| KEYWORD |
Area Engineering
Design of novel inhibitors of the FAB12 protein for drug development against advanced prostate cancer
keywords CANCER THERAPY, DOCKING, HOMOLOGY MODELLING, PROTEINS
Reference persons JACEK ADAM TUSZYNSKI
Research Groups 28- biomedica
Thesis type COMPUTATIONAL
Description Rational drug design involves prediction of the selectivity and specificity of drug-protein interactions. Numerous (over 20) atomic resolution structures of FABP exist in the Protein Data Bank (PDB) but they are from different FABPs and animal sources and hence must be refined for human FABP12 through homology modeling based on the existing crystal structure scaffolds. Molecular dynamics will be used to model multiple equilibrated states of the solvated proteins representing their range of flexibility in solution. We will accurately characterize protein-protein and protein-drug interactions, and perform binding free energy analysis using the MM/PBSA method. We will then generate chemical structures in silico (with the Molecular Operating Environment and/or the Schrodinger Drug Discovery software) to create synthetically accessible compounds. Ligand preparation software will generate representative 3D structures and their tautomeric and stereochemical variants, which will be filtered for PK or toxic liabilities using ADME prediction software estimates. We will apply consensus docking methodology (with e.g. AutoDock, Vina, DOCK, etc.) for the target protein and all compounds, ranking them based on their target protein affinity and accounting for molecular weight, lipophilicity, chemical tractability, cell membrane permeability, and patentability. This task will utilize cheminformatics, combinatorial chemistry and molecular modeling.
The student will be able to perform the tasks for the project in collaboration with researchers at the University of Alberta in Edmonton, Canada.
dynamics, and molecular docking
fragments from library screenings, and build synthesizable de novo molecules to be tested in cell-based assays.
Required skills basic knowledge of bioinformatics, chemoinformatics, docking and molecular modeling
Notes The student may be able to spend a part of the time dedicated to this project at the University of Alberta in Edmonton, Canada. The student's travel costs and subsistence will be covered by the host institution.
Deadline 08/08/2025
PROPONI LA TUA CANDIDATURA