In silico study on indole derivatives as anti HIV-1 agents: a combined docking, molecular dynamics and 3D-QSAR study

다국어 초록 (Multilingual Abstract)

The HIV-1 envelope glycoprotein gp120 playsa vital role in the entry of virus into the host cells and is apotential antiviral drug target. Recently, indole derivativeshave been reported to inhibit HIV-1 through binding togp120, and this prevents gp120 and CD4 interaction toinhibit the infectivity of HIV-1. In this work, moleculardocking, molecular dynamics (MD) and three-dimensionalquantitative structure–activity relationship studies werecarried out. Molecular docking studies of the most activeand the least active compounds were performed to identifyimportant residues in the binding pocket. We refined thedocked poses by MD simulations which resulted in conformationalchanges. After equilibration, the structure ofthe ligand and receptor complex was stable. Therefore, wejust took the last snapshot as the representative bindingpose for this study. This pose for the most active inhibitorwas used as a template for receptor-based alignment whichwas subsequently used for comparative molecular fieldanalysis. Resultant 3D contour maps suggested smaller substituents are desirable at the 7-position of indole ring toavoid steric interactions with Ser375, Phe382 and Tyr384residues in the active site. These results can be exploited todevelop potential leads and for structure-based drug designof novel HIV-1 inhibitors.

참고문헌 (Reference)

1 Teixeira, C., "Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1 : Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug" 46 : 979-992, 2011

2 Clark, M., "Validation of the general purpose Tripos 5. 2 force field" 10 : 982-1012, 1989

3 Blacklow, S.C., "Trimeric subdomain of the simian immunodeficiency virus envelope glycoprotein" 34 : 14955-14962, 1995

4 Wold, S., "The collinearity problem in linear regression. The partial least squares(PLS)approach to generalized inverses" 5 : 735-743, 1984

5 Wyatt, R., "The HIV-1 envelope glycoproteins : Fusogens, antigens, and immunogens" 280 : 1884-1888, 1998

6 Dalgleish, A.G., "The CD4(T4)antigen is an essential component of the receptor for the AIDS retrovirus" 312 : 763-767, 1984

7 Zhan, P., "Targeting protein–protein interactions : A promising avenue of anti-HIV drug discovery" 17 : 3393-3409, 2010

8 Kadow, J., "Small-molecule HIV-1gp120 inhibitors to prevent HIV-1 entry : An emerging opportunity for drug development" 7 : 721-726, 2006

9 Powell, M.J.D., "Restart procedures for the conjugate gradient method" 12 : 241-254, 1977

10 Sanner, M.F., "Python : A programming language for software integration and development" 17 : 57-61, 1999

11 Kong, R., "Prediction of the binding mode between BMS-378806 and HIV-1 gp120 by docking and molecular dynamics simulation" 1764 : 766-772, 2006

12 Kilby, J.M., "Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry" 4 : 1302-1307, 1998

13 Xiang, S.H., "Mutagenic stabilization and/or disruption of a CD4-bound state reveals distinct conformations of the human immunodeficiency virus type 1 gp120 envelope glycoprotein" 76 : 9888-9899, 2002

14 Gadhe, C.G., "Molecular modeling study of HIV-1 gp120 attachment inhibitors" 21 : 1892-1904, 2012

15 Brasseur, R., "Mode of insertion into a lipid membrane of the N-terminal HIV gp41 peptide segment" 4 : 83-90, 1988

16 Dorr, P., "Maraviroc(UK-427, 857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5with broad-spectrum anti-human immunodeficiency virus type 1activity" 49 : 4721-4732, 2005

17 Gasteiger, J., "Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges" 36 : 3219-3228, 1980

18 Teixeira, C., "Is the conformational flexibility of piperazine derivatives important to inhibit HIV-1replication?" 44 : 91-103, 2013

19 Yeung, K.S., "Inhibitors of HIV-1 attachment. Part 8 : The effect of C7-heteroaryl substitution on the potency, and in vitro and in vivo profiles of indolebased inhibitors" 23 : 203-208, 2013

20 Yeung, K.S., "Inhibitors of HIV-1 attachment. Part 7 : Indole-7-carboxamides as potent and orally bioavailable antiviral agents" 23 : 198-202, 2013

21 Bosch, M.L., "Identification of the fusion peptide of primate immunodeficiency viruses" 244 : 694-697, 1989

22 Kowalski, M., "Functional regions of the envelope glycoprotein of human immunodeficiency virus type 1" 237 : 1351-1355, 1987

23 Teixeira, C., "Docking and 3D-QSAR studies of BMS-806 analogs as HIV-1 gp120entry inhibitors" 44 : 3524-3532, 2009

24 Wang, J., "Development and testing of a general amber force field" 25 : 1157-1174, 2004

25 Lasky, L.A., "Delineation of a region of the human immunodeficiency virus type 1gp120 glycoprotein critical for interaction with the CD4receptor" 50 : 975-985, 1987

26 Hornak, V., "Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins : Structure Function" 65 : 712-725, 2006

27 Berger, E.A., "Chemokine receptors as HIV-1 coreceptors : Roles in viral entry, tropism, and disease" 17 : 657-700, 1999

28 Helseth, E., "Changes in the transmembrane region of the human immunodeficiency virus type 1 gp41 envelope glycoprotein affect membrane fusion" 64 : 6314-6318, 1990

29 Morris, G.M., "Automated docking using a Lamarckian genetic algorithmand an empirical binding free energy function" 19 : 1639-1662, 1998

30 Morris, G.M., "AutoDock4 and AutoDock-Tools4 : Automated docking with selective receptor flexibility" 30 : 2785-2791, 2009

31 Hou, T., "Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations" 51 : 69-82, 2011

32 Case, D.A., "AMBER 12" University of California 2012

33 Lu, M., "A trimeric structural domain of the HIV-1 transmembrane glycoprotein" 2 : 1075-1082, 1995

34 Essmann, U., "A smooth particle mesh Ewald method" 103 : 8577-8593, 1995