High rates of mutation in the TP53 tumor suppressor gene have been found in many human cancers, including breast tumors, making p53 one of the most studied proteins in oncology. However, the prognostic and predictive value of alterations in this gene remains ambiguous. To analyze the clinical value of somatic TP53 mutations, we collected clinical and molecular data on 210 women with primary breast cancer. We found significant associations of p53 mutations with tumor grade, metastasis, molecular subtype, Her2 status and inverse correlations with estrogen and progesterone receptor status. Cox proportional hazard analysis confirmed a strong prognostic value of p53 mutation for overall survival rate and highlighted significant interactions with lymph node involvement and tumor size. In relation to treatment options, TP53 mutations were associated with poor response to anthracyclines and radiotherapy. Categorization of TP53 mutations according to their type and location revealed that patients with nonsense mutation have the poorest prognosis in comparison with wild-type cases and other types of mutations in this gene. Classification of TP53 mutations with respect to the degree of disturbance of protein structure showed association of disruptive mutations with poorer patients' outcome in contrast to wild-type and non-disruptive mutations. In conclusion, the present study confirms p53 as a potential predictive and prognostic factor in oncology practice and highlights the growing evidence that distinct types of mutations have different clinical impacts.

• MeSH
• duktální karcinom prsu genetika   metabolismus   terapie   MeSH
• geny p53 genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lobulární karcinom genetika   metabolismus   terapie   MeSH
• mastektomie MeSH
• míra přežití MeSH
• missense mutace MeSH
• mutace genetika   MeSH
• nádory prsu genetika   metabolismus   terapie   MeSH
• nesmyslný kodon MeSH
• prognóza MeSH
• proporcionální rizikové modely MeSH
• protinádorové látky terapeutické užití   MeSH
• radioterapie MeSH
• receptor erbB-2 metabolismus   MeSH
• receptory pro estrogeny metabolismus   MeSH
• receptory progesteronu metabolismus   MeSH
• senioři MeSH
• staging nádorů MeSH
• stupeň nádoru MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A semiempirical quantum mechanical PM6-DH2 method accurately covering the dispersion interaction and H-bonding was used to score fifteen structurally diverse CDK2 inhibitors. The geometries of all the complexes were taken from the X-ray structures and were reoptimised by the PM6-DH2 method in continuum water. The total scoring function was constructed as an estimate of the binding free energy, i.e., as a sum of the interaction enthalpy, interaction entropy and the corrections for the inhibitor desolvation and deformation energies. The applied scoring function contains a clear thermodynamical terms and does not involve any adjustable empirical parameter. The best correlations with the experimental inhibition constants (ln K (i)) were found for bare interaction enthalpy (r (2) = 0.87) and interaction enthalpy corrected for ligand desolvation and deformation energies (r (2) = 0.77); when the entropic term was considered, however, the correlation becomes worse but still acceptable (r (2) = 0.52). The resulting correlation based on the PM6-DH2 scoring function is better than previously published function based on various docking/scoring, SAR studies or advanced QM/MM approach, however, the robustness is limited by number of available experimental data used in the correlation. Since a very similar correlation between the experimental and theoretical results was found also for a different system of the HIV-1 protease, the suggested scoring function based on the PM6-DH2 method seems to be applicable in drug design, even if diverse protein-ligand complexes have to be ranked.

• MeSH
• cyklin-dependentní kinasa 2 antagonisté a inhibitory   metabolismus   MeSH
• inhibitory proteinkinas chemie   farmakologie   MeSH
• kvantová teorie MeSH
• lidé MeSH
• ligandy MeSH
• molekulární modely MeSH
• racionální návrh léčiv MeSH
• termodynamika MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH