title: In-silico designing of a potent analogue against HIV-1 Nef protein and protease by predicting its interaction network with host cell proteins.
abstract: BACKGROUND
  HIV-1 has numerous proteins encoded within its genome, which acquaints it with the required arsenal to establish a favorable host cell environment suitable for viral replication and pathogenesis. Among these proteins, one protein that is indispensable and ambiguous is the Nef protein.
  
  
  OBJECTIVE
  Interaction of Nef protein with different host-cell protein was predicted and subsequently the down regulation of cluster of differentiation 4 (CD4) was targeted through designing of inhibitors of Nef protein for either preventing or if not at least delaying pathogenesis.
  
  
  METHODS
  The interaction network of Nef protein with host-cell proteins were predicted by PIMRider. Analogue of Lopinavir were prepared and evaluated considering all factors affecting the drug stability and toxicity. Finally Docking simulation were performed using an Auto-Dock Tool 4.0.
  
  
  RESULTS
  In the interaction network of Nef protein with different host-cell proteins it was found out that 22 host cell proteins are involved in the interaction and execution of different types of functions in host cell but these functions are altered with the interaction with the Nef protein. After extensive and controlled in silico analysis it has been observed that the analogue LOPI1 binds to Nef protein (2NEF) at CD4 interacting site residues giving minimum binding energy of -7.68 Kcal/mole, low Ki value of 2.34 μM, maximum number of hydrogen bonds (8), good absorption, distribution, metabolism and excretion properties, and less toxicity in comparison with the standard Lopinavir against HIV1 protease (1HPV).
  
  
  CONCLUSIONS
  The newly designed analogue (LOPI1) is showing significant in silico interaction with Nef protein and protease and can be taken forward as a potent drug lead, which may finally emerge out to be even better than the standard Lopinavir.
authors.affiliation: Department of Bioinformatics, UIET, CSJM University, Kanpur, Uttar Pradesh, India.
authors.forename: Shikha
authors.initials: S
authors.lastname: Pal
authors.forename: Madhur
authors.initials: M
authors.lastname: Mishra
authors.forename: D Raja
authors.initials: DR
authors.lastname: Sudhakar
authors.forename: Mohammed Haris
authors.initials: MH
authors.lastname: Siddiqui
keywords: CD4 down regulation; HIV-1; key regulator; pathogenesis; protein-protein interaction modules
references.citation: Science. 1985 Nov 15;230(4727):810-3
references.pmid: 2997921
references.citation: J Gen Virol. 2004 Jun;85(Pt 6):1451-1461
references.pmid: 15166428
references.citation: Eur Rev Med Pharmacol Sci. 2011 Aug;15(8):916-30
references.pmid: 21845802
references.citation: Retrovirology. 2008 Sep 22;5:84
references.pmid: 18808677
references.citation: Lab Chip. 2010 Jan 7;10(1):13-22
references.pmid: 20024044
references.citation: Biochemistry. 1997 May 20;36(20):5970-80
references.pmid: 9166767
references.citation: Bioinformation. 2011 Mar 26;6(2):74-7
references.pmid: 21544169
references.citation: Cell. 1996 Jun 14;85(6):931-42
references.pmid: 8681387
references.citation: J Biol Chem. 2003 Sep 5;278(36):33912-9
references.pmid: 12816953
references.citation: Cell. 1994 Jan 28;76(2):263-74
references.pmid: 8293463
references.citation: Br Med Bull. 2001;58:19-42
references.pmid: 11714622
references.citation: Bioinformation. 2012;8(3):128-33
references.pmid: 22368384
references.citation: J Biosci. 2003 Apr;28(3):323-35
references.pmid: 12734410
references.citation: Org Biomol Chem. 2003 Jan 7;1(1):5-14
references.pmid: 12929379
references.citation: Eur J Biochem. 1994 Apr 15;221(2):811-9
references.pmid: 8174561
references.citation: Bioorg Med Chem. 2010 Nov 1;18(21):7446-57
references.pmid: 20884214
references.citation: Rev Med Virol. 2008 May-Jun;18(3):159-75
references.pmid: 18265424
references.citation: Int J Bioinform Res Appl. 2013;9(4):336-48
references.pmid: 23797993
references.citation: Indian J Med Res. 2005 Apr;121(4):315-32
references.pmid: 15817946
references.citation: Phytother Res. 2011 Nov;25(11):1586-95
references.pmid: 21394808
references.citation: Curr HIV Res. 2003 Apr;1(2):167-84
references.pmid: 15043201
references.citation: EMBO Rep. 2001 Jul;2(7):580-5
references.pmid: 11463741
references.citation: Nature. 1985 Sep 26-Oct 2;317(6035):366-8
references.pmid: 2995822
references.citation: Adv Pharmacol. 2007;55:389-409
references.pmid: 17586321
references.citation: J Immunol. 1984 Jul;133(1):123-8
references.pmid: 6327821
references.citation: Bioinformation. 2011 Mar 26;6(2):57-60
references.pmid: 21544165
references.citation: JAMA. 1997 Jan 8;277(2):145-53
references.pmid: 8990341
references.citation: Cell. 1994 Mar 11;76(5):853-64
references.pmid: 8124721
references.citation: Cell. 1993 Apr 23;73(2):209-12
references.pmid: 8477442
references.citation: Annu Rev Biochem. 1998;67:1-25
references.pmid: 9759480
references.citation: J Biol Chem. 1994 Dec 2;269(48):30073-6
references.pmid: 7982906
references.citation: Nature. 1995 Jan 12;373(6510):102
references.pmid: 7816085
references.citation: Cell. 1999 Apr 2;97(1):63-73
references.pmid: 10199403
references.citation: Eur J Biochem. 1994 Jul 15;223(2):589-93
references.pmid: 8055930
references.citation: J Exp Med. 1993 Jun 1;177(6):1561-6
references.pmid: 8098729
references.citation: J Virol. 2002 May;76(9):4625-33
references.pmid: 11932428
references.citation: Nat Struct Biol. 1996 Apr;3(4):340-5
references.pmid: 8599760
references.citation: Biochemistry. 1996 Aug 13;35(32):10256-61
references.pmid: 8756680