Abstract
Fifteen KSP inhibitors were docked into the receptor and the binding mode was analyzed for the first time. It was considered that in addition to the main binding pocket all the inhibitors merged in, there exists a cooperative minor binding pocket, which could be explored for significantly increased binding affinity. In addition, a good linear relationship between the biological activities and the lowest binding free energies has also been found. This may help in predicting the binding affinity of newly designed KSP inhibitors.
Similar content being viewed by others
References
Sharp DJ, Rogers GC, Scholey JM (2000) Nature 407:41–47
Mandelkow E, Mandelkow EM (2002) Trends Cell Biol 12:585–591
Endow SA, Baker DS (2003) Annu Rev Physiol 65:161–175
Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ (1999) Science 286:971–974
Kapoor TM, Mayer TU, Coughlin ML, Mitchison TJ (2000) J Cell Biol 150:975–988
Sakowicz R, Finer JT, Beraud C, Crompton A, Lewis E, Fritsch A, Lee Y, Mak J, Moody R, Turincio R, Chabala JC, Gonzales P, Roth S, Weitman S, Wood K W (2004) Cancer Res 64:3276–3280
Turner J, Anderson R, Guo J, Beraud C, Fletterick R, Sakowicz R (2001) J Biol Chem 276:25496–25502
Yan YW, Sardana V, Xu B, Homnick C, Halczenko W, Buser CA, Schaber M, Hartman GD, Huber HE, Kuo LC (2004) J Mol Biol 335:547–554
Burris H, LoRussoZ P, Jones S, McCormickz J, Willcutt N, Hodge J, Bush P, Pandite L, Sabry J, Ho P, Cannon S (2003) A phase I study to determine the safety and pharmacokinetics of intravenous administration of SB715992 on a once weekly for three consecutive weeks schedule in patients with refractory solid tumors. European Cancer Conference (ECCO), Poster 570, Sept 23
Bergnes G, Ha E, Feng B, Yao B, Smith WW, Tochimoto T, Lewis ER, Lee YY, Moody R, Turincio RA, Finer JT, Wood KW, Sakowicz R, Crompton AM, Chabala JC, Morgans DJ Jr, Sigal NH, Sabry JH (2002) Mitotic kinesin-targeted antitumor agents: discovery, lead optimization and anti-tumor activity of a series of novel quinazolinones as inhibitors of kinesin spindle protein (KSP). 93rd American Association for Cancer Reseach (AACR) Annual Meeting, San Francisco USA, April, Abstract 3648
Brier S, Lemaire D, DeBonis S, Forest E, Kozielski F (2004) Biochemistry 43:13072–13082
Cox CD, Breslin MJ, Mariano BJ, Coleman PJ, Buser CA, Walsh ES, Hamilton K, Huber HE, Kohl NE, Torrent M, Yan Y, Kuo LC, Hartmana GD (2005) Bioorg Med Chem Lett 15:2041–2045
Sunder-Plassmann N, Sarli V, Gartner M, Utz M, Seiler J, Huemmer S, Mayer TU, Surreyb T, Giannisa A (2005) Bioorg Med Chem 13:6094–6111
Hotha S, Yarrow JC, Yang JG, Garrett S, Renduchintala KV, Mayer TU, Kapoor TM (2003) Angew Chem Int Ed 42:2379–2382
Nakazawa J, Yajima J, Usui T, Ueki M, Takatsuki A, Imoto M, Toyoshima YY, Osada H (2003) Chem Biol 10:131–137
Fraley ME, Garbaccio RM, Arrington KL, Hoffman WF, Tasber ES, Coleman PJ, Buser CA, Walsh ES, Hamilton K, Fernandes C, Schaber MD, Lobell RB, Tao W, South VJ, Yan Y, Kuo LC, Prueksaritanont T, Shu C, Torrent M, Heimbrook DC, Kohl NE, Huber HE, Hartman GD (2006) Bioorg Med Chem Lett 16:1775–1779
Garbaccio RM, Fraley ME, Tasber ES, Olson CM, Hoffman WF, Arrington KL, Torrent M, Buser CA, Walsh ES, Hamilton K, Schaber MD, Fernandes C, Lobell RB, Tao W, South VJ, Yan Y, Kuo LC, Prueksaritanont T, Slaughter DE, Shu C, Heimbrook DC, Kohl NE, Huber HE, Hartman GD (2006) Bioorg Med Chem Lett 16:1780–1783
Cox CD, Torrent M, Breslin MJ, Mariano BJ, Whitman DB, Coleman PJ, Buser CA, Walsh ES, Hamilton K, Schaber MD, Lobell RB, Tao W, South VJ, Kohl NE, Yan Y, Kuo LC, Prueksaritanont T, Slaughter DE, Li C, Mahan E, Lu B, Hartman GD (2006) Bioorg Med Chem Lett 16:3175–3179
Kim KS, Lu S, Cornelius LA, Lombardo LJ, Borzilleri RM, Schroeder GM, Sheng C, Rovnyak G, Crews D, Schmidt RJ, Williams DK, Bhide RS, Traeger SC, McDonnell PA, Mueller L, Sheriff S, Newitt JA, Pudzianowski AT, Yang Z, Wild R, Lee FY, Batorsky R, Ryder JS, Ortega-Nanos M, Shen H, Gottardis M, Roussell DL (2006) Bioorg Med Chem Lett 16:3937–3942
Tarby CM, Kaltenbach RF, Huynh T, Pudzianowski A, Shen H, Ortega-Nanos M, Sheriff S, Newitt JA, McDonnell PA, Burford N, Fairchild CR, Vaccaro W, Chen Z, Borzilleri RM, Naglich J, Lombardo LJ, Gottardis M, Trainor GL, Roussell DL (2006) Bioorg Med Chem Lett 16:2095–2100
Jiang C, You QD, Li ZY, Guo QL (2006) Expert Opin Ther Pat 16:1517–1532
Liu F, You QD, Chen YD (2007) Bioorg Med Chem Lett 17:722–726
Cogan EB, Birell GB, Griffith OH (1999) Anal Biochem 271:29–35
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) J Comput Chem 19:1639–1662
Acknowledgement
The authors thank Prof. Toshio Fujita from Kyoto University for comments to this paper. This work was financially supported by a grant from “The Six Top Talents” of Jiangsu Province (No. 06-C-023) and Specialized Research Fund for the Doctoral Program of Higher Education P.R.C. (No. 20060316006).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jiang, C., Chen, Y., Wang, X. et al. Docking studies on kinesin spindle protein inhibitors: an important cooperative ‘minor binding pocket’ which increases the binding affinity significantly. J Mol Model 13, 987–992 (2007). https://doi.org/10.1007/s00894-007-0219-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00894-007-0219-2