CMB  Vol.5 No.2 , June 2015
Molecular Docking Studies of Myricetin and Its Analogues against Human PDK-1 Kinase as Candidate Drugs for Cancer
ABSTRACT
Phosphoinositide-dependent protein kinase-1 (PDK1), the class of serine threonine kinase, is a master regulator of the AGC family of kinases. It is a main component of the PI3K pathway. As it is reported that this pathway is most commonly, and this pathway is the most commonly deregulated among many cancers. So designing a selective inhibitor of PDK1 may have the efficacy as an anticancer agent. Herein, we describe our work focused on the structure based on screening of 95% similar analogues of Myricetin deposited in PubChem database as earlier studies have been suggested that myricetin acts as an anti cancer agent. Further molecular docking as well as the in silico ADMET studies are incorporated on these compounds to evaluate the binding and pharmacokinetic properties of these compounds. Due to low oral bioavailability, clinical use of myricetin is limited. Therefore this study is an attempt towards screening of structurally similar better compounds as compare with myricetin which can act as better inhibitor against PDK-1.

Cite this paper
Singh, S. and Srivastava, P. (2015) Molecular Docking Studies of Myricetin and Its Analogues against Human PDK-1 Kinase as Candidate Drugs for Cancer. Computational Molecular Bioscience, 5, 20-33. doi: 10.4236/cmb.2015.52004.
References
[1]   Fabian, M.A., Biggs III, W.H., Treiber, D.K., Atteridge, C.E., Azimioara, M.D., Benedetti,M.G., Carter, T.A., Ciceri, P., Edeen, P.T., Floyd, M., Ford, M., Galvin, J.M., Gerlach, M., Gortzfeld, J.L., Herrgard, R.M., Insko, S., Insko, M.A., Lai, A.G., Lelias, J.M., Mehta, S.A., Milanov, Z.V., Velasco, A.M., Wodicka, L.M., Patel, H.K., Zarrinkar, P.P. and Lockhart, D.J. (2005) A Small Molecule—Kinase Interaction Map for Clinical Kinase Inhibitors. Nature Biotechnology, 23, 329-336.
http://dx.doi.org/10.1038/nbt1068

[2]   Manning, G., Whyte, D.B., Martinez, R., Hunter, T. and Sudarsanam, S. (2002) The Protein Kinase Complement of the Human Genome. Science, 298, 1912-1934.
http://dx.doi.org/10.1126/science.1075762

[3]   Akritopoulou-Zanze, I. and Hajduk, P.J., (2009) Kinase-Targeted Libraries: The Design and Synthesis of Novel, Potent and Selective Kinase Inhibitors. Drug. Drug Discovery Today, 14, 291-297.
http://dx.doi.org/10.1016/j.drudis.2008.12.002

[4]   Anderson, S.L., Stokoe, D., Erdjument-Bromage, H., Painter, G.F., Holmes, A.B., Gaffney, P.R., Reese, C.B., McCormick, F., Tempst, P., Coadwell, J. and PHawkins, T. (1998) Protein Kinase B Kinases That Mediate Phosphatidylinositol 3,4,5-Trisphosphate-Dependent Activation of Protein Kinase B. Science, 279,710-714.
http://dx.doi.org/10.1126/science.279.5351.710

[5]   Alessi, D.R., Deak, M., Casamayor, A., Caudwell, F.B., Morrice, N., Norman, D.G., Gaffney, P., Reese, C.B., MacDougall, C.N., Harbison, D., Ashworth, A. and Bownes, M. (1997) 3-Phosphoinositide-Dependent Protein Kinase-1 (PDK1): Structural and Functional Homology with the Drosophila DSTPK61 Kinase. Current Biology, 7, 776-789.
http://dx.doi.org/10.1016/s0960-9822(06)00336-8

[6]   Currie, R.A., Walker, K.S., Gray, A., Deak, M., Casamayor, A., Downes, C.P., Cohen, P., Alessi, D.R. and Lucocq, J. (1999) Role of Phosphatidylinositol 3,4,5-Trisphosphate in Regulating the Activity and Localization of 3-Phosphoinositide-Dependent Protein Kinase-1. Biochemical Journal, 337, 575-583.
http://dx.doi.org/10.1042/0264-6021:3370575

[7]   Kobayashi, T. and Cohen, P. (1999) Activation of Serum- and Glucocorticoid-Regulated Protein Kinase by Agonists That Activate Phosphatidy-linositide 3-Kinase Is Mediated by 3-Phosphoinositide-Dependent Protein Kinase-1 (PDK1) and PDK2. Biochemical Journal, 339, 319-328.
http://dx.doi.org/10.1042/0264-6021:3390319

[8]   Kobayashi, T., Deak, M., Morrice, N. and Cohen, P. (1999) Characterization of the Structure and Regulation of Two Novel Isoforms of Serum- and Glucocorticoid-Induced Protein Kinase. Biochemical Journal, 344,189-197.
http://dx.doi.org/10.1042/0264-6021:3440189

[9]   Park, J., Leong, M.L., Buse, P., Maiyar, A.C., Firestone, G.L. and Hemmings, B.A. (1999) Serum and Glucocorticoid-Inducible Kinase (SGK) Is a Target of the PI 3-Kinase-Stimulated Signaling Pathway. EMBO Journal, 18, 3024-3033.
http://dx.doi.org/10.1093/emboj/18.11.3024

[10]   Pullen, N., Dennis, P.B., Andjelkovic, M., Dufner, A., Kozma, S.C., Hemmings, B.A. and Thomas, G. (1998) Phosphorylation and Activation of p70s6k by PDK1. Science, 279, 707-710.
http://dx.doi.org/10.1126/science.279.5351.707

[11]   Alessi, D.R., Kozlowski, M.T., Weng, Q.-P., Morrice, N. and Avruch, J. (1997) 3-Phosphoinositide-Dependent Protein Kinase 1 (PDK1) Phosphorylates and activates the p70 S6 Kinase in vivo and in vitro. Current Biology, 8, 69-81.
http://dx.doi.org/10.1016/S0960-9822(98)70037-5

[12]   Mora, A., Komander, D., van Aalten, D.M. and Alessi, D.R., (2004) PDK1, the Master Regulator of AGC Kinase Signal Transduction. Seminars in Cell Developmental Biology, 15, 161-170.
http://dx.doi.org/10.1016/j.semcdb.2003.12.022

[13]   Dahia, P.L. (2000) PTEN, a Unique Tumor Suppressor Gene. Endocrine-Related Cancer, 7, 115-129.
http://dx.doi.org/10.1677/erc.0.0070115

[14]   Sansal, I. and Sellers, W.R. (2004) The Biology and Clinical Relevance of the PTEN Tumor Suppressor Pathway. Journal of Clinical Oncology, 22, 2954-2963.
http://dx.doi.org/10.1200/JCO.2004.02.141

[15]   Cully, M., You, H., Levine, A.J. and Mak, T.W. (2006) Beyond PTEN Mutations: the PI3K Pathway as an Integrator of Multiple Inputs during Tumorigenesis. Nature Reviews Cancer, 6, 184-192.
http://dx.doi.org/10.1038/nrc1819

[16]   Brooks, B.R., Brucolleri, R.E., Olafson, B.D., States, D.J., Swaminathan, S. and Karplus, M. (1983) CHARMM: A Program for Macromolecular Energy, Minimization, and Dynamics Calculations. Journal of Computational Chemistry, 4, 187-217.
http://dx.doi.org/10.1002/jcc.540040211

[17]   Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J. (2001) Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Advanced Drug Delivery Reviews, 46, 3-26.
http://dx.doi.org/10.1016/S0169-409X(00)00129-0

[18]   (2009) Accelrys Discovery Studio 2.5. Accelrys, San Diego.
http://www.accelrys.com

[19]   Komander, D., Kular, G.S., Schüttelkopf, A.W., Deak, M., Prakash, K.R., Bain, J., Elliott, M., Garrido-Franco, M., Kozikowski, A.P., Alessi, D.R. and van Aalten, D.M. (2004) Interactions of LY333531 and Other Bisindolyl Maleimide Inhibitors with PDK1. Structure, 12, 215-226.
http://dx.doi.org/10.1016/j.str.2004.01.005

[20]   Wu, G.S., Daniel, H., Robertson, C.L. and Brooks III, M.V. (2003) Detailed Analysis of Grid-Based Molecular Docking: A Case Study of CDOCKER—A CHARMm-Based MD Docking Algorithm. Journal of Computational Chemistry, 24, 1549-1562.
http://dx.doi.org/10.1002/jcc.10306

[21]   Egan, W.J., Merz, K.M. and Baldwin, J.J. (2000) Prediction of Drug Absorption Using Multivariate Statistics. Journal of Medicinal Chemistry, 43, 3867-3877.
http://dx.doi.org/10.1021/jm000292e

[22]   Cheng, A.L. and Merz, K.M. (2003) Prediction of Aqueous Solubility of a Diverse Set of Compounds Using Quantitative Structure-Property Relationships. Journal of Medicinal Chemistry, 46, 3572-3580.
http://dx.doi.org/10.1021/jm020266b

[23]   Susnow, R.G. and Dixon, S.L. (2003) Use of Robust Classification Techniques for the Prediction of Human Cytochrome P450 2D6 Inhibition. Journal of Chemical Information and Computer Sciences, 43, 1308-1315.
http://dx.doi.org/10.1021/ci030283p

[24]   Dixon, S.L. and Merz, K.M., (2001) One-Dimensional Molecular Representations and Similarity Calculations: Methodology and Validation. Journal of Medicinal Chemistry, 44, 3795-3809.
http://dx.doi.org/10.1021/jm010137f

[25]   Ertl, P., Rohde, B. and Selzer, P. (2003) Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment-Based Contributions and Its Application to the Prediction of Drug Transport Properties. Journal of Medicinal Chemistry, 43, 3714-3717.
http://dx.doi.org/10.1021/jm000942e

[26]   Waterbeemd, H., Van de Smith, D.A. and Jones, B.C. (2001) Lipophilicity in PK Design: Methyl, Ethyl, Futile. Journal of Computer-Aided Molecular Design, 15, 273-286.
http://dx.doi.org/10.1023/A:1008192010023

[27]   Xia, X.Y., Maliski, E.G., Gallant, P. and Rogers, D. (2004) Classification of Kinase Inhibitors Using a Bayesian Model. Journal of Medicinal Chemistry, 47, 4463-4470.
http://dx.doi.org/10.1021/jm0303195

[28]   Ong, K.C. and Khoo, H.E. (1997) Biological Effects of Myricetin. General Pharmacology, 29, 121-126
http://dx.doi.org/10.1016/S0306-3623(96)00421-1

[29]   Ross, J.A. and Kasum, C.M. (2002) Dietary Flavonoids: Bioavailability, Metabolic Effects, and Safety. Annual Review of Nutrition, 22, 19-34.
http://dx.doi.org/10.1146/annurev.nutr.22.111401.144957

 
 
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