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Biopsycho

The Biopsycho project

Schizophrenia is a frequent and debilitating mental disorder that affects up to 1% of the general population. Useful antipsychotic drugs have a complex pharmacological profile, being able to interact with many receptors with different binding affinity. Moreover, their mechanisms of action are complex since they act not only activating or blocking the receptors, but also modifying the receptor population and conformational distribution.The Biopsycho project is a coordinated research project aiming to the development of a novel strategies for the discovery of antipsychotic drugs. This project is the last edition of a long term collaboration between the departments of Pharmacology and Medicinal Chemistry of the University of Santiago de Compostela and the GRIB at University Pompeu Fabra.

This edition was funded in 2005 by the Spanish Ministerio de Educacion y Ciencia (SAF2005-08025) as a coordinated project involving three diferent subprojects:

Objectives

  • Define Multireceptoral Pharmacological Profiles (PFM) associated to therapeutic effects of antipsychotics
  • Define Conformational Pharmacological Profiles (PCM) through the analysis of the conformational expression of the GPCRs involved in psychosis
  • Build and validate mathematical models of the relation structure/PFM/PFC
  • Design and synthesize compounds with optimum pharmacological profiles

Role of GRIB-CADD in the Biopsycho project

Biocomputational methods are an essential tool for integrating and exploiting the data coming from the three subprojects.The methods used belong to the following two categories:

Direct Methods: Characterization of the receptorome binding sites.

    • Obtaining structural models of the binding sites for all the receptors involved in psychosis. The last models are based on the recently published structure of the human β2 adrenergic receptor (PDB:2RH1) and have been obtained following an automated protocol to guarantee that the structures can be compared

    • Building and analysing the structures of key ligand-receptor complexes. These structures allow to study the differences in affinity of a compound for different receptors as well as the differences of different compounds for the same receptor.

Clozapine in D2/5HT2A

Indirect Methods: Multivariate analysis of the data.

  • Multivariate statistic methods (PCA, PLS) are being used in order to unveil the associations present between different levels of description (clinical, in vitro, in vivo, molecular) of antipsychotic drugs used in clinical practice
  • The chemical structure of the compounds studied were described using a new generation of alignment-independent molecular descriptors  (GRIND-2), using the software Pentacle developed in our laboratory.
  • We have built advanced 3D QSAR models, relating the structures of diverse series of molecules with their pharmacological properties, and providing useful information for the design of novel compounds
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For further information visit the official Biopsycho webpage