Structure-guided fragment-based in silico drug design of dengue protease inhibitors

被引:50
作者
Knehans, Tim [1 ,2 ,3 ]
Schueller, Andreas [1 ]
Doan, Danny N. [1 ]
Nacro, Kassoum [4 ]
Hill, Jeffrey [4 ]
Guentert, Peter [2 ,3 ]
Madhusudhan, M. S. [5 ]
Weil, Tanja [6 ]
Vasudevan, Subhash G. [1 ]
机构
[1] Duke NUS Grad Med Sch, Program Emerging Infect Dis, Singapore 169857, Singapore
[2] Goethe Univ Frankfurt, Inst Biophys Chem, Ctr Biomol Magnet Resonance, D-60438 Frankfurt, Germany
[3] Goethe Univ Frankfurt, Frankfurt Inst Adv Studies, D-60438 Frankfurt, Germany
[4] ASTAR, Ctr Expt Therapeut, Singapore 138669, Singapore
[5] ASTAR, Bioinformat Inst, Singapore 138671, Singapore
[6] Univ Ulm, Inst Organ Chem Macromol Chem 3, D-89069 Ulm, Germany
关键词
Dengue virus; NS2B-NS3; protease; West Nile virus; Protease inhibitor; Fragment-based drug design (FBDD); Homology modeling; WEST-NILE-VIRUS; TETRAPEPTIDE ALDEHYDE INHIBITORS; NS3; PROTEASE; PEPTIDE INHIBITORS; SERINE-PROTEASE; NS2B/NS3; SCORING FUNCTION; DOCKING; PROTEINASE; DISCOVERY;
D O I
10.1007/s10822-011-9418-0
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
An in silico fragment-based drug design approach was devised and applied towards the identification of small molecule inhibitors of the dengue virus (DENV) NS2B-NS3 protease. Currently, no DENV protease co-crystal structure with bound inhibitor and fully formed substrate binding site is available. Therefore a homology model of DENV NS2B-NS3 protease was generated employing a multiple template spatial restraints method and used for structure-based design. A library of molecular fragments was derived from the ZINC screening database with help of the retrosynthetic combinatorial analysis procedure (RECAP). 150,000 molecular fragments were docked to the DENV protease homology model and the docking poses were rescored using a target-specific scoring function. High scoring fragments were assembled to small molecule candidates by an implicit linking cascade. The cascade included substructure searching and structural filters focusing on interactions with the S1 and S2 pockets of the protease. The chemical space adjacent to the promising candidates was further explored by neighborhood searching. A total of 23 compounds were tested experimentally and two compounds were discovered to inhibit dengue protease (IC50 = 7.7 mu M and 37.9 mu M, respectively) and the related West Nile virus protease (IC50 = 6.3 mu M and 39.0 mu M, respectively). This study demonstrates the successful application of a structure-guided fragment-based in silico drug design approach for dengue protease inhibitors providing straightforward hit generation using a combination of homology modeling, fragment docking, chemical similarity and structural filters.
引用
收藏
页码:263 / 274
页数:12
相关论文
共 60 条
[1]
*ACC INC, 2007, PIP PIL
[2]
Structural evidence for regulation and specificity of flaviviral proteases and evolution of the Flaviviridae fold [J].
Aleshin, Alexander E. ;
Shiryaev, Sergey A. ;
Strongin, Alex Y. ;
Liddington, Robert C. .
PROTEIN SCIENCE, 2007, 16 (05) :795-806
[3]
[Anonymous], 2002, PYMOL MOL GRAPHICS S
[4]
[Anonymous], 2009, GRAPHPAD PRISM
[5]
The properties of known drugs .1. Molecular frameworks [J].
Bemis, GW ;
Murcko, MA .
JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (15) :2887-2893
[6]
Fragment-based flexible ligand docking by evolutionary optimization [J].
Budin, N ;
Majeux, N ;
Caflisch, A .
BIOLOGICAL CHEMISTRY, 2001, 382 (09) :1365-1372
[7]
Serotype-Specific Structural Differences in the Protease-Cofactor Complexes of the Dengue Virus Family [J].
Chandramouli, Sumana ;
Joseph, Jeremiah S. ;
Daudenarde, Sophie ;
Gatchalian, Jovylyn ;
Cornillez-Ty, Cromwell ;
Kuhn, Peter .
JOURNAL OF VIROLOGY, 2010, 84 (06) :3059-3067
[8]
Competitive inhibition of the dengue virus NS3 serine protease by synthetic peptides representing polyprotein cleavage sites [J].
Chanprapaph, S ;
Saparpakorn, P ;
Sangma, C ;
Niyomrattanakit, P ;
Hannongbua, S ;
Angsuthanasombat, C ;
Katzenmeier, G .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2005, 330 (04) :1237-1246
[9]
Insights to substrate binding and processing by West Nile Virus NS3 protease through combined modeling, protease mutagenesis, and kinetic studies [J].
Chappell, Keith J. ;
Stoermer, Martin J. ;
Fairlie, David P. ;
Young, Paul R. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (50) :38448-38458
[10]
CHAPPELL KJ, 2007, THESIS U QUEENSLAND