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Int. J. LifeSc. Bt & Pharm. Res. 2012 R Aarthi et al., 2012 ISSN XXXX-XXXX www.ijlbpr.com Vol.1, Issue. 1, January 2012 2012 IJLBPR. All Rights Reserved VIRTUAL SCREENING OF ANDROGRAPHOLIDE INHIBITOR FOR HIV ENV GP 160 R Aarthi1*, R S Narmadha2 and Puniethaa Prabhu3 *Corresponding Author: R Aarthi,  aarthi.ravindran@gmail.com The AIDS is caused by HIV, a pandemic disease. The search for effective therapies to treatAIDS is needed. The synthetic drugs like EFV (Efavirenz), TDF (Tenofovir), FTC (Emtricitabine),d4T (Zerit/Stavudine) and many are used in the antiretroviral treatment which causes perilouseffect to patients. Thus, herbal medicines can be used as an alternative medicinal therapy forHIV positive patient. Efforts for identification of more effective and less toxic anti-HIV agents arerequired. Andrographis paniculata is an herbaceous plant in family Acanthaceae, which iseconomically available source used in Siddha and Ayurvedic system of medicine in India andother countries. Protease inhibition is the mechanism for therapeutic value of Andrographispaniculata. Andrographolide is an active secondary metabolite in Andrographis paniculata. Inthis paper, we report the Virtual screening of Andrographolide using Docking tools against HIV-1 env gp160. The envelope glycoprotein (env gp160) of HIV interacts with the CD4 moleculespresent on the membrane of CD4+ cells and involved in the pathobiology of HIV infection. Theseenv gp160 is chopped into pieces as env gp120 and env gp41 on viral membrane. From thisstudy a new inhibitor is developed for the HIV through docking tools with a good dock score.
Keywords: Andrographolide, env gp 160, env gp 120, env gp 41, Docking, 1AIK, 1G9M, infections and tumors. Two major types of HIV have been identified so far, HIV-1 and HIV -2. In Acquired immunodeficiency syndrome (AIDS) is these types HIV-1 causes the worldwide epidemic a pandemic diseases caused by Human and it is a highly variable virus, which mutates immunodeficiency virus (HIV), which causes readily. HIV2 is much less pathogenic and occurs profound immunosuppressant and leaves rarely; it is found mostly in West Africa (www.ars- individuals susceptible to many opportunistic Department of Biotechnology, K.S.Rangasamy College of Technology, Tiruchengode. E-mail: aarthi.ravindran@gmail.com Department of Biotechnology, K.S.Rangasamy College of Technology, Tiruchengode.
Professor, Department of Biotechnology, K.S.Rangasamy College of Technology, Tiruchengode.
This article can be downloaded from http://www.ijlbpr.com/currentissue.php Int. J. LifeSc. Bt & Pharm. Res. 2012 R Aarthi et al., 2012 HIV has been a serious life threatening health Figure 1: Structure of Envelope problem since the first case was identified in 1981 Globulin Protein 160 (www.ars-grin.gov). Although treatments for AIDS and HIV can slow the course of the disease, there is no drug currently to cure. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but these drugs are expensive and routine access to antiretroviral medication is not available in all countries.
Due to the difficulty in treating HIV infection, preventing infection is a key aim in controlling the AIDS pandemic, with health organizations promoting safe sex and needle-exchange program in attempts to slow the spread of the virus (Carlo Calabrese et al., 2000) It was estimated that 33.2 million people lived with AIDS It is an herbaceous plant in the family throughout the world, among that 2.1 million Acanthaceae, mostly the leaves and roots were people were killed, including 330,000 children in used for medicinal purposes. It is negative to India 2007 (Carlo Calabrese et al., 2000). Since it is and Sri Lanka. It is widely cultivated in southern pandemic diseases there is a need to search for Asia, where it is used to treat infections and some novel drug and necessity to prevent this disease diseases, often being used before antibiotics were (Carlo Calabrese et al., 2000).
created. Since ancient times, A. paniculata is The "env" gene in HIV encodes a single protein, used in traditional Siddha and Ayurvedic systems gp160. Cellular enzymes attack it when it travels of medicine as well as in tribal medicine in India to the cell surface, then protein gp 160 is chopping and some other countries for multiple clinical into two pieces gp120 and gp41. If and when new applications (De Silva U C et al., 2010). The virus particles bud off from the host cell, these therapeutic value of Kalmegh is due to its two pieces lie on opposite sides of the virus mechanism which perhaps is by enzyme membrane. gp120 sits on the outside of the virus induction. The plant extracts exhibit antityphoid particle, forming the virus's spikes, while gp41 and antifungal, antihepatotoxic, antibiotic, antimalarial, antihepatitic, antithrombogenic, sits just on the inside of the membrane – each antiinflammatory, anti-snake venom, and protein is being anchored to each other through antipyretic properties to mention a few, besides the membrane (Chan et al., 1997, Coon and its general use as an immunostimulating agent Ernst, 2004).
(Eglen and Allen, 2009). Andrographolide is a The env gp160 is chopped into env gp 41 and labdane diterpenoid that is the main bioactive env gp120 as shown in the fig-1.1 which is present component of the medicinal plant Andrographis on the HIV viral membrane. Each spike of gp160 paniculata which is an extremely bitter substance is made up of three subunits.
extracted from the stem and leaves of the This article can be downloaded from http://www.ijlbpr.com/currentissue.php Int. J. LifeSc. Bt & Pharm. Res. 2012 R Aarthi et al., 2012 andrographis paniculata (Harrar Sari). A recent professor of the Institute of Bioinformatics, study confirms that andrographolide has anti-HIV National Chiao Tung University. It's a Generic activity (www.gemdock.life.nctu.edu.tw/dock). In Evolutionary Method for molecular docking.
the present study the andrographolide was iGEMDOCK is a program for computing a ligand checked for inhibition against env gp 120 and env conformation and orientation relative to the active gp 41 using docking tools Argus lab and site of target protein. It is a graphical-automatic drug discovery system used for integrating docking, screening, post-analysis, and visualization of various ligands. The main features Molecular docking is a method which predicts of iGemdock are scoring function and evolutionary binding of one molecule towards its docking algorithm. In scoring function the complicated partners to form a complex and stable structure AMBER-based energy function is replaced by (Jain, 2006). The stability of complex is measured local minima. The new rotamer based mutations by the scoring functions which are mathematical operator is used to reduce search space in the calculation for calculating the binding affinity of ligand structure which is an advantage over the the chemical compound or drug and the target Gaussian and Cauchy mutation effects protein or receptor (Kwong et al., 2000). Docking (Nishikawa and Kimura, 1994). The core idea in also develops the score functions for the it is Generic algorithm, Scoring function.
intramolecular interactions for the two proteins (Lengauer and Rarey, 1996) or between the Argus lab
protein and DNA (Lensink et al., 2007). One of Argus Lab was found by Mark A. Thomposon, the major advantages conferred by docking is that Planarai software LLC, Seattle, WA [13]. It uses it allows researchers to quickly screen large two types of algorithm Argus dock and genetic databases of potential drugs which would algorithm. They dock with the protein which has otherwise require tedious and prolonged work in active site and smaller molecules. These smaller the lab using traditional drug discovery procedures molecules are replaced by the ligand we use.
in addition to sheer chance. The method of They will analysis the docking and the scoring is docking is carried out on two basic components done by calculating free energy. In this study HIV the search algorithm and the scoring function env gp proteins are inhibited with andrographolide A search algorithm finds the best docking pose by Argus algorithm.
measured by the scoring function. A scoring function discriminates correct docking poses from PUBCHEM and PDB SUM
incorrect ones. A low Gibb's energy confirms a PUBCHEM is used to obtain the database of the stable conformation than a high energy. There protein like primary, 2D; 3D and other literature are two classes of protein docking, Protein- survive of researchers. The ligand and analogues Protein and Protein-Ligand.
andrographolide of Andrographis paniculata is MATERIALS AND METHODS derived from PUBCHEM. PDB SUM is used for finding the active site, number of chains, the number of amino acids present in the each chain The tool was developed by Jinn-Moon Yang, a and motif details. The Figures 2.1 and 2.2, This article can be downloaded from http://www.ijlbpr.com/currentissue.php



Int. J. LifeSc. Bt & Pharm. Res. 2012 R Aarthi et al., 2012 represents structure of HIV env proteins env gp From Figure 2.2 we can examine 4 sheets, 7 41 and env gp 120 respectively obtained from beta hairpins, 5 beta bulges, 20 strands, 5 helices, 1 helix-helix interaction, 23 beta turn, 3 gamma turn, 7 disulphide bond. This protein has 4 chains G, C, L and H and they possess 305aa, 181aa, 1AIK is viral core protein structure of HIV 214aa and 117aa respectively.
glycoprotein 41 (Reddy et al., 2005). They Preparation Of Target Protein Structure
Figure 2: Structure of 1AIK Protein Data Bank (PDB) is a repository of 3-D structural data of bio macromolecules (Robertson Figure 2.3a Structure of env gp 120, Figure 3: Structure of 1G9M Figure 2.3b Structure of env gp 41, possess two chains N and C of amino acid residue 37 and 35 respectively. It is isolated from the strain HIV-1m:b_hxbr and tax id is 562.(19) It is viral envelope glycoprotein 120 structure of strain HIV-1 hxbc2 complicated with the CD4 and induced neutralizing antibody 17b (UNAIDS, This article can be downloaded from http://www.ijlbpr.com/currentissue.php Int. J. LifeSc. Bt & Pharm. Res. 2012 R Aarthi et al., 2012 and Varani, 2007). In the present study, the Figure 2.4: Active Compound Andrographolide structure of env gp 120 and env gp 41 was from Andrographis paniculata, the chemical ID of natural compound Andrographolide from procured from PDB as given below.
PUBCHEM is CID 5318517 Preparation of ligand
Ligand or active drug compound is prepared based on Lipinski's Rule of Five. It is a rule of thumb to determine whether a chemical compound has certain properties like pharmacological or biological activity that would make it a likely orally active drug in humans. The rule was formulated by Christopher A. Lipinski in 1997, based on the observation that most medication drugs are relatively small and lipophilic molecules (www.rcsb.org). It describes about the molecular properties and it's important for a drug's pharmacokinetics in the human body, which includes "ADME" property. However, the rule does The andrographolide and its analogues are not predict if a compound is pharmacologically active compound which follows Lipinski's five active. So for the development of lead structure that is pharmacologically active and optimized in The chemical compound CID 5318517, which step-wise manner for increment activity and follows Lipinski's rule of molecular weight is Figure 2.5: Structure of Analogs The modification of the molecular structure of Andrographolide. The chemical ID often leads to drugs with higher molecular weight, more rings, more rotatable bonds, and a higher lipophilicity (www.rcsb.org). Lipinski's rule says that, in general, an orally active drug has no more than one violation of the following criteria: Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms).
Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms).
A molecular weight under 500 Daltons.
An octanol-water partition coefficient log P of less than 5.
This article can be downloaded from http://www.ijlbpr.com/currentissue.php Int. J. LifeSc. Bt & Pharm. Res. 2012 R Aarthi et al., 2012 350.449[g/mol], molecular formula is C H O The chemical CID 44437486 is following XLogP3-AA 2.2, H-bond donor are 3 and H-bond Lipinski's rule as they posses molecular weight acceptor are 5.
of 410.5027 [g/mol], molecular formula of C H O the XLogP3-AA 4.5, the H-bond donor Figure 2.6: Structure of Analog are 2 and the H-bond acceptor are 5.
Andrographolide, the Chemical ID from the PUBCHEM is CID 44437486 Figure 2.8: Structure of Analog Andrographolide, the Chemical ID from the PUBCHEM is CID 44411425 The molecular weight is 466.65208 [g/mol], the molecular formula is C H O the XLogP3-AA The analogue CID compound has molecular 7.1, the H-bond donor are 2 and the H-bond weight is 362.4599 [g/mol], the molecular acceptor are 4 for CID 44437479.
formulaC H O the XLogP3-AA3.1, the H-bond donor is 1 and the H-bond acceptor is 5 for CID Figure 2.7: Structure of Analog Andrographolide, the Chemical ID from the PUBCHEM is CID44437437 The analogue CID 44411425 has molecular weight of 468.58184 [g/mol], molecular formula is C H O , the XLogP3-AA value is 4.1, the H- bond donor is 1 and the H-bond acceptors are 6.
Open Babel and Molecular Converter
Open Babel is free software, a chemical expert system mainly used for converting chemical file formats. Due to the strong relationship to informatics this program belongs more to the category cheminformatics than to molecular modeling. It is distributed under the GNU GPL (Weiss, 1993).
This article can be downloaded from http://www.ijlbpr.com/currentissue.php




Int. J. LifeSc. Bt & Pharm. Res. 2012 R Aarthi et al., 2012 Molecular converter is a online tool, used for CID 44411425 is docked with the envelope converting the molecular files from one format to glycoprotein 41.
required format according to the requirement of the docking software [22]. The usage is this Figure 3.3: CID5318517 is Docked with 1AIK software's in docking process is carried since the analogues and ligand of andrographolide must be in the .mol format for complex structure.
RESULTS AND DISCUSSIONS Argus Lab
The various ligand compound like CID 5318517, CID 44437479, CID 44437486, CID 44437437, Figure 3.1: Active Site of 1AIK Figure 3.4: Docking Result of 1AIK-First Pose in Argus lab is –8.22 Kcal/mol Figure 3.2: CID 44437479 Docked with 1AIK Figure 3.5: Docking Result of 1AIK-first Active site in Argus lab is –6.55 Kcal/mol This article can be downloaded from http://www.ijlbpr.com/currentissue.php Int. J. LifeSc. Bt & Pharm. Res. 2012 R Aarthi et al., 2012 The ligand of CID 44437479 is not docked Figure 3.8: Docking of 1G9M with CID5318517 properly as in Figure 3.2. And also for the other Shows a Good Dock Score of –6.38Kcal/mol ligand like CID44437486, CID44437437, CID44411425 is not docked. Hence we can say that analogous of andrographolide won't suit for inhibition of HIV.
Figure 3.6: CID44437479 Docked with 1G9M Figure 3.7: CID5318517 is Docked with 1G9M 1ACE (first) active site and -8.22 kcal/mol for env gp 41 of 2ACE (second) active site i.e. 1AIK with the ligand of CID 5318517. Docking of env gp 120 i.e.1G9M with ligand CID5318517 shows -6.38 kcal/mol of dock score.
3.2 iGemdock Results
The ligand compound like CID 44437479, CID 44437486, CID 44437437, CID 44411425 is Figure 3.9a and b Fitness Value of Ligand Andrographolide in 1AIK The ligand CID 44437479 and other like CID 44437486, CID 44437437, CID 44411425 is not docked with 1G9M.
The best score is seen in docking of the pubchem molecule of CID 5318517 with the env The best ligand pose was found to be with binding energy of -6.55kcal/mol for env gp 41 of This article can be downloaded from http://www.ijlbpr.com/currentissue.php Int. J. LifeSc. Bt & Pharm. Res. 2012 R Aarthi et al., 2012 docked with the envelope glycoprotein 41 i.e. 1AIK Represent the increased binding affinity in and envelope glycoprotein 120, i.e., 1G9M.
negative, which shows the formation of stable Docking is not possible due to properties of ligand complex molecule between the ligand and target protein env gp160.
Figure 3.12: xxxxxxxxxxxxxxx Figure 3.10a and 3.10b Fitness Value of ligand Andrographolide in 1G9M It represent the increased fitness value is more for 1AIK against the envelope globulin protein than Table 1: Results of 1AIK and 1G9M for 1G9M. Hence the binding affinity between in Arguslab and iGemdock target and ligand is stable.
Argus lab[Binding Affinity] First active site –8.222) From this we conclude that the ligand Second pose –6.55 andrographolide (CID 5318517) the active compound of Andrographis paniculata is effective Figure 3.11: Results in Argus Lab Figure 24 in inhibiting the HIV env gp proteins like gp120 and gp41, while its analogues are not effective due to changes in side chain of original compound. Hence andrographolide can be selected for further analysis of ADME properties Argus Lab (Binding and the proceeding preclinical trials.
"Andrographis paniculata information from Results of 1AIK in iGemdock
Results of 1G9M in iGemdock
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Berichte Silmaril 2009 4. Bericht: 19. August bis 25. November 2009 von Svolvær 68° 14.4'N, 14°34.4'E bis Litlebergen 60 32.3'N, 5°14.2'E mit Unterbruch von zwei Reisen in die Schweiz Am 11. August starb Alexs Mutter, Hanny. Wir haben für sie eine sehr familiäre und schöne Abschiedsfeier in der Kirche in Interlaken erleben dürfen. Die ganze Familie und viele Freunde und Bekannte von Hanny sind angereist. Wir hatten ein gutes Gefühl, bald nach der Beerdigung wieder abzureisen. Am Mittwoch, 19. August reisten wir zusammen mit Renzo in aller Herrgottsfrühe wieder nach Svolvær ab. Tagwacht um 04:20, Fahrt per Auto zum Flughafen Zürich, Abflug nach Stockholm, nach Stunden Weiterflug nach Oslo, dann recht zügig Oslo-Bodø und schlussendlich Bodø-Svolvær. Die Flugzeuge wurden immer kleiner, ab Oslo waren wir mit Propellerflugzeugen unterwegs. Die letzte Strecke war sagenhaft eindrücklich, das Wetter perfekt und die Flughöhe so tief, dass jedes Schaf (Grössenangabe!) auf den vielen kleinen Inseln im blauen Wasser zu sehen gewesen wäre. Gesehen haben wir allerdings keine. Todmüde nach 16 Stunden Reise kamen wir bei Silmaril an, machten aber trotzdem noch klar Schiff, damit wir am nächsten Tag früh aufbrechen konnten. Wir waren von Anfang an unter Zeitdruck, da wir die Rückreise in die Schweiz mit Renzo schon vor unserer überstürzten Rückkehr in die Schweiz am 12. August gebucht hatten. Wir wurden in der Schweiz auch erwartet. Ein Treffen mit Freunden und eine Klassenzusammenkunft waren seit Monaten geplant. Wir mussten die Strecke nach Ålesund bis zum 28. August schaffen. Am 29. sollten wir fliegen.