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

Area of Science:

• Biochemistry
• Computational Chemistry
• Oncology

Background:

• Cancer patients undergoing chemotherapy or immunotherapy may face severe COVID-19 outcomes.
• Restoring the function of mutated p53 protein is crucial for cancer treatment.
• Novel therapeutic strategies are needed for cancer patients co-infected with SARS-CoV-2.

Purpose of the Study:

• To identify small molecules capable of restoring the function of p53 cancer mutants (p53^R175H and p53^G245S).
• To evaluate the potential of these compounds as therapeutic agents against COVID-19 in cancer patients.

Main Methods:

• Applied computational techniques to screen compounds targeting p53 cancer mutants.
• Utilized Molecular Dynamics (MD) simulations to assess binding affinity and stability of inhibitors (CTU, NPC) with the SARS-CoV-2 receptor-binding domain (RBD).
• Compared the efficacy of identified compounds with dexamethasone.

Main Results:

• Two potent inhibitors, CTU and NPC, were identified with high binding affinities.
• CTU demonstrated strong binding to RBD pocket 1, with an average free energy of -21.65 ± 2.89 kcal/mol.
• NPC exhibited dual binding site potential in pocket 1 and pocket 2, with free energies of -15.59 ± 5.98 kcal/mol and -18.90 ± 5.02 kcal/mol, respectively.
• Results were comparable to the control ligand, dexamethasone (-18.45 ± 2.42 kcal/mol).

Conclusions:

• CTU and NPC show significant potential for restoring p53 function and inhibiting SARS-CoV-2.
• These compounds could serve as a basis for developing novel small molecules against COVID-19 in cancer patients.
• Further research may facilitate dual-acting therapies for cancer and viral infections.