edoc

Extending Halogen-based Medicinal Chemistry to Proteins: IODO-INSULIN AS A CASE STUDY

El Hage, Krystel and Pandyarajan, Vijay and Phillips, Nelson B. and Smith, Brian J. and Menting, John G. and Whittaker, Jonathan and Lawrence, Michael C. and Meuwly, Markus and Weiss, Michael A.. (2016) Extending Halogen-based Medicinal Chemistry to Proteins: IODO-INSULIN AS A CASE STUDY. Journal of Biological Chemistry, 291 (53). pp. 27023-27041.

[img]
Preview
PDF - Published Version
5Mb

Official URL: http://edoc.unibas.ch/53177/

Downloads: Statistics Overview

Abstract

Insulin, a protein critical for metabolic homeostasis, provides a classical model for protein design with application to human health. Recent efforts to improve its pharmaceutical formulation demonstrated that iodination of a conserved tyrosine (Tyr(B26)) enhances key properties of a rapid-acting clinical analog. Moreover, the broad utility of halogens in medicinal chemistry has motivated the use of hybrid quantum- and molecular-mechanical methods to study proteins. Here, we (i) undertook quantitative atomistic simulations of 3-[iodo-Tyr(B26)]insulin to predict its structural features, and (ii) tested these predictions by X-ray crystallography. Using an electrostatic model of the modified aromatic ring based on quantum chemistry, the calculations suggested that the analog, as a dimer and hexamer, exhibits subtle differences in aromatic-aromatic interactions at the dimer interface. Aromatic rings (Tyr(B16), Phe(B24), Phe(B25), 3-I-Tyr(B26), and their symmetry-related mates) at this interface adjust to enable packing of the hydrophobic iodine atoms within the core of each monomer. Strikingly, these features were observed in the crystal structure of a 3-[iodo-Tyr(B26)]insulin analog (determined as an R6 zinc hexamer). Given that residues B24-B30 detach from the core on receptor binding, the environment of 3-I-Tyr(B26) in a receptor complex must differ from that in the free hormone. Based on the recent structure of a "micro-receptor" complex, we predict that 3-I-Tyr(B26) engages the receptor via directional halogen bonding and halogen-directed hydrogen bonding as follows: favorable electrostatic interactions exploiting, respectively, the halogen's electron-deficient σ-hole and electronegative equatorial band. Inspired by quantum chemistry and molecular dynamics, such "halogen engineering" promises to extend principles of medicinal chemistry to proteins.
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Physikalische Chemie (Meuwly)
UniBasel Contributors:Meuwly, Markus
Item Type:Article, refereed
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
e-ISSN:1083-351X
Note:Publication type according to Uni Basel Research Database: Journal article -- The final publication is available at Journal of Biological Chemistry, see DOI link.
Language:English
Identification Number:
Last Modified:21 Nov 2017 11:42
Deposited On:25 Jan 2017 10:28

Repository Staff Only: item control page