In-Silico Mining of the Toxins Database (T3DB) towards Hunting Prospective Candidates as ABCB1 Inhibitors: Integrated Molecular Docking and Lipid Bilayer-Enhanced Molecular Dynamics Study
Multidrug resistance (MDR) is one of the most problematic issues in chemotherapeutic carcinoma therapy. The ABCB1 transporter, a drug efflux pump overexpressed in cancer cells, has been thoroughly investigated for its association with MDR. Thus, discovering ABCB1 inhibitors can reverse the MDR in ca...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-07-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/16/7/1019 |
| _version_ | 1797587871177113600 |
|---|---|
| author | Mahmoud A. A. Ibrahim Khlood A. A. Abdeljawaad Alaa H. M. Abdelrahman Peter A. Sidhom Ahmed M. Tawfeek Gamal A. H. Mekhemer Mohamed K. Abd El-Rahman Eslam Dabbish Tamer Shoeib |
| author_facet | Mahmoud A. A. Ibrahim Khlood A. A. Abdeljawaad Alaa H. M. Abdelrahman Peter A. Sidhom Ahmed M. Tawfeek Gamal A. H. Mekhemer Mohamed K. Abd El-Rahman Eslam Dabbish Tamer Shoeib |
| author_sort | Mahmoud A. A. Ibrahim |
| collection | DOAJ |
| description | Multidrug resistance (MDR) is one of the most problematic issues in chemotherapeutic carcinoma therapy. The ABCB1 transporter, a drug efflux pump overexpressed in cancer cells, has been thoroughly investigated for its association with MDR. Thus, discovering ABCB1 inhibitors can reverse the MDR in cancer cells. In the current work, a molecular docking technique was utilized for hunting the most prospective ABCB1 inhibitors from the Toxin and Toxin-Target Database (T3DB). Based on the docking computations, the most promising T3DB compounds complexed with the ABCB1 transporter were subjected to molecular dynamics (MD) simulations over 100 ns. Utilizing the MM-GBSA approach, the corresponding binding affinities were computed. Compared to ZQU (calc. −49.8 kcal/mol), Emamectin B1a (T3D1043), Emamectin B1b (T3D1044), Vincristine (T3D4016), Vinblastine (T3D4017), and Vindesine (T3D2479) complexed with ABCB1 transporter demonstrated outstanding binding affinities with Δ<i>G</i><sub>binding</sub> values of −93.0, −92.6, −93.8, −92.2, and −90.8 kcal/mol, respectively. The structural and energetic investigations confirmed the constancy of the identified T3DB compounds complexed with the ABCB1 transporter during the 100 ns MD course. To mimic the physiological conditions, MD simulations were conducted for those identified inhibitors complexed with ABCB1 transporter in the presence of a POPC membrane. These findings revealed that Emamectin B1a, Emamectin B1b, Vincristine, Vinblastine, and Vindesine are promising ABCB1 inhibitors that can reverse the MDR. Therefore, subjecting those compounds to further in-vitro and in-vivo investigations is worthwhile. |
| first_indexed | 2024-03-11T00:44:56Z |
| format | Article |
| id | doaj.art-7e5037ee26d54f91b9400d8ba459232d |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T00:44:56Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-7e5037ee26d54f91b9400d8ba459232d2023-11-18T20:53:14ZengMDPI AGPharmaceuticals1424-82472023-07-01167101910.3390/ph16071019In-Silico Mining of the Toxins Database (T3DB) towards Hunting Prospective Candidates as ABCB1 Inhibitors: Integrated Molecular Docking and Lipid Bilayer-Enhanced Molecular Dynamics StudyMahmoud A. A. Ibrahim0Khlood A. A. Abdeljawaad1Alaa H. M. Abdelrahman2Peter A. Sidhom3Ahmed M. Tawfeek4Gamal A. H. Mekhemer5Mohamed K. Abd El-Rahman6Eslam Dabbish7Tamer Shoeib8Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, EgyptComputational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, EgyptComputational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, EgyptChemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi ArabiaComputational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, EgyptDepartment of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USADepartment of Chemistry, The American University in Cairo, New Cairo 11835, EgyptDepartment of Chemistry, The American University in Cairo, New Cairo 11835, EgyptMultidrug resistance (MDR) is one of the most problematic issues in chemotherapeutic carcinoma therapy. The ABCB1 transporter, a drug efflux pump overexpressed in cancer cells, has been thoroughly investigated for its association with MDR. Thus, discovering ABCB1 inhibitors can reverse the MDR in cancer cells. In the current work, a molecular docking technique was utilized for hunting the most prospective ABCB1 inhibitors from the Toxin and Toxin-Target Database (T3DB). Based on the docking computations, the most promising T3DB compounds complexed with the ABCB1 transporter were subjected to molecular dynamics (MD) simulations over 100 ns. Utilizing the MM-GBSA approach, the corresponding binding affinities were computed. Compared to ZQU (calc. −49.8 kcal/mol), Emamectin B1a (T3D1043), Emamectin B1b (T3D1044), Vincristine (T3D4016), Vinblastine (T3D4017), and Vindesine (T3D2479) complexed with ABCB1 transporter demonstrated outstanding binding affinities with Δ<i>G</i><sub>binding</sub> values of −93.0, −92.6, −93.8, −92.2, and −90.8 kcal/mol, respectively. The structural and energetic investigations confirmed the constancy of the identified T3DB compounds complexed with the ABCB1 transporter during the 100 ns MD course. To mimic the physiological conditions, MD simulations were conducted for those identified inhibitors complexed with ABCB1 transporter in the presence of a POPC membrane. These findings revealed that Emamectin B1a, Emamectin B1b, Vincristine, Vinblastine, and Vindesine are promising ABCB1 inhibitors that can reverse the MDR. Therefore, subjecting those compounds to further in-vitro and in-vivo investigations is worthwhile.https://www.mdpi.com/1424-8247/16/7/1019MDRABCB1 transporterToxin and Toxin-Target Database (T3DB)docking computationsMD simulations |
| spellingShingle | Mahmoud A. A. Ibrahim Khlood A. A. Abdeljawaad Alaa H. M. Abdelrahman Peter A. Sidhom Ahmed M. Tawfeek Gamal A. H. Mekhemer Mohamed K. Abd El-Rahman Eslam Dabbish Tamer Shoeib In-Silico Mining of the Toxins Database (T3DB) towards Hunting Prospective Candidates as ABCB1 Inhibitors: Integrated Molecular Docking and Lipid Bilayer-Enhanced Molecular Dynamics Study Pharmaceuticals MDR ABCB1 transporter Toxin and Toxin-Target Database (T3DB) docking computations MD simulations |
| title | In-Silico Mining of the Toxins Database (T3DB) towards Hunting Prospective Candidates as ABCB1 Inhibitors: Integrated Molecular Docking and Lipid Bilayer-Enhanced Molecular Dynamics Study |
| title_full | In-Silico Mining of the Toxins Database (T3DB) towards Hunting Prospective Candidates as ABCB1 Inhibitors: Integrated Molecular Docking and Lipid Bilayer-Enhanced Molecular Dynamics Study |
| title_fullStr | In-Silico Mining of the Toxins Database (T3DB) towards Hunting Prospective Candidates as ABCB1 Inhibitors: Integrated Molecular Docking and Lipid Bilayer-Enhanced Molecular Dynamics Study |
| title_full_unstemmed | In-Silico Mining of the Toxins Database (T3DB) towards Hunting Prospective Candidates as ABCB1 Inhibitors: Integrated Molecular Docking and Lipid Bilayer-Enhanced Molecular Dynamics Study |
| title_short | In-Silico Mining of the Toxins Database (T3DB) towards Hunting Prospective Candidates as ABCB1 Inhibitors: Integrated Molecular Docking and Lipid Bilayer-Enhanced Molecular Dynamics Study |
| title_sort | in silico mining of the toxins database t3db towards hunting prospective candidates as abcb1 inhibitors integrated molecular docking and lipid bilayer enhanced molecular dynamics study |
| topic | MDR ABCB1 transporter Toxin and Toxin-Target Database (T3DB) docking computations MD simulations |
| url | https://www.mdpi.com/1424-8247/16/7/1019 |
| work_keys_str_mv | AT mahmoudaaibrahim insilicominingofthetoxinsdatabaset3dbtowardshuntingprospectivecandidatesasabcb1inhibitorsintegratedmoleculardockingandlipidbilayerenhancedmoleculardynamicsstudy AT khloodaaabdeljawaad insilicominingofthetoxinsdatabaset3dbtowardshuntingprospectivecandidatesasabcb1inhibitorsintegratedmoleculardockingandlipidbilayerenhancedmoleculardynamicsstudy AT alaahmabdelrahman insilicominingofthetoxinsdatabaset3dbtowardshuntingprospectivecandidatesasabcb1inhibitorsintegratedmoleculardockingandlipidbilayerenhancedmoleculardynamicsstudy AT peterasidhom insilicominingofthetoxinsdatabaset3dbtowardshuntingprospectivecandidatesasabcb1inhibitorsintegratedmoleculardockingandlipidbilayerenhancedmoleculardynamicsstudy AT ahmedmtawfeek insilicominingofthetoxinsdatabaset3dbtowardshuntingprospectivecandidatesasabcb1inhibitorsintegratedmoleculardockingandlipidbilayerenhancedmoleculardynamicsstudy AT gamalahmekhemer insilicominingofthetoxinsdatabaset3dbtowardshuntingprospectivecandidatesasabcb1inhibitorsintegratedmoleculardockingandlipidbilayerenhancedmoleculardynamicsstudy AT mohamedkabdelrahman insilicominingofthetoxinsdatabaset3dbtowardshuntingprospectivecandidatesasabcb1inhibitorsintegratedmoleculardockingandlipidbilayerenhancedmoleculardynamicsstudy AT eslamdabbish insilicominingofthetoxinsdatabaset3dbtowardshuntingprospectivecandidatesasabcb1inhibitorsintegratedmoleculardockingandlipidbilayerenhancedmoleculardynamicsstudy AT tamershoeib insilicominingofthetoxinsdatabaset3dbtowardshuntingprospectivecandidatesasabcb1inhibitorsintegratedmoleculardockingandlipidbilayerenhancedmoleculardynamicsstudy |