the newly designed compounds, obeyed the Lipinski’s rule for oral bio-availability, showed high human intestinal absorption (HIA), low synthetic accessibility score, CNS and BBB permeability and were pharmacologically active. Conclusions The activities of the various maleimides were predicted excellently by the built QSAR model. Based on the pharmacokinetics and molecular docking studies therefore, the newly designed compounds are suggested for further practical evaluation and/or validation as potential drug candidates for the treatment of leishmaniasis. |
| first_indexed | 2024-04-12T22:44:01Z |
| format | Article |
| id | doaj.art-a529fab0fe124650b11fb259e48aeb7e |
| institution | Directory Open Access Journal |
| issn | 2522-8307 |
| language | English |
| last_indexed | 2024-04-12T22:44:01Z |
| publishDate | 2022-04-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | Bulletin of the National Research Centre |
| spelling | doaj.art-a529fab0fe124650b11fb259e48aeb7e2022-12-22T03:13:37ZengSpringerOpenBulletin of the National Research Centre2522-83072022-04-0146112310.1186/s42269-022-00779-zTheoretical activity prediction, structure-based design, molecular docking and pharmacokinetic studies of some maleimides against Leishmania donovani for the treatment of leishmaniasisFabian Audu Ugbe0Gideon Adamu Shallangwa1Adamu Uzairu2Ibrahim Abdulkadir3Department of Chemistry, Faculty of Physical Sciences, Ahmadu Bello UniversityDepartment of Chemistry, Faculty of Physical Sciences, Ahmadu Bello UniversityDepartment of Chemistry, Faculty of Physical Sciences, Ahmadu Bello UniversityDepartment of Chemistry, Faculty of Physical Sciences, Ahmadu Bello UniversityAbstract Background Leishmaniasis is a neglected tropical disease caused by a group of protozoan of the genus Leishmania and transmitted to humans majorly through the bite of the female sand fly. It is prevalent in the tropical regions of the world especially in Africa and estimated to affect a population of about 12 million people annually. This theoretical study was therefore conducted in support of the search for more effective drug candidates for the treatment of leishmaniasis. This study focuses on the in silico activity prediction of twenty-eight (28) maleimides, structure-based design, molecular docking study and pharmacokinetics analysis of the newly designed maleimides. All the studied compounds were drawn using ChemDraw Ultra and optimized by the density functional theory (DFT) approach using B3LYP with 6-31G⁄ basis set. Results The built QSAR model was found to satisfy the requirement of both internal and external validation tests for an acceptable QSAR model with R 2 = 0.801, R 2 adj = 0.748, Q 2 cv = 0.710, R 2 test = 0.892 and cR p 2 = 0.664 and has shown excellent prediction of the studied compounds. Among the five (5) protein receptors utilized for the virtual docking screening, pyridoxal kinase (PdxK) receptor (Pdb id = 6k91) showed the strongest binding interactions with compounds 14, 21 and 24 with the highest binding affinities of − 7.7, − 7.7 and − 7.8 kcal/mol, respectively. The selected templates (14, 21 and 24) were used to design twelve (12) new compounds (N1–N12) with higher docking scores than the templates. N7 (affinity = − 8.9 kcal/mol) and N12 (− 8.5 kcal/mol) showed higher binding scores than the reference drug pentamidine (− 8.10 kcal/mol), while N3 and N7–N12 showed higher predicted pIC50 than the templates. Also, the pharmacokinetics properties prediction revealed that the newly designed compounds, obeyed the Lipinski’s rule for oral bio-availability, showed high human intestinal absorption (HIA), low synthetic accessibility score, CNS and BBB permeability and were pharmacologically active. Conclusions The activities of the various maleimides were predicted excellently by the built QSAR model. Based on the pharmacokinetics and molecular docking studies therefore, the newly designed compounds are suggested for further practical evaluation and/or validation as potential drug candidates for the treatment of leishmaniasis.https://doi.org/10.1186/s42269-022-00779-zDFTLeishmaniasisL. DonovaniMolecular dockingPharmacokineticsQSAR |
| spellingShingle | Fabian Audu Ugbe Gideon Adamu Shallangwa Adamu Uzairu Ibrahim Abdulkadir Theoretical activity prediction, structure-based design, molecular docking and pharmacokinetic studies of some maleimides against Leishmania donovani for the treatment of leishmaniasis Bulletin of the National Research Centre DFT Leishmaniasis L. Donovani Molecular docking Pharmacokinetics QSAR |
| title | Theoretical activity prediction, structure-based design, molecular docking and pharmacokinetic studies of some maleimides against Leishmania donovani for the treatment of leishmaniasis |
| title_full | Theoretical activity prediction, structure-based design, molecular docking and pharmacokinetic studies of some maleimides against Leishmania donovani for the treatment of leishmaniasis |
| title_fullStr | Theoretical activity prediction, structure-based design, molecular docking and pharmacokinetic studies of some maleimides against Leishmania donovani for the treatment of leishmaniasis |
| title_full_unstemmed | Theoretical activity prediction, structure-based design, molecular docking and pharmacokinetic studies of some maleimides against Leishmania donovani for the treatment of leishmaniasis |
| title_short | Theoretical activity prediction, structure-based design, molecular docking and pharmacokinetic studies of some maleimides against Leishmania donovani for the treatment of leishmaniasis |
| title_sort | theoretical activity prediction structure based design molecular docking and pharmacokinetic studies of some maleimides against leishmania donovani for the treatment of leishmaniasis |
| topic | DFT Leishmaniasis L. Donovani Molecular docking Pharmacokinetics QSAR |
| url | https://doi.org/10.1186/s42269-022-00779-z |
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