Computational studies suggest compounds restoring function of p53 cancer mutants can bind SARS-CoV-2 spike protein

Abstract

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 p53^R175H and p53^G245S. 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 $\pm$ 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 $\pm$ 5.98 kcal/mol) and pocket 2 (−18.90 $\pm$ 5.02 kcal/mol). The obtained results for these two compounds are in good agreement with dexamethasone (−18.45$\mathrm{ }\pm$ 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

Graphical Abstract

Keywords:

• COVID-19
• molecular dynamics
• p53 cancer mutants
• RBD
• small molecules

Acknowledgments

The authors acknowledge the Department of Chemistry, the University of Calcutta for computational facilities, and Tanushree Das is grateful to the Government of West Bengal for granting fellowship.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

The author(s) reported there is no funding associated with the work featured in this article.