Structure Based Drug Designing When Active Site Is Known But No Known Inhibitors Available Present ?

Question

[Zak]

I am doing a project on structure based drug designing , and i have a protein-protein interaction site for which no known inhibitors are known and there are no related proteins with inhibitors. What should i do ?? can i use random drug like molecules from zinc database??

I would also like to know about any academic free software's for QSAR.

Thanks in advance

[Michael Schubert]

so, is it a PPI surface or an active site? ..not entirely sure from title+text

Answer 1

[Michael Schubert]

You have got 2 choices here:

• select a large dataset from a database of small molecules, e.g. ZINC, as you suggested
• try to design a molecule to fit your binding pocket

To find suitable potential inhibitors, you can make use of the fact that an inhibitor is in most cases structurally related to the substrate. E.g., you could enter the substrate in ZINC and search for structures of 80% similarity as a basis of your virtual screening experiment.

For academically licensed docking tools, you can have a look at AutoDock or UCSF Dock.

edit: I missed the PPI here. The workflow is generally the same, but you of course don't have a substrate to start your search with. You could look for compounds structurally similar to a part of the interfacing area or do a random set of small molecules (which may not work too well).

Answer 2

[Egon Willighagen]

For free QSAR software there are a couple of options. Part of that, is the calculation of descriptors for which you can use the Chemistry Development Kit. Bioclipse provides a graphics user interface for this (and for the JOELib and OpenTox descriptors too):

See this paper. The Bioclipse authors are working on integrating R so that you can also make regression models inside Bioclipse too.

Answer 3

[Vladimir Chupakhin]

1. Define the binding site - small, big, flexible, some sites can be druggable, some not.
2. Search similar binding site in databases with site comparison software
3. Generate the pharmacophore for protein-protein itneraction - search with pharmacophore
4. etc

Answer 4

[Keith Callenberg]

There is a nice list of QSAR software, some free for academics, here: http://www.click2drug.org/index.html#QSAR