Computer-Aided Drug Design Tutorials: 4.2. Docking Homework
Protein Kinase Inhibitors
This homework continues the protein kinase project that you started with the previous homework. The protein kinase that you optimized the lead for was cyclin-dependent kinase 2 (CDK2). There are several crystal structures of human CDK2 in complex with different inhibitors in the PDB. Design of CDK2 inhibitors is described in this publication.
Perform the following task with a docking program of your choice. The programs DOCK and UCSF Chimera are available on drug1 and drug2 workstations. Drug3 is unavailable this week.
- Describe in your own words the biological role of CDK2 and explain how inhibition of CDK2 may slow down tumour growth.
- Search PDB for structures of human CDK2. Make a list of relevant structures and provide the structure of the bound ligand for each.
- Obtain or create 3D structures of all the inhibitors in Figure 1 of the CDK inhibitor paper. If you like, you can search the literature for binding constants for additional ligands that you found in the PDB.
- Prepare two different CDK2 files from PDB for docking.
- Prepare all the ligands for which the experimental binding constants are available for docking. Using a tool of your choice, add hydrogens to each ligand. Pay close attention to where hydrogens are added and what is the geometry of hydrogen-carrying molecule. You may need to manually correct or minimize some structures. To select atoms for deletion in UCSF Chimera, hold down Alt key while clicking on the atom. If you choose to minimize the correctly protonated molecule, use semiempirical AM1 method or HF/6-31G* methods for minimization unless you have plenty of computer resources available.
- Perform rigid docking of each of the ligands to both protein structures. Visually check that the docking program finds the poses that mimic the bound ligands in cases where the PDB structure s available. Evaluate if the docking score correlates with experimental binding affinities.
- Perform flexible docking of each of the ligands to both protein structures. Visually check that the docking program finds the poses that mimic the bound ligands in cases where the PDB structure s available. Evaluate if the docking score correlates with experimental binding affinities. Did ligand flexibility help in this case?
- Develop your best docking strategy by varying options to the grid and dock programs such that docking results would correlate with experimental binding affinities.
- Create two images showing the overlays of two best poses of docked and experimental Compound 4 of Vulpetti et al in the binding pocket of CDK2.
- Using the best docking strategy that you have developed, dock the two molecules that you designed in the previous homework to the CDK2 binding site.
- Create two images showing the overlays of each of these two compounds with the experimental structure of Compound 4 of Vulpetti et al in the binding pocket of CDK2.
- Based on the new information that you have gained from docking and from analysis of the CDK2 inhibitor paper, propose and test one new modification that is predicted to bind as well or better than Compound 4 of Vulpetti et al. Create an image showing how this compound overlays with experimental structure of bound Compound 4.