Pharmacophore guided diversity-oriented synthesis and its application in discovering inhibitors of protein-protein interactions between RAD51 and BRCA2

Projektinformationen

Pharmcophore-DOS

ID Finanzhilfevereinbarung: 654912

DOI

10.3030/654912

Projekt abgeschlossen

EK-Unterschriftsdatum 25 März 2015

Startdatum 1 Juni 2015

Enddatum 31 Mai 2017

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 195 454,80

EU-Beitrag

€ 195 454,80

Koordiniert durch

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom

Periodic Reporting for period 1 - Pharmcophore-DOS (Pharmacophore guided diversity-oriented synthesis and its application in discovering inhibitors of protein-protein interactions between RAD51 and BRCA2)

Berichtszeitraum: 2015-06-01 bis 2017-05-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Given the difficulty in drug discovery, in particular when protein-protein interactions are targeted, we proposed a innovative strategy to identify hits and lead compounds for non- or difficult-drugged targets. Such an approach could accelerate the drug discovery and enhance the possibility of success in launching novel therapy to suffering patients. In our research, this novel strategy was developed and validated, and is hopeful to be expanded to more targets.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

• Following the novel strategy proposed, corresponding pharmocophore models were established via a structure-based approach.
• As unforeseeable difficulty was encountered in targeting RAD51 and BRAC2, we switched our target to the protein interface between the α and β subunits of CK2. As this proposal focused on the development and validation of this innovative strategy, the change of target showed no influence on objectives and expected outcomings.
• Pharmacophore models of both targets were established.
• Based on the pharmocophore model established (described in previous report), five compound libraries were designed, virtually evaluated and synthesized.
• The Synthesized are evaluated for their ability to bind to the target and potency in disturbing Protein-protein interaction via X-ray crystallography and FP assays, which are currently still ongoing.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

The ability of discovering new drugs are expected to be further enhanced with the innovative strategy, i.e. pharmacophore guided diversity-oriented synthesis. After validation, this novel approach could be employed by other researcher as well and thus push the development of now therapies for unmet medical needs. Such a progress is welcome by suffering patents and their families and could also save hundreds of billions of public health costs.

Pharmacophore model on the protein-protein interface of the α and β subunits of CK2