Resumen de Computer-Aided Drug Design applied to marine drug discovery
The potential of natural products in general,and marine natural productsin particular, as pharmacological entities has been widely demonstrated in recent years.Marine benthic ecosystemscontain an extraordinary range of diverse organisms that possess bioactive natural compounds, which are commonly used as defensive or protective chemical mechanisms. These effective defensive strategies are based on secondary metabolitesthat are crucial for the species survival.Thepharmacological properties of theseunique chemical compoundsconstitute an interesting and emerging hot research line, based upon exploitingthem for the development of new drugs. The evolution, biodiversity,and specific environmental conditions found in marine ecosystems, such as Antarctica and the Mediterranean Sea, make them an amazing source of potential therapeutic agents. Interestingly, some of these natural productsare capable to modulate protein functions in pathogenesis-related pathways. The process of discoveryand development ofnew drugs, for instance small molecules, with the aforementioned capacity to modulate protein functions,is a tedious procedurethat requires economic resources and time. To reduce these drawbacks, computer-aided drug design (CADD) has emerged as one of the most effective methods.A rapid exploration of the chemical space can be done with computational methods, andthey are very interesting and useful complementaryapproaches to experimental methods. CADDtechniques can be applied indifferent steps of the drug discovery pipeline,andalso, can cover several phases of this pipeline. To that end, several objectiveshave been set and reachedin this thesis: 1.To find possible therapeutic activities and to establish the capability to modulate protein functions in pathogenesis-related pathways from marine molecules by using different CADD tools and techniques: I. Improve the drug discovery pipeline by the elucidation of the possible therapeutic potential of a set of marine molecules against a list of targets related to different pathologies. II. Elucidation of different pharmacophoric features of marine compounds and a precise in silicobinding study, highlighting the power of CADD techniques, and reporting the inhibitory activity of different natural products and indole scaffold derivatives as GSK3β, CK1δ, DYRK1A, and CLK1inhibitors. III.Computational study and an experimental validationof meridianins and lignarenones as possible ATP and/or substrate inhibitors of GSK3β. The main conclusionsof this thesis arethat marine molecules can be used as therapeutic agents against protein kinases related to the AD,and the exemplification of CADD potential applied to marine drug discovery
