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Molecular docking study of HIV NS3 protease

inhibitors on dengue virus
Raghunath Satpathy1, Gyan Ranjan Satpathy2, Prangya Ranjan Rout2
1
MIRC Laboratory, Department of Biotechnology, MITS Engineering College,
Rayagada, Odisha, 765017, India; E-mail: rnsatpathy@gmail.com
2
Department of Biotechnology and Medical Engineering, National Institute of
Technology, Rourkela, Odisha, 769008, India

ABSTRACT
Dengue virus belongs to the family Flaviviridae and is a major emerging pathogen for which the development
of drugs, vaccines and antiviral therapy has seen little success. The NS3 viral protease is a potential target for
antiviral drugs since it is required for virus replication. In this work, the HIV NS3 protease inhibitors were
used to evaluate binding affinity on dengue virus NS3 protease. All total 19 inhibitors were obtained from
Pubchem database and after energy minimization docking was performed by taking NS3 protease of dengue
virus as a receptor (PDB ID 2FOM). Interestingly the docking energy for the two of the ligands having
Pubchem database ID CID 482206 and CID 484561 shows highest value equally as -400.08. Conformation of
ligands, sequence and structure analysis has been performed to observe the relationship between the Dengue
and HIV NS3 protease enzyme.

Keywords: dengue virus, NS3 protease inhibitor, docking study, antiviral drugs

INTRODUCTION

Dengue virus (DENV) is considered as one of the most important global pathogens and also it
represents a global pandemic type of infection [1]. The current estimate indicates approximately 2.5
billion people worldwide at risk for dengue infection among which 1.5 million infected individuals
presenting with clinical symptoms and 500,000 infections progressing to the serious disease states
of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Each year, dengue
infections result in 25000 deaths, primarily in children [2]. After malaria, DENV is the most
common mosquito borne pathogen that infects humans and mostly transmitted by mosquitoes of the
Aedes genus among infected human hosts, with the main vector Aedes aegypti. Aedes albopictus
and Aedes polynesiensis have also been implicated in dengue outbreaks [3]. There is currently no
specific treatment for dengue disease [4].
There are five basic types non structural proteins NS1, NS2, NS3, NS4, NS5 along with
subtypes are present in case of dengue virus which are associated unwinding double stranded DNA
during viral replication [5]. These non-structural proteins forms the replication complex which
includes the NS3 protease with its NS2B as cofactor and the protein serve as potential inhibitory
targets for antiviral agents since [6]. These functional roles were supported by recent flavivirus
helicase crystal structures and a recently solved crystal structure of linked NS3 protease domains
suggested the protease domain enhanced binding of RNA to the NS3 helicase [7]. The NS3 protease
is a primary target for development of dengue antiviral drugs since the NS2-NS3B protease is
required for virus replication and protease inhibitors have a successful history as being developed
into antiviral drugs [8].
Research Article, Biotechnol. Bioinf. Bioeng. 2011, 1(2):179-182
© 2011 Society for Applied Biotechnology. Printed in India.
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MATERIALS AND METHODS

The HIV NS3 inhibior molecules were retrieved from pubchem data base present in NCBI server
(http://pubchem.ncbi.nlm.nih.gov/). In total 19 numbers of inhibitor were collected and the structure
were drawn by Marvin sketch 5.0 tool (http://www.chemaxon.com/marvin/sketch/index.jsp) and
corresponding 3D structure were obtained. The molecules were then energy minimised by
PRODRG server [9]. Prodrg is an on line tool for energy minimization of small molecules where
the energy minimization of is performed by using Gromos 96 force field. Then molecular docking
was performed by the dengue NS3 protease enzyme obtained from Protein Data Bank (2FOM)
using HEX tool [10]. From the docking result various conformations of the ligand were analysed by
Swiss PDB Viewer tool [11]. Also the protein sequence comparison and motif prediction was
performed among the NS3 protease of dengue and HIV virus.

RESULTS AND DISCUSSION

The docking of the ligands was carefully observed for its conformation and docking energy. The
ligands having Pubchem database ID CID 482206 and CID 484561 shows highest binding affinity
as -400.08 (Table 1). The binding position of the highest docking energy were observed (Figure
1A,B). The conformations of the ligand were analysed by Swiss PDB viewer tool. The above two
ligands, which shows different conformation after docking (Figure 2A). The rest of 17 ligands were
observed to share a similar position in the protein also shows similar conformation (Figure 2B).

(A) (B)

Figure 1. The binding position of the ligand CID 482206 (A) and CID 484561 (B) shown as pink colour.

(A) (B)

Figure 2. Showing the conformation of ligands after docking; the conformation of best considered
ligands (A) and conformation of rest of the ligands (B).
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Table 1. Docking energy calculated for the considered ligands by Hex tool.

Pubchem Ligand Molecular Molecular Docking

ID formula weight (g/mol) Energy
CID 482206 C47H65N7O13 936.058100 -400.88
CID 482207 C46H66N8O12 923.062640 -355.44
CID 482209 C36H58N6O14S 830.942520 -358.94
CID 482210 C38H55N5O7 693.872600 -346.37
CID 482211 C43H56N6O14S 913.001540 -310.67
CID 484561 C39H51N5O11S 797.914140 -400.88
CID 484563 C19H25N3O7S 439.482700 -222.51
CID 484564 C44H60N6O12S 897.045200 -313.19
CID 484565 C40H55N5O9S 781.957800 -292.62
CID 484566 C35H48N4O6S 652.843820 -273.89
CID 484567 C20H29N3O5S 423.526360 -229.06
CID 484568 C34H48N6O13S 780.842320 -251.07
CID 484570 C36H52N6O14S 824.894880 -344.75
CID 484571 C33H52N6O14S2 820.927780 -318.63
CID 484572 C44H61N7O12S 912.059840 -342.25
CID 484573 C37H48N6O14S2 864.938820 -314.63
CID 484574 C32H52N6O13S 760.852680 -324.20
CID 3002867 C21H15NO3S2 393.478700 - 226.72

Further the sequence of the NS3 protease of Dengue (2FOM) and HIV virus (3EKQ) were
obtained from PDB and analysed for the similarity. BLAST 2 was used for comparison which
shows no significant sequence similarity. Then the two sequences were searched for their common
motif by using EMBOSS tool [12]. In case of EMOSS tool the prediction of motif is done by
searching the pattern from the Prosite data base within the sequence (Table 2). The result shows
none of the sequence having the similar sequence pattern to each other.

Table 2. Showing motif prediction along with their positions for the NS3
proteases of HIV and dengue virus protein sequences computed from
EMBOSS tool.

No. Motif (HIV) Motif (Dengue)

1 IGTVLVGP (72-79) EVQVLALE (94-101)
2 LTQIGCT (90-96) LWDVPSPPPVGKA (4-16)
3 KMIVGIGGFVKVRQYDQ SPIVDKKGKVVGLYGNGV
IPIEICGHK (45-70) VTRSGAYVSAI(137-165)
4 TLWKRPIVTIR (4-14) TRGAVLMH (53-60)
5 KEALLDT (20-26) IGAVSLDFS (123-131)
6 ------------------------ KGILGYSQIGAGVY (33-41)
7 ------------------------ KKDLISY (73-79)
8 ------------------------ RAVQTKPGL (107-115)

The analysis indicates the conformation study of the ligands having its importance while
predicting the activity of drug molecule. The docking result suggests that different ligands bind to
the same binding site under different receptor conformations. Docking to different ligand
conformations also due to change of a receptor-specific conformation [13]. Since the viral proteases
are a primary target for antiviral drugs as very since they are common to most viruses and generally
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important for efficient replication. Again the HIV protease inhibitors could be used for the
development of other antiviral protease inhibitors. The applications of HIV inhibitors for the
treatment of human rhinovirus and hepatitis C virus protease inhibitors have also entered clinical
trials [14,15]. Despite of this application very few antiviral have been approved for human use. The
present study shows although HIV and Dengue belongs to different families of virus also the HIV
and Dengue NS3 protease are not similar to their sequence and structure but some available HIV
NS3 protease inhibitor molecules could be potentially used against Dengue as preventive drugs.

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