Selective Non-toxics Inhibitors Targeting DHFR for Tuberculosis and Cancer Therapy: Pharmacophore Generation and Molecular Dynamics Simulation
Dihydrofolate reductase (DHFR) is a crucial enzyme that catalyzes the conversion of folic acid. Its reserved properties and significance in both human (h-DHFR) and mycobacterium (mt-DHFR) make it a challenging target for developing drugs against cancer and bacterial infections. Although methotrexate...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2023-05-01
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| Series: | Bioinformatics and Biology Insights |
| Online Access: | https://doi.org/10.1177/11779322231171778 |
| _version_ | 1797831433975234560 |
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| author | Ghyzlane EL Haddoumi Mariam Mansouri Houda Bendani Mohammed Walid Chemao-Elfihri Jouhaina Kourou Hanane Abbou Lahcen Belyamani Ilham Kandoussi Azeddine Ibrahimi |
| author_facet | Ghyzlane EL Haddoumi Mariam Mansouri Houda Bendani Mohammed Walid Chemao-Elfihri Jouhaina Kourou Hanane Abbou Lahcen Belyamani Ilham Kandoussi Azeddine Ibrahimi |
| author_sort | Ghyzlane EL Haddoumi |
| collection | DOAJ |
| description | Dihydrofolate reductase (DHFR) is a crucial enzyme that catalyzes the conversion of folic acid. Its reserved properties and significance in both human (h-DHFR) and mycobacterium (mt-DHFR) make it a challenging target for developing drugs against cancer and bacterial infections. Although methotrexate (MTX) is commonly used for cancer therapy and bacterial infections, it has a toxic profile. In this study, we aimed to identify selective and non-toxic inhibitors against h-DHFR and mt-DHFR using an in silico approach. From a data set of 8 412 inhibitors, 11 compounds passed the toxicity and drug-likeness tests, and their interaction with h-DHFR and mt-DHFR was studied by performing molecular docking. To evaluate the inhibitory activity of the compounds against mt-DHFR, five known reference ligands and the natural ligand (dihydrofolate) were used to generate a pharmacophoric map. Two potential selective inhibitors for mt-DHFR and h-DHFR were selected for further investigation using molecular dynamics for 100 ns. As a result, BDBM18226 was identified as the best compound selective for mt-DHFR, non-toxic, with five features listed in the map, with a binding energy of –9.6 kcal/mol. BDBM50145798 was identified as a non-toxic selective compound with a better affinity than MTX for h-DHFR. Molecular dynamics of the two best ligands suggest that they provide more stable, compact, and hydrogen bond interactions with the protein. Our findings could significantly expand the chemical space for new mt-DHFR inhibitors and provide a non-toxic alternative toward h-DHFR for the respective treatment of tuberculosis and cancer therapy. |
| first_indexed | 2024-04-09T13:51:49Z |
| format | Article |
| id | doaj.art-c9eaad587cf24ab58195360779414f6c |
| institution | Directory Open Access Journal |
| issn | 1177-9322 |
| language | English |
| last_indexed | 2024-04-09T13:51:49Z |
| publishDate | 2023-05-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Bioinformatics and Biology Insights |
| spelling | doaj.art-c9eaad587cf24ab58195360779414f6c2023-05-08T14:34:06ZengSAGE PublishingBioinformatics and Biology Insights1177-93222023-05-011710.1177/11779322231171778Selective Non-toxics Inhibitors Targeting DHFR for Tuberculosis and Cancer Therapy: Pharmacophore Generation and Molecular Dynamics SimulationGhyzlane EL Haddoumi0Mariam Mansouri1Houda Bendani2Mohammed Walid Chemao-Elfihri3Jouhaina Kourou4Hanane Abbou5Lahcen Belyamani6Ilham Kandoussi7Azeddine Ibrahimi8Centre Mohammed VI for Research and Innovation (CM6), Rabat, MoroccoCentre Mohammed VI for Research and Innovation (CM6), Rabat, MoroccoCentre Mohammed VI for Research and Innovation (CM6), Rabat, MoroccoCentre Mohammed VI for Research and Innovation (CM6), Rabat, MoroccoCentre Mohammed VI for Research and Innovation (CM6), Rabat, MoroccoMohammed VI university of Health Sciences (UM6SS), Casablanca, MoroccoEmergency Department, Military Hospital Mohammed V, Rabat, MoroccoCentre Mohammed VI for Research and Innovation (CM6), Rabat, MoroccoMohammed VI university of Health Sciences (UM6SS), Casablanca, MoroccoDihydrofolate reductase (DHFR) is a crucial enzyme that catalyzes the conversion of folic acid. Its reserved properties and significance in both human (h-DHFR) and mycobacterium (mt-DHFR) make it a challenging target for developing drugs against cancer and bacterial infections. Although methotrexate (MTX) is commonly used for cancer therapy and bacterial infections, it has a toxic profile. In this study, we aimed to identify selective and non-toxic inhibitors against h-DHFR and mt-DHFR using an in silico approach. From a data set of 8 412 inhibitors, 11 compounds passed the toxicity and drug-likeness tests, and their interaction with h-DHFR and mt-DHFR was studied by performing molecular docking. To evaluate the inhibitory activity of the compounds against mt-DHFR, five known reference ligands and the natural ligand (dihydrofolate) were used to generate a pharmacophoric map. Two potential selective inhibitors for mt-DHFR and h-DHFR were selected for further investigation using molecular dynamics for 100 ns. As a result, BDBM18226 was identified as the best compound selective for mt-DHFR, non-toxic, with five features listed in the map, with a binding energy of –9.6 kcal/mol. BDBM50145798 was identified as a non-toxic selective compound with a better affinity than MTX for h-DHFR. Molecular dynamics of the two best ligands suggest that they provide more stable, compact, and hydrogen bond interactions with the protein. Our findings could significantly expand the chemical space for new mt-DHFR inhibitors and provide a non-toxic alternative toward h-DHFR for the respective treatment of tuberculosis and cancer therapy.https://doi.org/10.1177/11779322231171778 |
| spellingShingle | Ghyzlane EL Haddoumi Mariam Mansouri Houda Bendani Mohammed Walid Chemao-Elfihri Jouhaina Kourou Hanane Abbou Lahcen Belyamani Ilham Kandoussi Azeddine Ibrahimi Selective Non-toxics Inhibitors Targeting DHFR for Tuberculosis and Cancer Therapy: Pharmacophore Generation and Molecular Dynamics Simulation Bioinformatics and Biology Insights |
| title | Selective Non-toxics Inhibitors Targeting DHFR for Tuberculosis and Cancer Therapy: Pharmacophore Generation and Molecular Dynamics Simulation |
| title_full | Selective Non-toxics Inhibitors Targeting DHFR for Tuberculosis and Cancer Therapy: Pharmacophore Generation and Molecular Dynamics Simulation |
| title_fullStr | Selective Non-toxics Inhibitors Targeting DHFR for Tuberculosis and Cancer Therapy: Pharmacophore Generation and Molecular Dynamics Simulation |
| title_full_unstemmed | Selective Non-toxics Inhibitors Targeting DHFR for Tuberculosis and Cancer Therapy: Pharmacophore Generation and Molecular Dynamics Simulation |
| title_short | Selective Non-toxics Inhibitors Targeting DHFR for Tuberculosis and Cancer Therapy: Pharmacophore Generation and Molecular Dynamics Simulation |
| title_sort | selective non toxics inhibitors targeting dhfr for tuberculosis and cancer therapy pharmacophore generation and molecular dynamics simulation |
| url | https://doi.org/10.1177/11779322231171778 |
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