This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The P53 rumor suppressor protein is crucial to maintaining genomicintegrity. In the event of DNA damage, p53 activates transcription ofgenes that lead to apoptosis or cell cycle arrest. More than 50% of humancancers are associated with mutations to p53, and an estimated 95% of alltumorogenic mutations map to the region of the p53 gene that encodes thecore domain. The goal of our studies is to identify small moleculecompounds that can bind tightly to p53 and 'repair' the subset oftumor-derived p53 stability mutants. Such compounds may be useful forrescuing p53 stability mutants in vivo. Therefore, performing studies onthe development of small molecule compounds that can improve the stabilityof the p53 core domain may provide a useful therapeutic strategy forrestoring the function of common tumor-derived p53 proteins in a subset ofp53-mediated cancers.In this project, based on our crystal structure of p53 core domaincomplexes with small molecule compound, large-scale virtual screening as aroute to identify novel drug lead be performed. Virtual screening, or insilica screening, is a new approach that has attracted increased interestin the pharmaceutical industry as a productive and cost-effectivetechnology in the search for novel lead compounds. In this project ofmolecular docking, large scale virtual screening tools will be used toevaluate the binding modes and binding affinities of every compound inthe virtual-molecule-database to the binding site of the p53 core domain.This method not only represents a very detailed and relevant basis forprioritizing compounds biological screening, but also provides largenumbers of possible molecule candidates for bioassay. Therefore, thisproject will be very helpful for the rational design and development ofsmall molecule compounds that might target tumor-derived mutant p53 forthe treatment of human cancer.
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