title: Ranking the Binding Energies of p53 Mutant Activators and Their ADMET Properties.
abstract: The guardian of the genome, p53, is the most mutated protein found in all cancer cells. Restoration of wild-type activity to mutant p53 offers promise to eradicate cancer cells using novel pharmacological agents. Several molecules have already been found to activate mutant p53. While the exact mechanism of action of these compounds has not been fully understood, a transiently open pocket has been identified in some mutants. In our study, we docked twelve known activators to p53 into the open pocket to further understand their mechanism of action and rank the best binders. In addition, we predicted the absorption, distribution, metabolism, excretion and toxicity properties of these compounds to assess their pharmaceutical usefulness. Our studies showed that alkylating ligands do not all bind at the same position, probably due to their varying sizes. In addition, we found that non-alkylating ligands are capable of binding at the same pocket and directly interacting with Cys124. The comparison of the different ligands demonstrates that stictic acid has a great potential as a p53 activator in terms of less adverse effects although it has poorer pharmacokinetic properties.
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, AB, Canada, T6G 1Z2.
authors.forename: Sara Ibrahim
authors.initials: SI
authors.lastname: Omar
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, AB, Canada, T6G 1Z2.|Department of Physics, University of Alberta, Edmonton, AB, Canada, T6G 1Z2.
authors.forename: Jack
authors.initials: J
authors.lastname: Tuszynski
mesh_terms: D000478:Alkylation; D004999:Amifostine / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D001372:Aza Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D004611:Ellipticines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008624:Mercaptoethylamines / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010082:Oxepins / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D011812:Quinuclidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004611:Ellipticines; D006576:Heterocyclic Compounds, 4 or More Rings; D008024:Ligands; D008624:Mercaptoethylamines; D010082:Oxepins; D011743:Pyrimidines; D011812:Quinuclidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C522101:stictic acid; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; C034192:ellipticine; C008009:9-hydroxyellipticine; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one; C402665:CP 31398; D004999:Amifostine; C533410:eprenetapopt
keywords: ADMET properties; MD simulations; P53 activators; docking; p53-R273H