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

Información del proyecto

Pharmcophore-DOS

Identificador del acuerdo de subvención: 654912

DOI

10.3030/654912

Proyecto cerrado

Fecha de la firma de la CE 25 Marzo 2015

Fecha de inicio 1 Junio 2015

Fecha de finalización 31 Mayo 2017

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 195 454,80

Aportación de la UE

€ 195 454,80

Coordinado por

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)

Período documentado: 2015-06-01 hasta 2017-05-31

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

• 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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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