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Arylsulfonamides as Inhibitors for Carbonic Anhydrase : Prediction & Validation

Schmid, Maurus and Nogueira, Elisa S. and Monnard, Fabien W. and Ward, Thomas R. and Meuwly, Markus. (2012) Arylsulfonamides as Inhibitors for Carbonic Anhydrase : Prediction & Validation. Chemical Science, 3 (3). pp. 690-700.

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Official URL: http://edoc.unibas.ch/dok/A6002061

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Abstract

Arylsulfonamide derivs. are widely studied high affinity inhibitors of the isoenzyme human carbonic anhydrase II (hCA II).  From mol. dynamics simulations and MM-GBSA calcns., reliable (R = 0.89) relative binding free energies are detd. for 17 previously exptl. characterized protein-ligand complexes.  Decompn. of these energies led to the identification of crit. amino acid residues with a significant contribution to the affinity towards the ligands.  In particular, Leu198 was predicted as a key residue and was subjected to computational mutagenesis.  This prediction was verified exptl. by producing hCA II mutants L198A, L198F and L198Q and detg. the resulting affinities towards inhibitor 1.  The computed vs. exptl. energies are in good agreement thus suggesting that the force field parameters reported herein are useful for the in silico design of a wider range of carbonic anhydrase inhibitors.
Faculties and Departments:05 Faculty of Science > Departement Chemie
05 Faculty of Science > Departement Chemie > Chemie > Bioanorganische Chemie (Ward)
05 Faculty of Science > Departement Chemie > Chemie > Physikalische Chemie (Meuwly)
UniBasel Contributors:Meuwly, Markus and Ward, Thomas R. R. and Nogueira, Elisa S. and Schmid, Maurus and Monnard, Fabien and Worni, Isa
Item Type:Article, refereed
Publisher:Royal Society of Chemistry
ISSN:2041-6520
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:03 May 2017 07:48
Deposited On:08 Nov 2012 16:10

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