Modeling and exploring human IRE1 as a strategy to design novel inhibitors: a computational approach
Sammanfattning
Inositol Requiring Enzyme 1 (IRE1) is a bifunctional
serine/threonine kinase and endoribonuclease that is the major mediator of
the Unfolded Protein Response (UPR) during endoplasmic reticulum (ER) stress.
The association of IRE1 dysregulation with a wide range of human diseases,
stimulated research towards the discovery of small organic molecules able to
modulate IRE1 signalling, and to potentially be used as novel therapeutics.
In this thesis we performed in silico three-dimensional (3D) molecular modeling
analysis encompassing: (i) the selection of suitable protocols for docking and
virtual screening in the IRE1 serine/threonine kinase and endoribonuclease
domains studies, (ii) the exploration of IRE1 and PERK ligand interaction
networks, (iii) the study of IRE1-ligand recognition phenomena in order to
understand the mechanism of action of IRE1 small organic modulators and (iv)
offers important insights relevant to hit-discovery and lead optimization of
novel IRE1 modulators.
Our structure-based drug design approach provides useful information for
designing improved IRE1 ligands, as confirmed by one soon-to-be-filed patents
on new inhibitors targeting IRE1, developed during the PhD period.
Delarbeten
Carlesso, A.; Chintha, C.; Gorman, A. M.; Samali, A.; Eriksson, L. A. Binding
Analysis of the Inositol-Requiring Enzyme 1 Kinase Domain. ACS Omega 2018, 3
(10), 13313–13322. DOI: https://pubs.acs.org/doi/10.1021/acsomega.8b01404 Carlesso, A.; Chintha, C.; Gorman, A. M.; Samali, A.; Eriksson, L. A. Merits and
Pitfalls of Conventional and Covalent Docking in Identifying New Hydroxyl Aryl
Aldehyde like Compounds as Human IRE1 Inhibitors. Sci. Rep. 2019, 9 (1), 3407. DOI: https://www.nature.com/articles/s41598-019-39939-z Carlesso, A.; Eriksson, L. A. Selective Inhibition of IRE1 Signalling Mediated by
MKC9989: New Insights from Molecular Docking and Molecular Dynamics
Simulations. ChemistrySelect 2019, 4 (11), 3199–3203. DOI: https://doi.org/10.1002/slct.201900810 Carlesso A; Chintha C.; Gorman A. M.; Samali A.; Eriksson L. A. Effect of Kinase
Inhibiting RNase Attenuator (KIRA) Compounds on the Formation of Face-to-
Face Dimers of Inositol-Requiring Enzyme 1: Insights from Computational
Modeling. Int J Mol Sci. 2019;20(22). DOI: https://www.mdpi.com/1422-0067/20/22/5538 Chintha, C.; Carlesso, A.; Gorman, A. M.; Samali, A.; Eriksson, L. A. Molecular
modeling provides structural basis for PERK inhibitor selectivity towards RIPK1.
Status: under revision Doultsinos, D.; Carlesso, A.; Chintha, C.; Rainot , A. ; Paton, J.C.; Paton, A.W.;
Samali, A.;Chevet, E.; Eriksson, L. A. Peptidomimetic-based identification of FDA
approved compounds inhibiting IRE1 activity
Status: Manuscript in preparation
Examinationsnivå
Doctor of Philosophy
Universitet
University of Gothenburg. Faculty of Science
Institution
Department of Chemistry and Molecular Biology ; Institutionen för kemi och molekylärbiologi
Disputation
fredag den 31 01 2020 kl.10.00 i Waldemar Sjölander
Datum för disputation
2020-01-31
E-post
antonio.carlesso@gu.se
Datum
2019-12-12Författare
Carlesso, Antonio
Nyckelord
ER stress
unfolded protein response
cancer
inflammation
neurodegeneration
therapeutic targets
molecular docking
molecular dynamics
Publikationstyp
Doctoral thesis
ISBN
978-91-7833-755-2 (PDF)
978-91-7833-754-5 (PRINT)
Språk
eng