title: Investigation of binding mechanism of novel 8-substituted coumarin derivatives with human serum albumin and α-1-glycoprotein.
abstract: Coumarin molecules have biological activities possessing lipid-controlling activity, anti-hepatitis C activity, anti-diabetic, anti-Parkinson activity, and anti-cancer activity. Here, we have presented an inclusive study on the interaction of 8-substituted-7-hydroxy coumarin derivatives (Umb-1/Umb-2) with α-1-glycoprotein (AGP) and human serum albumin (HSA) which are the major carrier proteins in the human blood plasma. Binding constants obtained from fluorescence emission data were found to be KUmb-1=3.1 ± .01 × 10(4) M(-1), KUmb-2 = 7 ± .01 × 10(4) M(-1), which corresponds to -6.1 and -6.5 kcal/mol of free energy for Umb-1 and Umb-2, respectively, suggesting that these derivatives bind strongly to HSA. Also these molecules bind to AGP with binding constants of KUmb-1-AGP=3.1 ± .01 × 10(3) M(-1) and KUmb-2-AGP = 4.6 ± .01 × 10(3) M(-1). Further, the distance, r between the donor (HSA) and acceptor (Umb-1/Umb-2) was calculated based on the Forster's theory of non-radiation energy transfer and the values were observed to be 1.14 and 1.29 nm in Umb-1-HSA and Umb-2-HSA system, respectively. The protein secondary structure of HSA was partially unfolded upon binding of Umb-1 and Umb-2. Furthermore, site displacement experiments with lidocaine, phenylbutazone (IIA), and ibuprofen (IIIA) proves that Umb derivatives significantly bind to subdomain IIIA of HSA which is further supported by docking studies. Furthermore, Umb-1 binds to LYS402 with one hydrogen bond distance of 2.8 Å and Umb-2 binds to GLU354 with one hydrogen bond at a distance of 2.0 Å. Moreover, these molecules are stabilized by hydrophobic interactions and hydrogen bond between the hydroxyl groups of carbon-3 of coumarin derivatives.
authors.affiliation: a Department of Plant Sciences , School of Life Sciences, University of Hyderabad , Hyderabad 500046 , India.
authors.forename: Daniel Pushpa Raju
authors.initials: DP
authors.lastname: Yeggoni
authors.affiliation: b Department of Chemistry , Sri Venkateswara University , Tirupati , Andhra Pradesh 517502 , India.
authors.forename: Darla Mark
authors.initials: DM
authors.lastname: Manidhar
authors.affiliation: b Department of Chemistry , Sri Venkateswara University , Tirupati , Andhra Pradesh 517502 , India.
authors.forename: Cirandur
authors.initials: C
authors.lastname: Suresh Reddy
authors.affiliation: a Department of Plant Sciences , School of Life Sciences, University of Hyderabad , Hyderabad 500046 , India.
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Subramanyam
mesh_terms: D002942:Circular Dichroism; D003374:Coumarins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009961:Orosomucoid / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D008024:Ligands; D009961:Orosomucoid; D012709:Serum Albumin; C030123:coumarin
keywords: binding affinity; circular dichroism spectroscopy; coumarin derivatives; fluorescence emission; molecular docking; protein-ligand interaction