Hello structural biologists! I am interested in developing an inhibitor to target the assembly of a specific heteromultimeric complex. The complex exists in the cytoplasm of most eukaryotic cells. A crystal structure of the entire complex is available. I am interested in targeting the interaction surface between the two proteins.
The binding surface is comprised of two alpha helices, one from each protein. I am aware that PPIs are considered a particularly tough target for inhibitor development. However, I have an advantage here, as several residues in close proximity are known to be essential for complex formation. In a sense, these residues seem to form a binding pocket, albeit one shared between two proteins.
My goal is to develop a pharmacophore model of this 'binding site' so that I can apply virtual screening to look for compounds that can mask this interaction. I have not found much information on the generation of multi-protein pharmacophores. I would be grateful if someone could point me in the right direction.
Regards,
Patrick
The strategies used in the paper below can be helpful.
https://www.researchgate.net/publication/322950800_Combinatorial_Peptide_Library_Screening_for_Discovery_of_Diverse_a-glucosidase_Inhibitors_Using_Molecular_Dynamics_Simulations_and_Binary_QSAR_Models
You might be interested in the methodology I developed for predicting PPI partners in binary complexes. it is available in full at arXiv.org. Just log in and search for my name, "Vicente M. Reyes"; the article is one of 13. It is based on a reduced representation for proteins called "DCRR". Good luck.
Go through this article:
Pharmacophore based virtual screening for identification of marine bioactive compounds as inhibitors against Mip protein of Chlamydia trachomatis. February 2016, RSC Advances 6(23):18946-18957
DOI: 10.1039/C5RA24999F
Dear Patrick:
Go through this article: Discovery of small molecule inhibitors targeting the SUMO–SIM interaction using a protein interface consensus approach
http://pubs.rsc.org/en/content/articlelanding/2014/md/c3md00391d#!divAbstract
Hi.
You could use fragments pharmacophore-based screening. For generate pharmacophore, you can use the methodology described in these articles: https://pubs.acs.org/doi/abs/10.1021/ct300117j https://www.ncbi.nlm.nih.gov/pubmed/25622696
You can perform a simulation of molecular dynamics with both independent monomers and check the transient changes in interaction surface.
Excuse the language problems...
Best regards
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