Identification of P-glycoprotein binders based on an in-house prepared diverse set of structures
P-glycoprotein (Pgp) is known as a multidrug resistance protein. It belongs to the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. It was established that the drugs bind when the protein is in its Apo form, i.e. in an ATP free state. Thus, in various lead optimization drug design projects it is extremely important to know whether some biologically active compound is a potential Pgp target. However, the X-ray data provides only a partial answer due to the diverse set of likely structures that exist in the apo protein form.
In a collaboration with the University of Bonn, our scientist obtained several apo structures describing the changes in both the known and hidden binding sites. Our data have been well validated, agree well with the experimental observations and in particular the distances between individual residual pairs in the Nucleotide binding domains (NBDs) measured by DEER spectroscopy.
In conclusion, our models largely extended those retrieved by the X-ray method, and, based on our in house prepared diversity of structures, we can examine with a higher confidence level the possibility of a compound to be a Pgp binder. Thus, we offer as an outsourcing service to our clients such studies.