Estudio de interacciones ligando-receptor mediante técnicas computacionales. La adrenomedulina y las metaloproteasas de la matriz como dianas para el diseño racional de fármacos

Abstract

In this thesis work two different receptors have been used: adrenomedullin (AM) and matrix metalloproteinase type 2 (MMP-2). The main difference, from the drug design point of view is that, while AM is a peptide with an unknown tridimensional structure, thus indirect design must be undertaken, MMP-2 is a well known receptor, therefore direct drug design or structure-based drug design techniques can be applied. Ligand-receptor interactions: Adrenomedullin. AM is a 52 amino acid peptide that plays a critical role in several diseases such as hypertension, cancer, diabetes, and cardiovascular disorders, among others. A 3DQSAR study and conformational and molecular dynamics simulations have allowed us to figure out some key aspects of the structural requirements to bind AM. The derived 3D-QSAR model has been able to predict the affinity with a high predictive quality (q2 LOO = 0.87), as well as to highlight relevant features for the binding to AM. Ligand-receptor interactions: Matrix metalloproteinase type 2. Matrix metalloproteinases (MMPs) are a family of structurally related zinc containing enzymes that mediate the breakdown of connective tissue and, therefore, are targets for therapeutic inhibitors in many inflammatory, malignant, and degenerative diseases. AM is an interesting example of MMP substrate. AM has been reported to be cleaved by MMP-2, but not by MMP-9, therefore MMP-2 may be considered as a specific protease for AM. This work tries to shed light on the possibility that AM positive modulators may act as MMP inhibitors (MMPIs). As starting point 24 compounds, related to the positive modulator lead identified by HTS of the NCI collection, were used. We have developed a virtual screening method that allowed us to select three potentially active compounds. One of them has been identified as a new MMP-2 inhibitor by in vitro inhibition test. Finally, we propose the structure of new MMP-2 inhibitors based on the triazole ring with an electron donor atom at two bonds distance as novel zinc binding group (ZBG). The attached chain has been selected from a database of MMP-2 inhibitors that we have built for this purpose.