USR for the prospective identification of phenotypic hits

When expressed in its wild-type form (~50% of human tumors), the function of the tumour-supressor protein p53 can be inhibited by the Murine Double Minute 2 (MDM2) protein. Therefore, inhibition of the p53-MDM2 interaction, leading to the activation of p53 represents an attractive strategy against several types of cancers.

In this study, we have used Ultrafast Shape Recognition (USR) to screen the set of FDA-approved drugs for novel p53-MDM2 inhibitors using a potent binder of the p53-pocket on MDM2 of as template. Subsequent molecular modelling supported the potential role of the resulting USR hits as p53-MDM2 inhibitors. This was further supported by experimental tests showing that the treatment of human colon tumor cells with the top USR hit, telmisartan, led to a dose-dependent cell growth inhibition in a p53-dependent manner.

Telmisartan has a long history of safe human use as an approved anti-hypertension drug and thus may present an immediate clinical potential as a cancer therapeutic. Furthermore, it could also serve as a structurally-novel lead molecule for the development of more potent, small-molecule p53-MDM2 inhibitors against variety of cancers.

From a methodological perspective, this study demonstrates that the adopted USR-based virtual screening protocol is useful for identifying molecules with whole-cell anti-cancer activity as well as potential small molecule protein-protein interaction inhibitors.This is the fourth publication reporting a successful prospective application of USR (the others are here, here and here), with some more applications being currently prepared for publications.

The paper is available here.

CIBB 2014 will be held at the University of Cambridge

The 11th International Meeting on Computational Intelligence Methods for Bioinformatics and Biostatistics (CIBB) will be held at the Computer Laboratory in Cambridge on the 26-28 June 2014. We are organising a special session on computational methods for drug design within the conference (deadline for paper submUniversity of Cambridge Computer Laboratoryission is 15 March). Further information can be found in this call for papers: http://www.cussb.unisr.it/cibb2014/docs/SpecialSessionCall_DrugDesignMethods.pdf

To be considered for oral presentations, an extended abstract of 4-6 pages must be submitted (see instructions within the call above). A second submission of a 12-page version of the paper will be made after the conference for inclusion in a volume of the Springer’s LNBI series. The best papers across the conference will be invited to a special issue in BMC Bioinformatics.

If your work falls in other areas, these other calls for papers might be relevant to you: http://www.cussb.unisr.it/cibb2014/calls.html

We are fortunate to count with the following keynote speakers: http://www.cussb.unisr.it/cibb2014/conf.html

We look forward to seeing you at the CIBB 2014!