Publications > García-Marín et al

J Comput Aided Mol Des. 2022 Aug;36(8):575-589. doi: 10.1007/s10822-022-00466-1. PubMed 35869378

Insight into the mechanism of molecular recognition between human Integrin-Linked Kinase and Cpd22 and its implication at atomic level.

Javier García-Marín^1, a, Diego Rodríguez-Puyol^2, b, Juan J Vaquero^3, c

1. Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química Andrés M. del Río (IQAR), Universidad de Alcalá (IRYCIS), Alcalá de Henares, 28805, Madrid, Spain.  2. Departamento de Química Biológica y Estructural, Centro de Investigaciones Biológicas, CIB-CSIC, C/Ramiro de Maeztu 9, 28040, Madrid, Spain.  3. Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AX, UK.

a. javier.garciamarin@uah.es  b. javier.garciamarin@uah.es  c. javier.garciamarin@uah.es

Keywords: Cpd22; ILK; Integrin-linked kinase; Molecular dynamics; PELE; Pseudokinase

Abstract

Pseudokinases have received increasing attention over the past decade because of their role in different physiological phenomena. Although pseudokinases lack several active-site residues, thereby hindering their catalytic activity, recent discoveries have shown that these proteins can play a role in intracellular signaling thanks to their non-catalytic functions. Integrin-linked kinase (ILK) was discovered more than two decades ago and was subsequently validated as a promising target for neoplastic diseases. Since then, only a few small-molecule inhibitors have been described, with the V-shaped pyrazole Cpd22 being the most interesting and characterized. However, little is known about its detailed mechanism of action at atomic level. In this study, using a combination of computational chemistry methods including PELE calculations, docking, molecular dynamics and experimental surface plasmon resonance, we were able to prove the direct binding of this molecule to ILK, thus providing the basis of its molecular recognition by the protein and the effect over its architecture. Our breakthroughs show that Cpd22 binding stabilizes the ILK domain by binding to the pseudo-active site in a similar way to the ATP, possibly modulating its scaffolding properties as pseudokinase. Moreover, our results explain the experimental observations obtained during Cpd22 development, thus paving the way to the development of new chemical probes and potential drugs.

Publications > Milián et al

Angew Chem Int Ed Engl. 2022, e202205651 PubMed 35510716

Metal-Free Temperature-Controlled Regiodivergent Borylative Cyclizations of Enynes: BCl(3) -Promoted Skeletal Rearrangement.

Ana Milián, Manuel A Fernández-Rodríguez, Estíbaliz Merino, Juan J Vaquero, Patricia García-García

Universidad de Alcalá (IRYCIS). Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química "Andrés M. del Río" (IQAR). Campus Científico-Tecnológico, Facultad de Farmacia, Autovía A-II, Km 33.1, 28805-Alcalá de Henares, Madrid, Spain.

Keywords: Boron; Cyclization; Enynes; Phenanthrenes; Rearrangement

Abstract

Metal-free borylative cyclization of biphenyl-embedded 1,3,5-trien-7-ynes in the presence of simple and inexpensive BCl(3) provided synthetically useful borylated building blocks. The outcome of the process depends on the reaction temperature, with borylated phenanthrenes obtained at 60 °C and phenanthrene-fused borylated cyclobutanes formed at 0 °C. Based on DFT calculations, a mechanism for these novel transformations has been proposed, which involves an uncommon skeletal rearrangement, including migration of a methyl group and alkyne fragmentation, unprecedented in BCl(3) -promoted cyclization reactions.