Interaction of selected drugs at dimer interface of human 14-3-3ζ protein
The 14-3-3 proteins bind with thousands of binding partners and they are considered as promising drug targets in cancer and neuropsychiatry (1). It is family of adaptor proteins and there is no defined binding site for small organic molecules. 14-3-3 proteins function depends on their oligomeric form which may alter between the monomeric, homodimeric and heterodimeric states (2). In this project we have considered small FDA approved drugs (molecular weight ? 2000) and docked at the dimer interface of 14-3-3? dimer protein using autodock vina in triplicate. 18 consistent drugs selected based on cut-off ? -9 kcal/mol. Further, 10 ns all-atom molecular dynamics (MD) simulations have been performed for each of the 18 protein drug complexes and compare with apo form of the protein. The MM/GBSA (3) based binding energy have be calculated from MD simulations of protein drug complexes using 1000 snapshots. Based on binding energy four drugs selected for further analysis such as hydrogen bond, RMSD, RMSF, Rg etc.The computational predictions will be validated experimentally by NMR, ITC and fluorescence titration experiments.
KB and JH acknowledges funding from grant agency Masaryk University, Grant numbers: MUNI/G/1002/2021 and Czech Science Foundation [GF20-05789 L]. The computational resources were supplied by (Metacentrum and IT4Innovations National Supercomputing Centre (open-17-7)) the project “e-Infrastruktura CZ” (e-INFRA LM2018140 and ID:90140) provided within the program Projects of Large Research, Development and Innovations Infrastructures. KB is also supported by Brno PhD Talent Scholarship – funded by the Brno City Municipality, Brno, Czech Republic.
1. Waloen, K et al. (2021) Mol Pharmacol. 100:155–169.
2. Trošanová, Z. et al. (2022) Journal of Molecular Biology. 434:167479.
3. Valdés-Tresanco, M.S. et al. J. Chem. Theory Comput. 17:6281–6291.