Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Investigation of Binding Characteristics of Phosphoinositide-dependent Kinase-1 (PDK1) Co-crystallized Ligands Through Virtual Pharmacophore Modeling Leading to Novel Anti-PDK1 Hits

Author(s): Iman A. Mansi*, Mahmoud A. Al-Sha'er*, Nizar M. Mhaidat, Mutasem O. Taha and Rand Shahin

Volume 16, Issue 7, 2020

Page: [860 - 880] Pages: 21

DOI: 10.2174/1573406415666190724131048

Price: $65

Abstract

Background: 3-Phosphoinositide Dependent Protein Kinase-1 (PDK1) is being lately considered as an attractive and forthcoming anticancer target. A Protein Data Bank (PDB) cocrystallized crystal provides not only rigid theoretical data but also a realistic molecular recognition data that can be explored and used to discover new hits.

Objective: This incited us to investigate the co-crystallized ligands' contacts inside the PDK1 binding pocket via a structure-based receptor-ligand pharmacophore generation technique in Discovery Studio 4.5 (DS 4.5).

Methods: Accordingly, 35 crystals for PDK1 were collected and studied. Every single receptorligand interaction was validated and the significant ones were converted into their corresponding pharmacophoric features. The generated pharmacophores were scored by the Receiver Operating Characteristic (ROC) curve analysis.

Results: Consequently, 169 pharmacophores were generated and sorted, 11 pharmacophores acquired good ROC-AUC results of 0.8 and a selectivity value above 8. Pharmacophore 1UU3_2_01 was used in particular as a searching filter to screen NCI database because of its acceptable validity criteria and its distinctive positive ionizable feature. Several low micromolar PDK1 inhibitors were revealed. The most potent hit illustrated anti-PDK1 IC50 values of 200 nM with 70% inhibition against SW480 cell lines.

Conclusion: Eventually, the active hits were docked inside the PDK1 binding pocket and the recognition points between the active hits and the receptor were analyzed that led to the discovery of new scaffolds as potential PDK1 inhibitors.

Keywords: PDK, cancer, co-crystallized structure, docking, pharmacophore, ROC analysis, discovery studio molecular design.

« Previous Next »
Graphical Abstract

[1]
Fyffe, C.; Falasca, M. 3-Phosphoinositide-dependent protein kinase-1 as an emerging target in the management of breast cancer. Cancer Manag. Res., 2013, 5(1), 271-280.
[PMID: 24039447]
[2]
Medina, J.R.; Becker, C.J.; Blackledge, C.W.; Duquenne, C.; Feng, Y.; Grant, S.W.; Heerding, D.; Li, W.H.; Miller, W.H.; Romeril, S.P.; Scherzer, D.; Shu, A.; Bobko, M.A.; Chadderton, A.R.; Dumble, M.; Gardiner, C.M.; Gilbert, S.; Liu, Q.; Rabindran, S.K.; Sudakin, V.; Xiang, H.; Brady, P.G.; Campobasso, N.; Ward, P.; Axten, J.M. Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors. J. Med. Chem., 2011, 54(6), 1871-1895.
[http://dx.doi.org/10.1021/jm101527u] [PMID: 21341675]
[3]
Medina, J.R. Selective 3-phosphoinositide-dependent kinase 1 (PDK1) inhibitors: dissecting the function and pharmacology of PDK1. J. Med. Chem., 2013, 56(7), 2726-2737.
[http://dx.doi.org/10.1021/jm4000227] [PMID: 23448267]
[4]
Murphy, S.T.; Alton, G.; Bailey, S.; Baxi, S.M.; Burke, B.J.; Chappie, T.A.; Ermolieff, J.; Ferre, R.; Greasley, S.; Hickey, M.; Humphrey, J.; Kablaoui, N.; Kath, J.; Kazmirski, S.; Kraus, M.; Kupchinsky, S.; Li, J.; Lingardo, L.; Marx, M.A.; Richter, D.; Tanis, S.P.; Tran, K.; Vernier, W.; Xie, Z.; Yin, M.J.; Yu, X.H. Discovery of novel, potent, and selective inhibitors of 3-phosphoinositide-dependent kinase (PDK1). J. Med. Chem., 2011, 54(24), 8490-8500.
[http://dx.doi.org/10.1021/jm201019k] [PMID: 22040023]
[5]
Peifer, C.; Alessi, D.R. New anti-cancer role for PDK1 inhibitors: preventing resistance to tamoxifen. Biochem. J., 2009, 417(1), e5-e7.
[PMID: 19061482] [http://dx.doi.org/10.1042/BJ20082243]
[6]
Bhola, N.E.; Freilino, M.L.; Joyce, S.C.; Sen, M.; Thomas, S.M.; Sahu, A.; Cassell, A.; Chen, C-S.; Grandis, J.R. Antitumor mechanisms of targeting the PDK1 pathway in head and neck cancer. Mol. Cancer Ther., 2012, 11(6), 1236-1246.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0936] [PMID: 22491800]
[7]
Gu, Z.; Wu, J.; Wang, S.; Suburu, J.; Chen, H.; Thomas, M.J.; Shi, L.; Edwards, I.J.; Berquin, I.M.; Chen, Y.Q. Polyunsaturated fatty acids affect the localization and signaling of PIP3/AKT in prostate cancer cells. Carcinogenesis, 2013, 34(9), 1968-1975.
[http://dx.doi.org/10.1093/carcin/bgt147] [PMID: 23633519]
[8]
Backes, A.; Zech, B.; Felber, B.; Klebl, B.; Müller, G. Small-molecule inhibitors binding to protein kinases. Part I: exceptions from the traditional pharmacophore approach of type I inhibition. Expert Opin. Drug Discov., 2008, 3(12), 1409-1425.
[http://dx.doi.org/10.1517/17460440802579975] [PMID: 23506106]
[9]
Gopalsamy, A.; Shi, M.; Boschelli, D.H.; Williamson, R.; Olland, A.; Hu, Y.; Krishnamurthy, G.; Han, X.; Arndt, K.; Guo, B. Discovery of dibenzo[c,f][2,7]naphthyridines as potent and selective 3-phosphoinositide-dependent kinase-1 inhibitors. J. Med. Chem., 2007, 50(23), 5547-5549.
[http://dx.doi.org/10.1021/jm070851i] [PMID: 17941624]
[10]
Johnson, M.C.; Hu, Q.; Lingardo, L.; Ferre, R.A.; Greasley, S.; Yan, J.; Kath, J.; Chen, P.; Ermolieff, J.; Alton, G. Novel isoquinolone PDK1 inhibitors discovered through fragment-based lead discovery. J. Comput. Aided Mol. Des., 2011, 25(7), 689-698.
[http://dx.doi.org/10.1007/s10822-011-9456-7] [PMID: 21779981]
[11]
Muegge, I.; Bergner, A.; Kriegl, J.M. Computer-aided drug design at Boehringer Ingelheim. J. Comput. Aided Mol. Des., 2017, 31(3), 275-285.
[http://dx.doi.org/10.1007/s10822-016-9975-3] [PMID: 27650777]
[12]
McGaughey, G.; Patrick Walters, W. Modeling & informatics at vertex pharmaceuticals incorporated: our philosophy for sustained impact. J. Comput. Aided Mol. Des., 2017, 31(3), 293-300.
[http://dx.doi.org/10.1007/s10822-016-9994-0] [PMID: 27900588]
[13]
Wolber, G.; Langer, T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J. Chem. Inf. Model., 2005, 45(1), 160-169.
[http://dx.doi.org/10.1021/ci049885e] [PMID: 15667141]
[14]
Al-Sha’er, M.A.; Mansi, I.; Almazari, I.; Hakooz, N. Evaluation of novel Akt1 inhibitors as anticancer agents using virtual co-crystallized pharmacophore generation. J. Mol. Graph. Model., 2015, 62, 213-225.
[http://dx.doi.org/10.1016/j.jmgm.2015.10.004] [PMID: 26485540]
[15]
Islam, I.; Brown, G.; Bryant, J.; Hrvatin, P.; Kochanny, M.J.; Phillips, G.B.; Yuan, S.; Adler, M.; Whitlow, M.; Lentz, D.; Polokoff, M.A.; Wu, J.; Shen, J.; Walters, J.; Ho, E.; Subramanyam, B.; Zhu, D.; Feldman, R.I.; Arnaiz, D.O. Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 2: optimization of BX-517. Bioorg. Med. Chem. Lett., 2007, 17(14), 3819-3825.
[http://dx.doi.org/10.1016/j.bmcl.2007.05.060] [PMID: 17544272]
[16]
BIOVIA. Discovery Studio Modeling Environment, (Biovia 4.5 ed.), 2016.
[17]
Gaulton, A.; Bellis, L.J.; Bento, A.P.; Chambers, J.; Davies, M.; Hersey, A.; Light, Y.; McGlinchey, S.; Michalovich, D.; Al-Lazikani, B.; Overington, J.P. ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic Acids Res., 2012, 40(Database issue), D1100-D1107.
[http://dx.doi.org/10.1093/nar/gkr777] [PMID: 21948594]
[18]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The Protein Data Bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[19]
Irwin, J.J.; Shoichet, B.K. ZINC-a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model., 2005, 45(1), 177-182.
[http://dx.doi.org/10.1021/ci049714+] [PMID: 15667143]
[20]
Kirchmair, J.; Distinto, S.; Markt, P.; Schuster, D.; Spitzer, G.M.; Liedl, K.R.; Wolber, G. How to optimize shape-based virtual screening: choosing the right query and including chemical information. J. Chem. Inf. Model., 2009, 49(3), 678-692.
[http://dx.doi.org/10.1021/ci8004226]
[21]
Kirchmair, J.; Markt, P.; Distinto, S.; Wolber, G.; Langer, T. Evaluation of the performance of 3D virtual screening protocols: RMSD comparisons, enrichment assessments, and decoy selection--what can we learn from earlier mistakes? J. Comput. Aided Mol. Des., 2008, 22(3-4), 213-228.
[http://dx.doi.org/10.1007/s10822-007-9163-6] [PMID: 18196462]
[22]
Shahin, R.; Mansi, I.; Swellmeen, L.; Alwidyan, T.; Al-Hashimi, N.; Al-Qarar’h, Y.; Shaheen, O. Ligand-based computer aided drug design reveals new tropomycin receptor kinase a (TrkA) inhibitors. J. Mol. Graph. Model., 2018, 80, 327-352.
[http://dx.doi.org/10.1016/j.jmgm.2018.01.004] [PMID: 29454290]
[23]
Shahin, R.; Alqtaishat, S.; Taha, M.O. Elaborate ligand-based modeling reveal new submicromolar Rho kinase inhibitors. J. Comput. Aided Mol. Des., 2012, 26(2), 249-266.
[http://dx.doi.org/10.1007/s10822-011-9509-y] [PMID: 22167443]
[24]
Wolber, G.; Seidel, T.; Bendix, F.; Langer, T. Molecule-pharmacophore superpositioning and pattern matching in computational drug design. Drug Discov. Today, 2008, 13(1-2), 23-29.
[http://dx.doi.org/10.1016/j.drudis.2007.09.007] [PMID: 18190860]
[25]
Al-Sha’er, M.A.; Taha, M.O. Ligand-based modeling of Akt3 lead to potent dual Akt1/Akt3 inhibitor. J. Mol. Graph. Model., 2018, 83, 153-166.
[http://dx.doi.org/10.1016/j.jmgm.2018.02.001] [PMID: 29456101]
[26]
Swellmeen, L.; Shahin, R.; Al-Hiari, Y.; Alamiri, A.; Hasan, A.; Shaheen, O. Structure based drug design of Pim-1 kinase followed by pharmacophore guided synthesis of quinolone-based inhibitors. Bioorg. Med. Chem., 2017, 25(17), 4855-4875.
[http://dx.doi.org/10.1016/j.bmc.2017.07.036] [PMID: 28760531]
[27]
Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]
[28]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[29]
Gasteiger, J.; Marsili, M. Iterative partial equalization of orbital electronegativity-a rapid access to atomic charges. Tetrahedron, 1980, 36(22), 3219-3228.
[http://dx.doi.org/10.1016/0040-4020(80)80168-2]
[30]
Venkatachalam, C.M.; Jiang, X.; Oldfield, T.; Waldman, M. LigandFit: a novel method for the shape-directed rapid docking of ligands to protein active sites. J. Mol. Graph. Model., 2003, 21(4), 289-307.
[http://dx.doi.org/10.1016/S1093-3263(02)00164-X] [PMID: 12479928]
[31]
Thermofisher. Z'-LYTE® Kinase Assay, 2019.https://www.thermofisher.com/
[32]
Mhaidat, N.M.; Abdul-Razzak, K.K.; Alkofahi, A.S.; Alsarhan, A.M.; Aldaher, A.N.; Thorne, R.F. Altholactone induces apoptotic cell death in human colorectal cancer cells. Phytother. Res., 2012, 26(6), 926-931.
[http://dx.doi.org/10.1002/ptr.3666] [PMID: 22105918]
[33]
Mhaidat, N.M.; Zhang, X.D.; Allen, J.; Avery-Kiejda, K.A.; Scott, R.J.; Hersey, P. Temozolomide induces senescence but not apoptosis in human melanoma cells. Br. J. Cancer, 2007, 97(9), 1225-1233.
[http://dx.doi.org/10.1038/sj.bjc.6604017] [PMID: 17968428]
[34]
Al-Sha’er, M.A.; Al-Balas, Q.A.; Hassan, M.A.; Al Jabal, G.A.; Almaaytah, A.M. Combination of pharmacophore modeling and 3D-QSAR analysis of potential glyoxalase-I inhibitors as anticancer agents. Comput. Biol. Chem., 2019, 80(80), 102-110.
[http://dx.doi.org/10.1016/j.compbiolchem.2019.03.011] [PMID: 30947068]
[35]
Al-Sha’er, M.A.; Mansi, I.; Khanfar, M.; Abudayyh, A. Discovery of new heat shock protein 90 inhibitors using virtual co-crystallized pharmacophore generation. J. Enzyme Inhib. Med. Chem., 2016, 31(sup4), 64-77.
[http://dx.doi.org/10.1080/14756366.2016.1218485] [PMID: 27569779]
[36]
Al-Sha’er, M.A.; Taha, M.O. Application of docking-based comparative intermolecular contacts analysis to validate Hsp90α docking studies and subsequent in silico screening for inhibitors. J. Mol. Model., 2012, 18(11), 4843-4863.
[http://dx.doi.org/10.1007/s00894-012-1479-z] [PMID: 22707278]
[37]
Al-Sha’er, M.A.; Al-Aqtash, R.A.; Taha, M.O. Discovery of new Phosphoinositide 3-kinase delta (PI3Kdelta) inhibitors via virtual screening using crystallography-derived pharmacophore modelling and QSAR analysis. Med. Chem., 2019, 15(6), 588-601.
[http://dx.doi.org/10.2174/1573406415666190222125333] [PMID: 30799792]

Rights & Permissions Print Cite
Article Metrics
33
© 2024 Bentham Science Publishers | Privacy Policy