Journal Article

FZJ-2021-00884

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A computational strategy to understand structure-activity relationship of 1,3-disubstituted imidazole [1,5-α] pyrazine derivatives described as ATP competitive inhibitors of the IGF-1 receptor related to Ewing sarcoma

Guaitoli, V. ; Alvarez-Ginarte, Y. M. ; Montero-Cabrera, L. A. (Corresponding author) ; Bencomo-Martínez, A. ; Badel, Y. P. ; Giorgetti, A.FZJ* ; Suku, E.

2020
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00894-020-04470-w

Abstract: We followed a comprehensive computational strategy to understand and eventually predict the structure-activity relationship ofthirty-three 1,3-disubstituted imidazole [1,5-α] pyrazine derivatives described as ATP competitive inhibitors of the IGF-1receptor related to Ewing sarcoma. The quantitative structure-activity relationship model showed that the inhibitory potency iscorrelated with the molar volume, a steric descriptor and the net charge calculated value on atom C1 (q1) and N4 (q4) of thepharmacophore, all of them appearing to give a positive contribution to the inhibitory activity. According to experimental andcalculated values, the most potent compoundwould be 3-[4-(azetidin-2-ylmethyl) cyclohexyl]-1-[3-(benzyloxy) phenyl] imidazo[1,5-α]pyrazin-8-amine (compound 23). Docking was used to guess important residues involved in the ATP-competitive inhibitoryactivity. It was validated by 200 ns of molecular dynamics (MD) simulation using improved linear interaction energy (LIE)method. MD of previously preferred structures by docking shows that the most potent ligand could establish hydrogen bondswith the ATP-binding site of the receptor, and the Ser979 and Ser1059 residues contribute favourably to the binding stability ofcompound 23.MDsimulation also gave arguments about the chemical structure of the compound 23 being able to fit in the ATPbindingpocket, expecting to remain stable into it during the entire simulation and allowing us to hint the significant contributionexpected to be given by electrostatic and hydrophobic interactions to the ligand-receptor complex stability. This computationalcombined strategy here described could represent a useful and effective prime approach to guide the identification of tyrosinekinase inhibitors as new lead compounds.

Note: Unfortunately, the authors do not have a copy of the submitted version anymore

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)

Research Program(s):

1. 574 - Theory, modelling and simulation (POF3-574) (POF3-574)

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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