Vol. 4, No.

1 Jan 2013 ISSN 2079-8407

Journal of Emerging Trends in Computing and Information Sciences
©2009-2013 CIS Journal. All rights reserved.

http://www.cisjournal.org

Docking Studies of Competitive Interaction of Human Serum Albumin

with Ibuprofen and Aspirin Using the HEX Docking Software
1*
A. kazemi Babahedari, 1, 3 M. karimi Shamsabadi, 2 H.R. kabiri, 1Kh. Tavakoli
1
Department of Chemistry, Islamic Azad University, Shahrekord Branch, Shahrekord, Iran
2
Department of Biology, Islamic Azad University, Shahrekord Branch, Shahrekord, Iran
3
Young researchers club, Islamic Azad University, Shahrekord Branch, Shahrekord, Iran

ABSTRACT
Computational methods are playing increasingly larger and more important role in drug discovery and development and
are believed to offer means of improved efficiency for the industry. Serum albumin is the most abundant protein in blood
plasma. The binding of drugs with serum albumin plays an important role in the study of the bioavailability, efficacy,
transport and designing of the drugs. Two typical non-steroidal anti-inflammatory drugs are ibuprofen, and aspirin which
used commonly as analgesic drug in clinical medicine and sometimes are co-administered. Docking is conducted by a
procedure involving multiple conformer shape-matching alignment of a molecule to a cavity followed by energy
minimization on both the molecule and the protein residues at the binding region. In this work, we have taken the Human
serum albumin receptor and the commercially available drugs pain reliever. The receptor was docked to the above said
drugs and the energy value obtained as follows ibuprofen (-220.34) and aspirin (199.67) using the HEX (v6.1) docking
software. Depending on the energy values we have chosen the best drug that is ibuprofen. We attempted to improve the
binding efficiency and steric compatibility of the aspirin. Several modifications were made to the probable functional
groups which were interacting with the receptor molecule. Amongall the designed compounds, the one compound show
more binding energy value (-273.81).

Keywords: Human Serum Albumin, Ibuprofen, Aspirin, Docking, HEX.

1. INTRODUCTION In this work, we herein prepared those compounds to

Human serum albumin (HSA) the main protein study their biological activities. We focus on the
component of plasma, accounts for about 60% of the competitive binding of drugs which have different high-
plasma’s total protein contents, and contains three affinity binding sites on protein. These practical
homologous helical domains (I–III), each divided into A molecules were then docked in the active site of HAS
and B sub domains. The binding of drugs with serum (PDB code 1N5U) (Figure1) with Ibu and ASA (Figure2a,
albumin plays an important role in the study of the b) using the HEX algorithm.
bioavailability, efficacy, transport and toxicity of the
drugs. Many drugs bind to serum albumin at one of two
primary sites (I and II) located in sub domains IIA and
IIIA, respectively. The investigation of the interaction of
drugs and serum albumin appeals lots of interests [1-4].

Non-steroidal anti-inflammatory drugs have been

widely used in the pharmaceutical field as the
performances of treating inflammation, pain and fever,
especially in the treatment and prevention of Parkinson’s
disease (PD) [5] and Alzheimer’s disease (AD) [6]
Ibuprofen (Ibu) and aspirin (acetyl salicylic acid (ASA))
their derivatives are used commonly as analgesic and anti-
inflammatory drugs in clinical medicine[7]. Some
researchers studied the binding where legend (the drug
and the competitor) share the same binding site on the
protein [8,9].
Fig 1: Structure ofhuman serum albumin (HAS)
Computer-aided drug design (CADD) is a
rapidly evolving field that leverages new data and
methods to provide approaches for tackling the needs of
drug discovery. One such method is the docking of the
drug molecule with the receptor (target). The site of drug
action, which is ultimately responsible for the
pharmaceutical effect, is a receptor [10]. Docking is the
process by which two molecules fit together in 3D space.

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 Vol. 4, No. 1 Jan 2013 ISSN 2079-8407
Journal of Emerging Trends in Computing and Information Sciences
©2009-2013 CIS Journal. All rights reserved.

http://www.cisjournal.org
Graphics Program for calculating and displaying feasible
acids and small bimolecular. The program reads in
molecular coordinate files and interactively displays the
molecule on the screen in variety of representations and
color schemes, respectively. He is an interactive program
which lets a user load a pair of proteins, view them in a
variety of 3D graphical modes, perform docking
calculations, and visualize the results in a single easy-to-
use environment. Apair of protein structures in “PDB”
format (http://www.pdb.org) to be docked by Hex. The
(a) collection of Proguanil, its derivatives and receptor
complexes were identified via docking and their relative
stabilities were evaluated using molecular dynamics and
their binding affinities, using free energy simulations
[12].Docking experiments were performed using the
default Hex and default evolutionary parameters:
correlation type – shape only, FFT mode – 3D fast lite,
grid dimension – 0.6, receptor range – 180, legend range –
180, twist range – 360, distance range – 40.

(b) 3. RESULTS
Fig 2: Structure of a) Ibuprofen (Ibu), b) Aspirin (acetyl In general, Hex allows a given receptor and
salicylic acid (ASA)) legend residue to be rotated onto the z-axis before each
docking run. The calculation of descriptors by of HSA
with Ibuand ASA were exercise, Ibu and ASA had
2. COMPUTATIONAL METHODS
binding energies in the range of (-220.34) and (-199.67)
that Ibu is better as compared to that of ASA. Ibu is a prop
2.1 Software's and Data Sources
ionic acid derivative (2-[4-isobutylphenyl]- prop ionic
All software's applied for this analysis are freely
acid ) and is strongly bound to plasma proteins,
available for academic use. The Protein Data Bank (PDB)
particularly albumin [9]. We attempted to better the
(www.rcsb.org) is a universal repository for the
binding efficiency of the ASA with HSA. Several
processing and distribution of 3D biological
modifications were made to the probable functional
macromolecular structure data [11].Presently it has over
groups which were interacting with the receptor molecule.
20,000 structures found by X-ray diffraction. Protein
The results of docking are shown in table 1,2.Compound
structures may be downloaded from the site with septic
15(Figure3) showed an increase in the energy values of -
keywords or a PDB alphanumeric filename.
273.81 which means the compound 15 is more compatible
with the HSA than its predecessor.
The Drug Bank
(http://redpoll.pharmacy.ualberta.ca/drug bank/) database
[12] is a unique bioinformatics and chem. informatics
resource that aggregates detailed drug (i.e., chemical,
pharmacological and pharmaceutical) data.

The docking experiments were performed using

the docking software Hex. The legend structures were
optimized with the Argus lab program. Argus lab extends
quite good on-screen molecule-building facilities, with a
moderate library of useful molecules. It is a free
molecular modeling package that runs under Windows
[11].

2.2 Molecular Docking

Protein docking is the task of calculating the 3D
structure of a protein complex starting from the individual
Fig 3: Interaction and binding energy of human serum
structures of the constituent proteins. Because proteins
albumin with compound 15.
have intrinsically dynamical structures which may change
conformation on binding, this computationally intensive
Table1: Hex results for the docking of human serum
task could be likened to trying to assemble the pieces of a
albumin (HAS) with acetyl salicylic acid (ASA)
complex 3D jigsaw puzzle in which the given parts do not
derivatives (position R1)
fit together perfectly. He is an interactional Molecular
Compound R2 E-value

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 Vol. 4, No. 1 Jan 2013 ISSN 2079-8407
Journal of Emerging Trends in Computing and Information Sciences
©2009-2013 CIS Journal. All rights reserved.

http://www.cisjournal.org
docked fluoroquinolon antibiotic. J. Pharm. Biomed.Anal.
1 –(CH2)3COOCH3 -239.75 8, 67–71.
2 –(CH2)3COOCH3 -251.98
3 –(CH2)3C6H5 -251.08 [4] S.W. Cowan-Jacob, G. Fend rich, A. Floersheimer,
4 –(CH2)3C6H4–(p-OCH3) -248.02 P. Furet, J. Liebetanz, G. Rummel, P. Rheinberger,
5 –(CH2)3C6H5 -245.95 M. Centeleghe, D. Fabbro, P.W. Manley, Structural
6 –(CH2)2O(CH2)3OC6H5 -262.5 biology contributions to the discovery of drugs to
7 –(CH2)3OCOC6H5 -267.83 treat chronic
8 –(CH2)3OCOOCH2C6H5 -264.3 myelogenousleukaemia.ActaCrystallogr. Sect. D
9 –(CH2)3OCOC6H5 -268.64 63 (2007) 80–93.
Table 2: Hex results for the docking of human serum
[5] K.J. Fehske, W.E. Mullar, U. Wollart,The location
albumin (HAS) with acetyl salicylic acid (ASA)
of drug binding sites in human serum
derivatives (position R2)
albumin.Biochem.Pharmacol.30 (1981) 687–692.
Compound
R2 E-value [6] U.Hansen, V.T.Chuang, M.Otagiri, Practical
docked
10 –(CH2)3COOCH3 -244.63 aspects of the legend-binding and enzymatic
11 –(CH2)3COOCH3 -255.27 properties of human serum albumin, Biol. Pharm.
Bull. 25 (2002) 695–704
12 –(CH2)3C6H5 -253.77
13 –(CH2)3C6H4–(p-OCH3) -261.11
[7] M. T.Heneka, M. Sastre, G. E. Landreth. Acute
14 –(CH2)3C6H5 -248.65
treatmentwith the PPARg agonist pioglitazone and
15 –(CH2)2O(CH2)3OC6H5 -273.81 ibuprofen reduces glialinflammation and Ab 1 –42
16 –(CH2)3OCOC6H5 -258.46 levels in APPV717I transgenic mice.Brain.128
17 –(CH2)3OCOOCH2C6H5 -264.9 (2005)1442–1453.
18 –(CH2)3OCOC6H5 -270.49
Ibuprofen [8] A. C.McKee, I. Carreras, A. Dedeoglu. Ibuprofen
Aspirin reducesAb, hyperphosphorylated t and memory
deficits in Alzheimer mice. Brain Res. 1207
4. CONCLUSION (2008)225–236.
In this study, HSA which is main protein
component of plasma was used for docking-binding [9] F.P. Nicoletti,B.D.Howes, M.Fittipaldi,
interactions studies with ibuprofen and aspirin. The results Fanali,G.,Fasano, M.,Ascenzi, P., Smulevich, G.,
showed that the docking between al HSA and Ibu had Ibuprofen induces an allosteric conformational
good interaction having energy value of (-220.34). When transition in the heme complex of human serum
the modified ASA was docked against the receptor the albumin with significant effects on hemeligation, J.
energy value obtained was for compound 15 Am. Chem. Soc. 130 (2008)11677–11688.
(-273.81).
[10] A.Nooshin,A. Ahmad,S.Mohammad Reza,Ch.
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