Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline and memory loss. Apolipoprotein E4 (ApoE4) is a major genetic risk factor for AD, contributing to the disease by promoting amyloid-beta aggregation and tau pathology. ApoE4 is, therefore, a well-validated target in the drug development towards AD therapy. This thesis aims to identify potential small molecules targeting ApoE4 using a validated in-house virtual screening pipeline. Virtual screening is a computational technique that efficiently evaluates large libraries of compounds to identify promising drug candidates.
This research project will involve: i) benchmarking different docking protocols; ii) preparing and processing small molecules from the ZINC20 database and others using various software tools (e.g., PyMOL, Avogadro, Open Babel, Maestro, and Antechamber); iii) parametrizing the ligands and receptor (ApoE4 and homologues) for the screening; iv) conducting virtual screening of potential drugs using the Metacentrum HPC environment; v) performing molecular dynamics (MD) simulations to assess the effects of promising hits on the receptor; and vi) analysing and visualising the results.
 
References:

1. Petros AM, Korepanova A, Jakob CG, Qiu W, Panchal SC, Wang J, Dietrich JD, Brewer JT, Pohlki F, Kling A, Wilcox K, Lakics V, Bahnassawy L, Reinhardt P, Partha SK, Bodelle PM, Lake M, Charych EI, Stoll VS, Sun C, Mohler EG. Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer. J Med Chem. 2019; 62(8):4120-4130. doi: 10.1021/acs.jmedchem.9b00178. Epub 2019 Apr 12. PMID: 30933499.
2. Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019; 15(9):501-518. doi: 10.1038/s41582-019-0228-7. Epub 2019 Jul 31. PMID: 31367008; PMCID: PMC7055192.
3. Nemergut M, Marques SM, Uhrik L, Vanova T, Nezvedova M, Gadara DC, Jha D, Tulis J, Novakova V, Planas-Iglesias J, Kunka A, Legrand A, Hribkova H, Pospisilova V, Sedmik J, Raska J, Prokop Z, Damborsky J, Bohaciakova D, Spacil Z, Hernychova L, Bednar D, Marek M. Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate. Mol Neurodegener. 2023;18(1):38. doi: 10.1186/s13024-023-00620-9. PMID: 37280636; PMCID: PMC10245438.