Artikel ; Online: In silico screening of inhibitors against human dihydrofolate reductase to identify potential anticancer compounds.
Journal of biomolecular structure & dynamics
2023 Band 41, Heft 23, Seite(n) 14497–14509
Abstract: In all species, dihydrofolate reductase (DHFR) is an essential enzyme that regulates the cellular amount of tetrahydrofolate. Human DHFR (hDHFR) activity inhibition results in tetrahydrofolate depletion and cell death. This property has made hDHFR a ... ...
Abstract | In all species, dihydrofolate reductase (DHFR) is an essential enzyme that regulates the cellular amount of tetrahydrofolate. Human DHFR (hDHFR) activity inhibition results in tetrahydrofolate depletion and cell death. This property has made hDHFR a therapeutic target for cancer. Methotrexate is a well-known hDHFR inhibitor, but its administration has shown some light to severe adverse effects. Therefore, we aimed to find new potential hDHFR inhibitors using structure-based virtual screening, ADMET prediction, molecular docking, and molecular dynamics simulations. Here, we used the PubChem database to find all compounds with at least 90% structural similarity to known natural DHFR inhibitors. To explore their interaction pattern and estimate their binding affinities, the screened compounds (2023) were subjected to structure-based molecular docking against hDHFR. The fifteen compounds that showed higher binding affinity to the hDHFR than the reference compound (methotrexate) displayed important molecular orientation and interactions with key residues in the enzyme's active site. These compounds were subjected to Lipinski and ADMET prediction. PubChem CIDs: 46886812 and 638190 were identified as putative inhibitors. In addition, molecular dynamics simulations revealed that the binding of compounds (CIDs: 46886812 and 63819) stabilized the hDHFR structure and caused minor conformational changes. Our findings suggest that two compounds (CIDs: 46886812 and 63819) could be promising potential inhibitors of hDHFR in cancer therapy.Communicated by Ramaswamy H. Sarma. |
---|---|
Mesh-Begriff(e) | Humans ; Methotrexate/pharmacology ; Methotrexate/chemistry ; Tetrahydrofolate Dehydrogenase/chemistry ; Molecular Docking Simulation ; Folic Acid Antagonists/pharmacology ; Folic Acid Antagonists/chemistry ; Neoplasms ; Tetrahydrofolates |
Chemische Substanzen | Methotrexate (YL5FZ2Y5U1) ; Tetrahydrofolate Dehydrogenase (EC 1.5.1.3) ; Folic Acid Antagonists ; Tetrahydrofolates |
Sprache | Englisch |
Erscheinungsdatum | 2023-03-08 |
Erscheinungsland | England |
Dokumenttyp | Journal Article |
ZDB-ID | 49157-3 |
ISSN | 1538-0254 ; 0739-1102 |
ISSN (online) | 1538-0254 |
ISSN | 0739-1102 |
DOI | 10.1080/07391102.2023.2183038 |
Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
Zusatzmaterialien
Kategorien
Verfügbar in ZB MED Köln/Königswinter
Zs.A 2093: Hefte anzeigen | Standort: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG) |
Über subito bestellen
Dieser Service ist kostenpflichtig (siehe Lieferbedingungen von subito). Bestellungen, die einen Artikel nebst Supplementary Material umfassen, werden grundsätzlich wie mehrfache Bestellungen bearbeitet. Gebühren fallen in diesen Fällen für jede einzelne Bestellung an.