P53MUT. REACTIVATORS · Computer-assisted drug discovery and biophysical characterisation of mutant re-activators of the transcription factor p53 as putative tumour therapeutics
6РП — Действия „Мария Кюри“
- Период
- 2006-10-18 → 2008-03-17
- Финансиране от ЕС
- 115 032 €
- Участници
- 1
- Схема
- EIF
Линиите свързват координатора с партньорите.
Накратко на български
Протеинът p53, който потиска туморите, често се уврежда при рак, например чрез мутацията Y220C. Разработването на молекули, които стабилизират този протеин, помага за създаването на нови лекарства за терапия срещу раковите заболявания.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - P53MUT. REACTIVATORS (Computer-assisted drug discovery and biophysical characterisation of mutant reactivators of the transcription factor p53 ...)
The tumour suppressor p53 is mutationally inactivated in some 50% of human cancers. About a third of the mutations lower the melting temperature of the protein, leading to its rapid denaturation. Small molecules that bind to those mutants and stabilise them could be effective anti-cancer drugs. The mutation Y220C, which occurs in ~75,000 new cancer cases per annum, creates a surface cavity that destabilizes the protein by 4 kcal/mol, at a site that is not functional. We have designed a series of binding molecules from an in-silico analysis of the crystal structure using virtual screening and rational drug design. One of them (PhiKan083) binds to the cavity with a dissociation constant of ~ 150 µM. It raises the melting temperature of the mutant and slows down its rate of denaturation. We have solved the crystal structure of the protein-PhiKan083 complex at 1.5 A resolution. The structure implicates key interactions between the protein and ligand and conformational changes that occur on binding, which will provide a basis for lead optimisation. The Y220C mutant is an excellent 'druggable' target and hence there is every possibility that an anti-cancer drug could be developed from studies on the Y220C mutant.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Human cancer is still one of the most challenging areas for drug development. However, as the transcription factor p53 plays a pivotal role in intrinsic tumour suppression, the concept of rescuing mutant p53 by small organic molecules has an enormous potential for the treatment of human cancer.p53 is expressed and activated as a response to stress factors (DNA damage, hypoxia,...) and transactivates a wide variety of genes responsible for apoptosis, cell cycle arrest, DNA repair and antiangiogenesis.About 50% of human cancers lose p53 function as a result of mutations, which predominantly occur in the core DNA-binding domain. Some previous studies have gathered evidence that p53 is in fact a druggable target. However, unfocused screening approaches can be time consuming and cost intensive, and may lead to equivocal interpretations about the mechanism of action.Thus, computer-aided structure-based ligand design and ligand- and structure-based virtual screening methods shall be used to precede and iteratively complement a broad variety of established biophysical methods. To the best of our knowledge this is the first multidisciplinary approach that tries to combine computational and biophysical methods in the drug discovery process for p53 mutant reactivators.The primary objective is to identify lead structures for the interaction with suitable p53 substructures, which can be exploited for lead optimization in focused libraries. Characterization of protein-ligand interactions with biophysical methods (NMR, Xray) will facilitate the design process and allow for detailed investigations of the rescuing mechanism.
Оригинален текст от CORDIS (на английски).
Участници
- MEDICAL RESEARCH COUNCIL · LONDONКоординаторОбединеното кралство
Връзки
Данни: CORDIS, © Европейски съюз