Center for Molecular Modeling - S.N. Savvides

Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors

leen — Tue, 15 Feb 2022 10:04:58 +0000

L. Song, R. Merceron, F. Hulpia, A. Lucia, B. Gracia, Y. Jian, M. Risseeuw, T. Verstraelen, P. Cos, J. Ainsa, H. Boshoff, H. Munier-Lehmann, S.N. Savvides, S. Van Calenbergh

European Journal of Medicinal Chemistry

Volume 225, Article Number 113784

2021

Abstract

Mycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors. These efforts furnished the most potent MtTMPK inhibitors in our assay, with two analogues displaying low micromolar MIC values against H37Rv Mtb. Prepared inhibitors address new sub-sites in the MtTMPK nucleotide binding pocket, thereby offering new insights into its druggability. We studied the role of efflux pumps as well as the impact of cell wall permeabilizers for selected compounds to potentially provide an explanation for the lack of correlation between potent enzyme inhibition and whole-cell activity. (C) 2021 Elsevier Masson SAS. All rights reserved.

DOI

http://dx.doi.org/10.1016/j.ejmech.2021.113784

Private attachment

1-s2.0-S0223523421006334-main.pdf

Structural basis of the proinflammatory signaling complex mediated by TSLP

wim — Thu, 03 Apr 2014 09:56:31 +0000

K. Verstraete, L. van Schie, L. Vyncke, Y. Bloch, J. Tavernier, E. Pauwels, F. Peelman, S.N. Savvides, A. Bronselaer

Nature Structural & Molecular Biology

21 (2014), 375–382

2014

Abstract

Thymic stromal lymphopoietin (TSLP) is a cytokine critical for the development of chronic inflammatory disorders including asthma and atopic dermatitis. The structure of the ternary complex formed by TSLP and its coreceptors TSLPR and the interleukin-7 receptor reveal how TSLP is able to organize receptor-receptor contacts to facilitate intracellular signaling.

DOI

http://dx.doi.org/10.1038/nsmb.2794

Private attachment

14_Nature_Struct&Mol_Bio_xxxx_Verstraete.pdf

Human IL-34 and CSF-1 Establish Structurally Similar Extracellular Assemblies with Their Common Hematopoietic Receptor

wim — Tue, 26 Feb 2013 10:49:48 +0000

J. Felix, J. Elegheert, I. Gutsche, A. Shkumatov, Y. Wen, N. Bracke, E. Pannecoucke, I. Vandenberghe, B. Devreese, D.I. Svergun, E. Pauwels, B. Vergauwen, S.N. Savvides

Structure

21 (4), 528-539

2013

Abstract

The discovery that hematopoietic human colony stimulating factor-1 receptor (CSF-1R) can be activated by two distinct cognate cytokines, colony stimulating factor-1 (CSF-1) and interleukin-34 (IL-34), created puzzling scenarios for the two possible signaling complexes. We here employ a hybrid structural approach based on small-angle X-ray scattering (SAXS) and negative-stain EM to reveal that bivalent binding of human IL-34 to CSF-1R leads to an extracellular assembly hallmarked by striking similarities to the CSF-1:CSF-1R complex, including homotypic receptor-receptor interactions. Thus, IL-34 and CSF-1 have evolved to exploit the geometric requirements of CSF-1R activation. Our models include N-linked oligomannose glycans derived from a systematic approach resulting in the accurate fitting of glycosylated models to the SAXS data. We further show that the C-terminal region of IL-34 is heavily glycosylated and that it can be proteolytically cleaved from the IL-34:hCSF-1R complex, providing insights into its role in the functional nonredundancy of IL-34 and CSF-1.

DOI

http://dx.doi.org/10.1016/j.str.2013.01.018

Private attachment

13_Structure_21(4)528_Felix.pdf

An REMD and QM/MM study into the sequence effect on asparagine deamidation

wim — Tue, 19 Jun 2012 06:49:27 +0000

E. Pauwels, S.L. Moors, J. Felix, S.N. Savvides, M. Waroquier, V. Van Speybroeck, S. Catak

p. 9-10

Talk

Conference / event / venue

Enhancing Organocatalysis by Joining Advanced Theorectical and Experimental Approches

Lugano, Zwitseland

Wednesday, 13 June, 2012 to Friday, 15 June, 2012

Abstract (private)

2012 Abstract_CECAM_Lugano.pdf

Study of structure-function relationships in interleukin 34, a novel cytokine

ewald — Mon, 27 Feb 2012 22:36:51 +0000

J. Felix, J. Elegheert, N. Bracke, A. Shkumatov, E. Pauwels, S.N. Savvides

Poster

Conference / event / venue

2nd Belgian Biophysical Society Young Scientist Day

Ghent Belgium

Tuesday, 31 May, 2011

Peptide Deamidation: Effect of Neighboring Residues

wim — Fri, 23 Sep 2011 07:33:06 +0000

S. Catak, J. Felix, S.N. Savvides, V. Van Speybroeck, M. Waroquier, E. Pauwels

p. 53

Poster

Conference / event / venue

Conference on Molecular Simulations in Biosystems and Material Science (SimBioMa)

Konstanz, Germany

Wednesday, 28 September, 2011 to Saturday, 1 October, 2011

Abstract

2011 SIMBIOMA SCatak.pdf

Conference reference

SimBioMa 2011

Molecular modeling of flavin ring plasticity: in-silico mutation of an Old Yellow Enzyme

wim — Fri, 26 Aug 2011 13:05:22 +0000

E. Pauwels, J. Elegheert, M. Waroquier, S.N. Savvides

Talk

Conference / event / venue

2nd Belgian Biophysical Society Young Scientist Day

Ghent, Belgium

Tuesday, 31 May, 2011