Molecular dynamics simulation and density functional theory studies on the active pocket for the binding of paclitaxel to tubulin

被引:19
作者
Xu, Sichuan [1 ,2 ]
Chi, Shaoming [2 ]
Jin, Yi [2 ]
Shi, Qiang [1 ]
Ge, Maofa [1 ]
Wang, Shu [1 ]
Zhang, Xingkang [1 ]
机构
[1] Chinese Acad Sci, State Key Lab Struct Chem Unstable & Stable Speci, Beijing Natl Lab Mol Sci, Inst Chem, Beijing 100190, Peoples R China
[2] Yunnan Univ, Key Lab, Educ Minist Med Chem Nat Resource, Coll Chem Sci & Technol, Kunming 650091, Peoples R China
关键词
Paclitaxel; Tubulin; Binding pocket; MD simulation; DFT; PROTON-TRANSFER MECHANISM; ALPHA-BETA-TUBULIN; QUANTUM-MECHANICS; T-TAXOL; POLY(ADP-RIBOSE) POLYMERASE; CATALYTIC FRAGMENT; NATURAL-PRODUCTS; SCORING FUNCTION; DOCKING; CONFORMATION;
D O I
10.1007/s00894-011-1083-7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Paclitaxel (PTX) is used to treat various cancers, but it also causes serious side effects and resistance. To better design similar compounds with less toxicity and more activity against drug-resistant tumors, it is important to clearly understand the PTX-binding pocket formed by the key residues of active sites on beta-tubulin. Using a docking method, molecular dynamics (MD) simulation and density functional theory (DFT), we identified some residues (such as Arg278, Asp26, Asp226, Glu22, Glu27, His229, Arg369, Lys218, Ser277 and Thr276) on beta-tubulin that are the active sites responsible for interaction with PTX. Another two residues, Leu371 and Gly279, also likely serve as active sites. Most of these sites contact with the "southern hemisphere" of PTX; only one key residue interacts with the "northern hemisphere" of PTX. These key residues can be divided into four groups, which serve as active compositions in the formation of an active pocket for PTX binding to beta-tubulin. This active binding pocket enables a very strong interaction (the strength is predicted to be in the range of -327.8 to -365.7 kJ mol(-1)) between beta-tubulin and PTX, with various orientated conformations. This strong interaction means that PTX possesses a high level of activity against cancer cells, a result that is in good agreement with the clinical mechanism of PTX. The described PTX pocket and key active residues will be applied to probe the mechanism of tumor cells resistant to PTX, and to design novel analogs with superior properties.
引用
收藏
页码:377 / 391
页数:15
相关论文
共 123 条
[1]   Role of the active-site solvent in the thermodynamics of factor Xa ligand binding [J].
Abel, Robert ;
Young, Tom ;
Farid, Ramy ;
Berne, Bruce J. ;
Friesner, Richard A. .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2008, 130 (09) :2817-2831
[2]   T-taxol conformation [J].
Alcaraz, AA ;
Mehta, AK ;
Johnson, SA ;
Snyder, JP .
JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (08) :2478-2488
[3]  
[Anonymous], 1996, Biomolecular Simulation: the GROMOS96 Manual and User Guide
[4]   NUCLEAR OVERHAUSER EFFECT SPECTROSCOPY (NOESY) AND DIHEDRAL ANGLE MEASUREMENTS IN THE DETERMINATION OF THE CONFORMATION OF TAXOL IN SOLUTION [J].
BAKER, JK .
SPECTROSCOPY LETTERS, 1992, 25 (01) :31-48
[5]   DENSITY-FUNCTIONAL THERMOCHEMISTRY .3. THE ROLE OF EXACT EXCHANGE [J].
BECKE, AD .
JOURNAL OF CHEMICAL PHYSICS, 1993, 98 (07) :5648-5652
[6]  
Bene J. E. D., 1993, J PHYS CHEM, V97, P107
[7]   GROMACS - A MESSAGE-PASSING PARALLEL MOLECULAR-DYNAMICS IMPLEMENTATION [J].
BERENDSEN, HJC ;
VANDERSPOEL, D ;
VANDRUNEN, R .
COMPUTER PHYSICS COMMUNICATIONS, 1995, 91 (1-3) :43-56
[8]   MOLECULAR-DYNAMICS WITH COUPLING TO AN EXTERNAL BATH [J].
BERENDSEN, HJC ;
POSTMA, JPM ;
VANGUNSTEREN, WF ;
DINOLA, A ;
HAAK, JR .
JOURNAL OF CHEMICAL PHYSICS, 1984, 81 (08) :3684-3690
[9]   Prediction of binding constants of protein ligands: A fast method for the prioritization of hits obtained from de novo design or 3D database search programs [J].
Bohm, HJ .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 1998, 12 (04) :309-323
[10]   CALCULATION OF SMALL MOLECULAR INTERACTIONS BY DIFFERENCES OF SEPARATE TOTAL ENERGIES - SOME PROCEDURES WITH REDUCED ERRORS [J].
BOYS, SF ;
BERNARDI, F .
MOLECULAR PHYSICS, 1970, 19 (04) :553-&