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Advanced Glycation End Products Modulate Structure and Drug Binding Properties of Albumin
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0003-0185-5724
2015 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 12, no 9, 3312-3322 p.Article in journal (Refereed) Published
Abstract [en]

The extraordinary ligand binding properties of albumin makes it a key player in the pharmacokinetics and pharmacodynamics of many vital drugs. Albumin is highly susceptible for nonenzymatic glycation mediated structural modifications, and there is a need to determine structural and functional impact of specific AGEs modifications. The present study was aimed toward determining the AGE mediated structure and function changes, primarily looking into the effect on binding affinity of drugs in the two major drug binding sites of albumin. The impact of the two most predominant AGEs modifications, i.e., carboxyethyllysine (CEL) and argpyrimidine (Arg-P), was studied on the basis of the combination of in vitro and in silico experiments. In vitro studies were carried out by AGEs modification of bovine serum albumin (BSA) for the formation of Arg-P and CEL followed by drug interaction studies. In silico studies involved molecular dynamics (MD) simulations and docking studies for native and AGEs modified BSAs. In particular the side chain modification was specifically carried out for the residues in the drug binding sites, i.e., Arg-194, Arg-196, Arg-198, and Arg-217, and Lys-204 (site I) and Arg-409 and Lys-413 (site II). The equilibrated structures of native BSA (n-BSA) and glycated BSA (G-BSA) as obtained from MD were used for drug binding studies using molecular docking approach. It was evident from the results of both in vitro and in silico drug interaction studies that AGEs modification results in the reduced drug binding affinity for tolbutamide (TLB) and ibuprofen (IBP) in sites I and II. Moreover, the AGEs modification mediated conformational changes resulted in the shallow binding pockets with reduced accessibility for drugs.

Place, publisher, year, edition, pages
[Awasthi, Saurabh; Saraswathi, N. T.] SASTRA Univ, Sch Chem & Biotechnol, Mol Biophys Lab, Thanjavur 613401, Tamil Nadu, India. [Murugan, N. Arul] KTH Royal Inst Technol, Sch Biotechnol, Div Theoret Chem & Biol, SE-10691 Stockholm, Sweden., 2015. Vol. 12, no 9, 3312-3322 p.
Keyword [en]
advanced glycation end products, albumin, argpyrimidine, carboxyethyllysine, drug binding affinity, diabetes, molecular dynamics simulation
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:kth:diva-174235DOI: 10.1021/acs.molpharmaceut.5b00318ISI: 000361086800021PubMedID: 26281017Scopus ID: 2-s2.0-84941083634OAI: oai:DiVA.org:kth-174235DiVA: diva2:860016
Note

QC 20151009

Available from: 2015-10-09 Created: 2015-10-02 Last updated: 2017-12-01Bibliographically approved

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