ISSN: 0974-276X
Journal of Proteomics & Bioinformatics
Like us on:
Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
 
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on
Medical, Pharma, Engineering, Science, Technology and Business

Peptidomimetics Based Inhibitor Design for HIV 1 gp120 Attachment Protein

Umashankar Vetrivel1*, Priya Sankar2, Naveen kumar Nagarajan2, Gurunathan Subramanian1
1Department of Bioinformatics, SRM University, Ramapuram Campus, Chennai, India
2Deparment of Bioinformatics, University of Madras, Chennai, India
Corresponding Author : Dr. Umashankar Vetr ivel
Department of Bioinformatics, SRM University,
Ramapuram Campus, Chennai, India,
E-mail: vumashankar@gmail.com
Received October 29, 2009; Accepted November 25, 2009; Published November 25, 2009
Citation: Vetrivel U, Sankar P, Nagarajan NK, Subramanian G (2009) Peptidomimetics Based Inhibitor Design for HIV – 1 gp120 Attachment Protein. J Proteomics Bioinform 2:481-484. doi:10.4172/jpb.1000109
Copyright: © 2009 Vetrivel U, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Related article at
DownloadPubmed DownloadScholar Google

Visit for more related articles at Journal of Proteomics & Bioinformatics

Keywords
Peptidomimetics; HIV-I gp120; CD4; SCD4; Arguslab; MEDock
Introduction
HIV – 1 multiplies only inside human cells. They invade the host’s immune system after attaching to a special protein called CD4, which spans on host cell’s surface. HIV- 1’s surface molecule gp120 plays a crucial role in host infection, since it mediates attachment of virus to its target cells (Wyatt and Sodroski, 1998). The prime objective of the present study was to uncover a solution to inhibit this attachment via a novel peptidomimetic inhibitor. The discussed inhibitor is based on CD4 receptor region for gp120.
Gp120 (PDB ID: 1CE4) trimer with a Molecular weight of 120KDa is a glycoprotein present on the surface of HIV envelope. This glycoprotein comprises of five variable loop regions namely, V1, V2, V3, V4, and V5. The V3 loop region particularly interacts with first domain of CD4 protein with high affinity due to favourable amino acid interactions. The structure of V3 region of HIV gp120 was determined using NMR in 1999. This region is proven to be immunodominant and is composed of 35 amino acids (Kwong et al., 1998; Vranken et al., 2001; Lasky et al., 1987; Berger and Alkhatib, 2007).
Soluble CD4 (SCD4) is the precursor of CD4. Normally SCD4 induces conformational changes in gp120 synonymous to that of CD4 (Turner et al., 1992). The sub domain region of SCD4 N-termini (PDB ID: 1CDH) was proven to have high interaction towards gp120 than CD4. Hence, for the present study, SCD4’s sub domain region was utilized for pepdtidomimetic modeling. SCD4 was sequenced in the year 1986 and structure was elucidated by X-ray diffraction (Ryu et al., 1994).
The effective way to predict binding affinity of macromolecular structures is by docking simulation. Moreover, docking studies pave way for studying the interacting interfaces and their topology. Hence, in the present work SCD4 peptide’s sub-domain was docked with gp120 using MEDock software (http://bioinfo.mc.ntu.edu.tw/medock/). The interacting interface was scanned for residues conferring binding topology, which was in turn used to derive a chemical backbone mimicking the binding topology of SCD4 subdomain. Hence, implementing peptidomimetic approach, the chemical backbone structure was sketched and 3D optimized using Chemsketch. Finally, the sketched ligand was docked with gp120 using Arguslab (www.arguslab.com). It qualified in Lipinski drug calculator (http://www.scfbio-iitd.res.in/utility/LipinskiFilters.jsp).
Methods
Preparation of Target Protein Structure
Protein Data Bank (PDB) is a repository of 3-D structural data of bio macromolecules (http://www.rscb.org/pdb/). In the present study, the atomic coordinates of the HIV-V3 loop of the envelope glycoprotein gp120 (1CE4) was procured from the Protein Data Bank (PDB) (Vranken et al., 2001). It contains 35 amino acids with a disulphide bond. It forms 3 helices, 5 beta turn and 1 gamma turn (Vranken et al., 2001). The atomic coordinates were processed using Swiss PDB Viewer, a user friendly tool to analyze protein structures (http://spdbv.vital-it.ch/) (Figure 1).
Perparation of Ligand Through Peptidomimetics
The coordinates of SCD4 (1CDH) subdomain region was restricted using Rasmol, an interactive Molecular visualization and editing tool (www.umass.edu/microbio/rasmol/). (Figure 2). The restricted domain was docked with gp120 using MEdock, an online tool to predict ligand-binding interactions (http://bioinfo.mc.ntu.edu.tw/medock/). Binding interactions between SCD4 domain and gp120 were identified by MEdock. Five residues namely, Aspartate 10, Threonine 11, Valine12, Glutamate 13, and Leucine 14 of SCD4 showed significant interaction with Gp120. These five residues were restricted and extracted using Rasmol and were again docked with gp120 using MEDock. The best binding pose as per MEdock’s first rank was utilized for peptidomimetic study. Four hydrogen bonds were formed by Valine 12, Glutamate 13, Leucine 14 of SCD4 with that of Gp120. The Hydrogen bonds were visualized using Pymol, a python based molecular visualization tool used to produce publication quality images (www.pymol.org) (Figure 3).
Peptidomimetic ligand was sketched based on the interactive binding interface of gp120 and SCD4. The scaffold of hydrogen bonding residues of SCD4 (VAL-12, GLU -13, LEU- 14.) was taken as the backbone to sketch the peptidomimetic ligand namely, 2-formylamino-5-oxo-N-(2-oxoethyl)pentanamide employing Chemsketch, a freeware for chemical structure drawing and optimization from ACD Labs. This software also enables conversion of drawn 2D to 3D structure and subsequent Optimization, and was utilized for the same in this study (Figure 4) (www.acdlabs.com/download/).
Protein –ligand Docking
Docking of the receptor with the ligand was performed using Argus lab which operates on Lamarckian genetic algorithm (www.arguslab.com). Both the receptor and ligand were optimized for proper geometry using Argus lab, prior to docking. Finally, the best ligand pose was found to be with lowest binding energy of -6.86617 kcal/mol. The obtained complex showed six hydrogen bonds within the range of 3 Angstrom distance (Figure 5, Figure 6) (Table 1).
Lipinski 5 Screening
This screening methodology was implemented to analyze the Drug likeness of the proposed ligand. Lipinski’s rule of 5 is an essential screening methodology for rational drug design (Ekins and Rose, 2002; Miteva et al., 2006; Smith et al., 2004). It states that poor absorption or permeation are more likely when a ligand molecule violates Lipinski’s rule of five i.e., has more than 5 hydrogen bond donors, the molecular weight is over 500, the log P is over 5 and the sum of N and O is over 10. The Ligand of the present study has well qualified in Lipinski’s filter (http://www.scfbio-iitd.res.in/utility/LipinskiFilters.jsp) (Table 2).
Results and Discussion
HIV-1’s gp120 V3 region has high affinity towards SCD4 receptor [3].The present study was initiated to explore the possibility to develop an inhibitor mimicking the above mentioned interaction. Hence, Peptidomimetics approach was implemented to develop the inhibitor. The derived peptidomimetic inhibitor was docked with gp120 V3 region and was found to have significant affinity (Table 1) (Figure 5, Figure 6). We also screened the docked ligand for Lipinski’s rule of 5, which in turn proved to be a qualified drug (Table 2).
Entry inhibitors represent a new generation of antivirals for the treatment of HIV infection. Several compounds blocking the attachment of HIV gp120 to either the CD4 T cell receptor or the CCR5/CXCR4 co-receptors are currently in clinical development. Most of these compounds have different molecular structures and possess specific mode of action. These agents are eagerly awaited by a growing number of patients. Enfuvirtide is the first and the only clinically approved entry inhibitor for HIV, and it blocks HR1, HR2 zipping process in fusion step. So far three attachment inhibitors are designed namely, BMS-806, PRO 542, and TNX-355. These inhibitors are designed based on the existing drugs (Briz et al., 2006; Madani et al., 2006; Moore and Stevenson, 2000). Whereas, the drug designed in the present study is unique and is based on the gp120’s interaction with SCD4.
Conclusion
SCD4 has been found to prevent HIV attachment to cells in experiments, by the simple process of HIV’s envelope protein “spikes” attaching to it and thus being unable to attach to ordinary CD4 protein (Turner, 1992; Moore and Stevenson, 2000; O’Hara and Oslon, 2002; Layne et al., 1990). At low SCD4 concentration, the inhibition of HIV infection is propositional to the binding of gp120 with SCD4 (Layne et al., 1990). We propose that the drug designed in the present study might be more effective since it mimics the SCD4 interaction, as it also forms significant hydrogen bonds and qualifies in Lipinski’s filter. Hence, the proposed drug is presented to the scientific community for further experimental validation.
References
  1. Berger EA, Alkhatib G (2007) HIV gp120 interactions with coreceptors: insights from studies with ccr5-based peptides. Eur J Med Res 12: 403-407. »  CrossRef  »  PubMed  »  Google Scholar
  2. Briz V, Poveda E, Soriano V (2006) HIV entry inhibitors: mechanisms of action and resistance pathways. J Antimicrob Chemother 574: 619-627. »  CrossRef  »  PubMed  »  Google Scholar
  3. Ekins S, Rose J (2002) In silico ADME/Tox: the state of the art. J Mol Graph Model 20: 305-309. »  CrossRef  »  PubMed  »  Google Scholar
  4. Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, et al. (1998) Structure of an HIV gp120 envelope glycoproteinin complex with the CD4 receptor and a neutralizing human
    antibody. Nature 393: 648-659. »  CrossRef  »  PubMed  »  Google Scholar
  5. Lasky LA, Nakamura GM, Smith DH, Fennie C, Shimasaki C, et al. (1987) Delineation of a region of the Human Immunodeficiency Virus type I gpl20 glycoprotein critical for interaction
    with the CD4 receptor. Cell 50: 975-985. »  CrossRef  »  PubMed
  6. Layne SP, Merges MJ, Dembo M, Spouge JL, Nara PL (1990) HIV requires multiple gp120 molecules for CD4-mediated infection. Nature 346: 277-279. »  CrossRef  »  PubMed  »  Google Scholar
  7. Madani N, Hubicki A, Ng D, Smith A, Sodroski J (2006) The road to finding potent hiv-1 entry inhibitors: lessons learned from requirements for BMS -806 binding to HIV-1 envelope glycoprotein. Int Conf AIDS.
  8. Miteva MA, Violas S, Montes M, Gomez D, Tuffery P, et al. (2006) FAF-Drugs: free ADME/tox filtering of compound collections. Nucleic Acids Res 34: W738-W744. »  CrossRef  »  PubMed  »  Google Scholar
  9. Moore JP, Stevenson M (2000) New targets for inhibitors of HIV-1 replication. Nat Rev Mol Cell Biol 1: 40-49. »  CrossRef  »  PubMed  »  Google Scholar
  10. O’Hara BM, Olson WC (2002) Human Immunodeficiency Virus Type 1 Attachment, Coreceptor, and Fusion Inhibitors are active against both Direct and trans Infection of Primary Cells. Curr Opin Pharmacol 2: 523-528. »  CrossRef  »  PubMed  »  Google Scholar
  11. Ryu SE, Truneh A, Sweet RW, Hendrickson WA (1994) Structures of an HIV and MHC binding fragment from human CD4 as refined in two crystal lattices. Structure 21: 59- 74. »  CrossRef  »  PubMed  »  Google Scholar
  12. Smith PA, Sorich MJ, Low LS, McKinnon RA, Miners JO (2004) Towards integrated ADME prediction: past, present and future directions for modelling metabolism by UDPglucuronosyltransferases. J Mol Graph Model 22: 507-517. »  CrossRef  »  PubMed  »  Google Scholar
  13. Turner S, Tizard R, DeMarinis J, Pepinsky RB, Zullo J, et al. (1992) Resistance of primary isolates of human immunodeficiency virus type 1 to neutralization by soluble CD4 is not due to lower affinity with the viral envelope glycoprotein gpl20. Proc Nat Acad Sci USA Biochemistry 89: 1335- 1339. »  CrossRef  »  PubMed  »  Google Scholar
  14. Vranken WF, Fant F, Budesinsky M, Borremans FA (2001) Conformational model for the consensus V3 loop of the envelope protein gp120 of HIV-1 in a 20% trifluoroethanol/ water solution. Eur J Biochem 268: 2620-2628. »  CrossRef  »  PubMed  »  Google Scholar
  15. Wyatt R, Sodroski J (1998) The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science 280: 1884-1888. »  CrossRef  »  PubMed  »  Google Scholar
Select your language of interest to view the total content in your interested language
Post your comment

Share This Article

Relevant Topics

Recommended Conferences

Article Usage

  • Total views: 11263
  • [From(publication date):
    November-2009 - Sep 29, 2016]
  • Breakdown by view type
  • HTML page views : 7528
  • PDF downloads :3735
 
 

Post your comment

captcha   Reload  Can't read the image? click here to refresh

OMICS International Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
 
 
OMICS International Conferences 2016-17
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings
 
 

Contact Us

Agri, Food, Aqua and Veterinary Science Journals

Dr. Krish

agrifoodaquavet@omicsinc.com

1-702-714-7001 Extn: 9040

Clinical and Biochemistry Journals

Datta A

clinical_biochem@omicsinc.com

1-702-714-7001Extn: 9037

Business & Management Journals

Ronald

business@omicsinc.com

1-702-714-7001Extn: 9042

Chemical Engineering and Chemistry Journals

Gabriel Shaw

chemicaleng_chemistry@omicsinc.com

1-702-714-7001 Extn: 9040

Earth & Environmental Sciences

Katie Wilson

environmentalsci@omicsinc.com

1-702-714-7001Extn: 9042

Engineering Journals

James Franklin

engineering@omicsinc.com

1-702-714-7001Extn: 9042

General Science and Health care Journals

Andrea Jason

generalsci_healthcare@omicsinc.com

1-702-714-7001Extn: 9043

Genetics and Molecular Biology Journals

Anna Melissa

genetics_molbio@omicsinc.com

1-702-714-7001 Extn: 9006

Immunology & Microbiology Journals

David Gorantl

immuno_microbio@omicsinc.com

1-702-714-7001Extn: 9014

Informatics Journals

Stephanie Skinner

omics@omicsinc.com

1-702-714-7001Extn: 9039

Material Sciences Journals

Rachle Green

materialsci@omicsinc.com

1-702-714-7001Extn: 9039

Mathematics and Physics Journals

Jim Willison

mathematics_physics@omicsinc.com

1-702-714-7001 Extn: 9042

Medical Journals

Nimmi Anna

medical@omicsinc.com

1-702-714-7001 Extn: 9038

Neuroscience & Psychology Journals

Nathan T

neuro_psychology@omicsinc.com

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

John Behannon

pharma@omicsinc.com

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

social_politicalsci@omicsinc.com

1-702-714-7001 Extn: 9042

 
© 2008-2016 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version