¿Son los moduladores positivos de adrenomedulina nuevos inhibidores de metaloproteasas de la matriz?

Matrix metalloproteinases (MMPs), are a family of structurally related zinc containing enzymes that play a major role in the breakdown of connective tissue and therefore, are targets for therapeutic inhibitors in many inflammatory, malignant, and degenerative diseases. On the other hand, it has been recently demonstrated that one of these enzymes, MMP-2, a type IV collagenase, termed gelatinase A, cleaves the angiogenic peptide adrenomedullin (AM) (1). AM is a peptide hormone that plays a critical role in several diseases such as diabetes, hypertension and cancer. In a High Throughput Screening (HTS) carried out at the National Cancer Institute (NCI), a series of AM modulators were identified, with an interesting hypotensive activity (2). In order to shed light into the mechanism of action of these interesting compounds, we have hypothesized that they may be affecting the biodisponibility of AM in the blood stream by inhibiting the MMP-2 protease activity. In the present work, we present a theoretical study, making use of molecular mechanics, docking and virtual screening techniques, with the aim of demonstrating this hypothesis. Biological evaluation of MMP-2 inhibition by some selected compounds, followed the computational work, leading us to propose a structurally new type of MMP-2 inhibitors, with possible interest as anticancer and antiangiogenic agents.Las metaloproteasas de la matriz (MMPs) pertenecen a la familia de enzimas que contienen zinc y juegan un papel predominante en la degradación del tejido conectivo. Por ello se consideran dianas terapéuticas para procesos de inflamación y enfermedades malignas y degenerativas. Por otro lado, se ha demostrado recientemente que un miembro de esta familia, MMP-2, una colagenasa de tipo IV también conocida como gelatinasa A, es capaz de degradar un péptido angiogénico denominado adrenomedulina (AM) (1). AM es una hormona peptídica que desarrolla un papel importante en diversas patologías como diabetes, hipertensión y cáncer. Se ha identificado mediante un cribado de alto rendimiento (HTS) de la colección de compuestos del Instituto Nacional del Cáncer (NCI), una serie de moduladores con interesante actividad hipotensora (2). El mecanismo de acción de estos moduladores es desconocido y nosotros proponemos que pueden afectar a la biodisponibilidad de la AM en el torrente sanguíneo por medio de la inhibición de la actividad de la MMP-2. En este trabajo presentamos un estudio teórico que hace uso de técnicas como mecánica molecular, docking y Cribado Virtual con el objetivo de demostrar esa hipótesis. A continuación del estudio computacional se llevó a cabo la evaluación biológica de algunos compuestos, permitiéndonos proponer un nuevo tipo de ZBG que puede ser interesante para el diseño de nuevos inhibidores de MMPS, con interés como agentes anticancerosos y antiangiogénicos

Design, Synthesis, X-ray analysis and preliminary Biological evaluation of Powerful Dual inhibitors for MMP homodimerization.

AIMS OF THE THESIS This work aims to investigate the role of the linker when used to join two different or identical chemical entities in a biological context. The chemical structure of the linker has been given little importance and the possible interaction that it makes with proteins overlooked. The difficulty in going beyond the consideration of length and branch point is given by the difficulty in obtaining structural information. In this work we have been able to overcome these difficulties and by employing crystallization and X-ray structure determination to understand how linker length and branch point influences the inhibition of MMPs, our model enzyme system. The results presented here can be used to pursue a more detailed structure-guided spacer design