Antonio Viayna Gaza, PhD
Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), and Institute of Theoretical and Computational Chemistry (IQTC-UB), University of Barcelona, Santa Coloma de Gramanet E-08921, Spain
Title: “Characterizing the bioactive species: the relevance of physicochemical properties”
Abstract: A correct definition of the bioactive species is fundamental in the drug discover and design process. On one hand, because it defines a series of molecular determinants that define the ligand binding and recognition. On the other hand, because it establishes the molecular basis for the structure-activity relationships (SAR). However, its prediction is not trivial, since it depends on the interplay between different complicating factors. In the present conference, different projects will be shown that involve the consideration or estimation of this complicating factors, such as the correct definition of the conformational landscape, protonation state, lipophilicity and tautomerism.
Carolina Estarellas Martín, PhD
Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, Institute of Theoretical and Computational Chemistry (IQTC-UB), University of Barcelona, Santa Coloma de Gramanet E- 08921, Spain
Title: “Understanding the selectivity for β-isoforms of direct allosteric modulators of AMPK”
Abstract: AMPK is a key energy sensor regulating the cell metabolism in response to energy supply and demand. The evolutionary adaptation of AMPK to different tissues is accomplished through the expression of distinct isoforms that can form up to 12 complexes, which exhibit notable differences in the sensitivity to allosteric activators. To shed light into the allosteric regulation of this energy sensor, we have assessed the structural and dynamical properties of β1- and β2- containing AMPK complexes formed with small molecules that could act as direct activators, in some cases activating specifically only one of the β-isoforms, while in other cases these ligands could act as a pan-activators.[2,3] So, which are the molecular factors that determine these differences?
We have run molecular simulations of several complexes formed by α2β1 and α2β2 AMPK subunits with A-769662, SC4, PF739 and MT47-100, dissecting the mechanical response leading to active-like enzyme conformations through the analysis of interaction networks between structural domains. The results reveal the mechanical sensitivity of the α2β1 complex, in contrast with a larger resilience of the α2β2 species, especially regarding modulation by A-769662. Furthermore, binding of activators to α2β1 consistently promotes the preorganization of the ATP-binding site, acting as a molecular glue between α- and β- subunits, thus favoring the adoption of activated states of the enzyme. These findings are discussed considering the changes in the residue content of β-subunit isoforms, particularly regarding the β1Asn111--> β2Asp111 substitution as a key factor in modulating the mechanical sensitivity of β1- and β2-containing AMPK complexes. [4,5,6] Our studies pave the way for the design of activators tailored for improving the therapeutic treatment of tissue-specific metabolic disorders.