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Area Engineering
Computational design of novel PROTAC structures targeting the p53 mutants for degradation
keywords CANCER THERAPY, COMPUTATIONAL DRUG DESIGN, P53, PROTAC
Reference persons MARCO AGOSTINO DERIU, JACEK ADAM TUSZYNSKI
Research Groups 28- biomedica
Thesis type COMPUTATIONAL
Description The p53 protein is a key regulator of the cell cycle and a so-called guardian of the genome. It is mutated in 50% of all cancer cells and this poses a major problem for cancer therapy. There is only one drug available that targets p53 non-specifically (nutlin) and one drug in development designed for p53 mutant activation with a fairly broad target spectrum (PRIMA-1). Previously, my group designed a number of specific activators of p53 mutants corresponding to some "hot spot" mutations. This project will involve computational design of a novel chemical entity, which will be constructed from an activator of a p53 mutant, a linker molecule and a new E3 ligase binding compound discovered earlier by Drs. Richard Fahlman and Jack Tuszynski at the University of Alberta. The student will generate a small combinatorial library of such constructs and simulate their stability in silico. The various structures will differ in the linker molecule lengths and attachment sites. Subsequent simulations will demonstrate which of the new entities preserve the binding activities to both p53 mutants and E3, respectively. Part of the activities planned in this project will take place at the University of Alberta, Canada, in collaboration with Drs. M. Aminpour (Department of Biomedical Engineering), R. Fahlman (Department of Biochemistry) and an industrial partner, Dr. J. Yao of Hermay Pharmaceuticals, which will perform chemical synthesis of the top ranked compounds.
Required skills basic familiarity with computational drug design, molecular dynamics , docking and pharmacokinetic modeling; ability to use MOE software
Notes Due to on-going COVID pandemic, travel to Canada will require mandatory vaccination and approval from the University of Alberta as a formal exchange student. The tuition fees at the University of Alberta will be paid by the host.
Deadline 30/11/2022
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