Project 8. In silico studies on p63 as a new drug-target protein. 

 

Key project members: Gijs Schaftenaar, Niels Verbaandert, Anna Karawajczyk

 

Sponsor: EPISTEM

 

Project Goals

  • Obtaining an optimized p63 structural model of wild-type form of the protein and disease- related mutations of the protein
  • To characterize the structural properties of p63 mutants
  • Characterizing of potential binding modes of small molecules such as PRIMA, MIRA and STIMA known to be able to reactivate mutants
  • Identify possible Mechanisms of Action (MoA)
  • Identify potential pharmacophores for rational drug design

 

Approach

The p63 protein that is a key regulator of ectodermal, orofacial and limb development is studied. Mutants of this protein are involved in the development of rare skin diseases such as EEC syndrome (Ectrodactyly-ectodermal dysplasia-clefting), Hay-Wells syndrome (AEC), Limb-mammary syndrome (LMS) and ADULT syndrome. The X-ray structure of the p63 is not known yet, however it shares a high sequence homology with the tumor suppressor p53. It was observed that small molecules like PRIMA, MIRA and STIMA are capable of reactivating a wide range of mutant forms of the p53 protein. By analogy it is believed these molecules can also interact with p63 with similar biological effects. Modern homology building and pharmacophore modeling approaches are applied to improve insight into the mechanism of action of the reactivating molecules (activators).

 

Results

1. A homology model of the wild type DNA binding domain of p63 is built and optimized.

2. A homology model of R249S mutant of the DNA binding domain of p63 is built and optimized.

3. Number of disease related mutations in the DNA binding domain of p63 is structurally characterized based on current models.

4. Number of possible binding sites is investigated based on the current models using a variety of computational tools.