Computer-aided drug design based on phosphatases (ptprz, ptprgamma, ptp1b), kinases (ck2) and histone deacetylases (hdac1, hdac6) as drug targets

Resumen

This thesis focuses on the strategy of the design of Receptor-type tyrosine-protein phosphatase zeta or PTPRZ1 for the treatment of alcohol use disorder and its rewarding effects. The final objective of this work has been the design of a new series of small molecules with the ability to cross the blood brain barrier, which present a great activity and selectivity against PTPRZ1. For this process, the use of computational tools has been fundamental. The mechanism of action of these molecules is based on the direct inhibition of the PTPRZ1 catalytic activity, in order to mimic the activity of pleiotrophin (PTN), a brain hormone involved in neurodegenerative diseases that is the natural ligand of this phosphatase. As a result, two small molecules 10a and 12b have been selected for their high activity against PTPRZ1, with values below micromolar, and for their ability to cross the blood brain membrane in in vitro and in vivo assays. In addition, these small molecules have been tested in other phosphatases in order to assess their selectivity profile. The promising results obtained with 10a and 12b have allowed testing these compounds directly in mice, which has corroborated the implication of PTPRZ1 in the mechanism of drug addiction, and its potential as a pharmacological target for this type of diseases. With this pharmacological assay we have not only observed a decrease in the alcohol consumption, additionally the inhibitory effect on alcohol-reinforcing mechanisms in mice has also been confirmed. During this work, the computational methods have been used to establish ligand-receptor binding models, which have not only served to explain and rationalize the activity and selectivity of the developed compounds but have also served as support in the design of new molecules. Homology models, docking, molecular dynamics, ab initio and free energy calculation techniques have been used in this chapter to study, from a structural point of view, the PTPRZ1 receptor; as well as the possible mechanism of action of the molecules described by our research group. Also, during this thesis new approach in pharmacology known as “multitarget” has been applied the development of compounds known as dual inhibitors is described, since they are capable of inhibiting two types of enzymes involved in tumor processes: Casein Kinase type 2 (CK2) and histone deacetylase (HDAC). Finally, the initiation of a new line of research within the group in which another novel pharmacological approach is faced, the selective degradation of druggable targets. They are the so called PROTAC molecules, whose name stands for “PROteolysis TArgeting Chimeras”.