Computational studies suggest compounds restoring function of p53 cancer mutants can bind SARS-CoV-2 spike protein
It is reasonable to think that cancer patients undergoing chemotherapy or immunotherapy may have a more aggressive course if they are positive for the novel coronavirus disease. Their compulsive condition requires investigation into effective drugs. We applied computational techniques to a series of compounds known for restoring the function of p53 cancer mutant p53R175H and p53G245S. Two potent inhibitors, 1-(3-chlorophenyl)-3-(1, 3 -thiazol-2-yl) urea (CTU, PubChem NSC321792) with the highest binding affinity -6.92 kcal/mol followed by a thiosemicarbazone compound N'-(1-(Pyridin-2-yl)ethylidene) azetidine - 1 -carbothiohydrazide (NPC, PubChem NSC319726) with -6.75 kcal/mol were subjected to Molecular Dynamics simulation with receptor binding domain (RBD) and compared with control ligand dexamethasone. In particular, CTU adheres to pocket 1 with an average free energy of binding -21.65 ± 2.89 kcal/mol at the RBD - angiotensin-converting enzyme 2 binding region with the highest frequency of amino acid residues after reaching a local equilibrium in 100 ns MD simulation trajectory. A significant enthalpy contribution from the independent simulations unfolds the possibility of dual binding sites for NPC as shifted pocket 1 (-15.59 ± 5.98 kcal/mol) and pocket 2 (-18.90 ± 5.02 kcal/mol). The obtained results for these two compounds are in good agreement with dexamethasone (-18.45 ± 2.42 kcal/mol). Taken together our findings could facilitate the discovery of small molecules that restore the function of p53 cancer mutants newly against COVID-19 in cancer patients.Communicated by Ramaswamy H. Sarma.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:41 |
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| Enthalten in: |
Journal of biomolecular structure & dynamics - 41(2023), 8 vom: 15. Mai, Seite 3368-3381 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Das, Tanushree [VerfasserIn] |
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7S5I7G3JQL |
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| Anmerkungen: |
Date Completed 02.05.2023 Date Revised 03.05.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1080/07391102.2022.2048081 |
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| 520 | |a It is reasonable to think that cancer patients undergoing chemotherapy or immunotherapy may have a more aggressive course if they are positive for the novel coronavirus disease. Their compulsive condition requires investigation into effective drugs. We applied computational techniques to a series of compounds known for restoring the function of p53 cancer mutant p53R175H and p53G245S. Two potent inhibitors, 1-(3-chlorophenyl)-3-(1, 3 -thiazol-2-yl) urea (CTU, PubChem NSC321792) with the highest binding affinity -6.92 kcal/mol followed by a thiosemicarbazone compound N'-(1-(Pyridin-2-yl)ethylidene) azetidine - 1 -carbothiohydrazide (NPC, PubChem NSC319726) with -6.75 kcal/mol were subjected to Molecular Dynamics simulation with receptor binding domain (RBD) and compared with control ligand dexamethasone. In particular, CTU adheres to pocket 1 with an average free energy of binding -21.65 ± 2.89 kcal/mol at the RBD - angiotensin-converting enzyme 2 binding region with the highest frequency of amino acid residues after reaching a local equilibrium in 100 ns MD simulation trajectory. A significant enthalpy contribution from the independent simulations unfolds the possibility of dual binding sites for NPC as shifted pocket 1 (-15.59 ± 5.98 kcal/mol) and pocket 2 (-18.90 ± 5.02 kcal/mol). The obtained results for these two compounds are in good agreement with dexamethasone (-18.45 ± 2.42 kcal/mol). Taken together our findings could facilitate the discovery of small molecules that restore the function of p53 cancer mutants newly against COVID-19 in cancer patients.Communicated by Ramaswamy H. Sarma | ||
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