Unraveling the stability of plasma proteins upon interaction of synthesized uridine products

biophysical and molecular dynamics approach

Shreya Dubey, Suneel Kumar Madana, Monika Kallubai, Arijit Sarkar, S. Rajagopal

Research output: Contribution to journalArticle

Abstract

Most of the drugs binding to human serum albumin (HSA) are transported to various parts of the body. Here, we have studied the molecular interaction between HSA and synthesized uridine derivatives, 1-[(3R, 4S, 5 R)-2-methyl-3, 4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dion.)(C-MU); [(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl] methyl methyl phosphochloridate (CM-MU) and [(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-2-methyl-3,4-dihydroxyoxolan-2-yl] methyl dihydrogen phosphate (P-MU). Cytotoxic studies of these synthesized compounds with mouse macrophages (RAW 246.7) and HeLa cells (human cervical cancer cells) and binding mechanism of these uridine derivatives with HSA were performed. Subsequently, fluorescence quenching was observed upon titration of uridine derivatives with HSA via static mode of quenching, and the binding constants (K2-C-MU = 4 ± 0.03 × 104M−1, K5-CM-MU = 1.95 ± 0.03 × 104 M−1 and K5-P-MU =1.56 ± 0.03 × 104 M−1) were found to be in sync with the computational results. Further, molecular displacement and molecular docking data revealed that all the derivatives are binding in the subdomain IIA and IIB regions of HSA. The protein secondary structure of complexes was determined by circular dichroism, indicating partial unfolding of the protein upon addition of the uridine derivatives. Furthermore, atomic force microscopy data reveal the change in topology upon binding of 2-C-MU, 5-CM-MU and 5-P-MU with HSA, indicating change in the microenvironment around tryptophan region. Additionally, cytotoxicity studies on HeLa and Raw Cell lines suggested that these molecules have significant anti-proliferative and anti-inflammatory properties. Hence, the study may be of help for development of new drugs based on uridine derivatives which may be helpful for combating various potential diseases. Communicated by Ramaswamy H. Sarma.

Original languageEnglish
JournalJournal of Biomolecular Structure and Dynamics
DOIs
Publication statusPublished - Jan 1 2019

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Uridine
Molecular Dynamics Simulation
Blood Proteins
Serum Albumin
HeLa Cells
Secondary Protein Structure
Protein Unfolding
Atomic Force Microscopy
Circular Dichroism
Human Body
Tryptophan
Uterine Cervical Neoplasms
Pharmaceutical Preparations
Anti-Inflammatory Agents
Fluorescence
Macrophages
Phosphates
Cell Line

Keywords

  • Drug binding
  • human serum albumin
  • molecular dynamics simulations
  • MTT assay
  • protein conformation
  • uridine derivatives

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Unraveling the stability of plasma proteins upon interaction of synthesized uridine products : biophysical and molecular dynamics approach. / Dubey, Shreya; Madana, Suneel Kumar; Kallubai, Monika; Sarkar, Arijit; Rajagopal, S.

In: Journal of Biomolecular Structure and Dynamics, 01.01.2019.

Research output: Contribution to journalArticle

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