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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

Forging New Scaffolds from Old: Combining Scaffold Hopping and Hierarchical Virtual Screening for Identifying Novel Bcl-2 Inhibitors

Author(s): Vishnupriya Kanakaveti, Sakthivel Rathinasamy, Suresh K. Rayala and Michael Gromiha*

Volume 19, Issue 13, 2019

Page: [1162 - 1172] Pages: 11

DOI: 10.2174/1568026619666190618142432

Price: $65

Abstract

Background: Though virtual screening methods have proven to be potent in various instances, the technique is practically incomplete to quench the need of drug discovery process. Thus, the quest for novel designing approaches and chemotypes for improved efficacy of lead compounds has been intensified and logistic approaches such as scaffold hopping and hierarchical virtual screening methods were evolved. Till now, in all the previous attempts these two approaches were applied separately.

Objective: In the current work, we made a novel attempt in terms of blending scaffold hopping and hierarchical virtual screening. The prime objective is to assess the hybrid method for its efficacy in identifying active lead molecules for emerging PPI target Bcl-2 (B-cell Lymphoma 2).

Methods: We designed novel scaffolds from the reported cores and screened a set of 8270 compounds using both scaffold hopping and hierarchical virtual screening for Bcl-2 protein. Also, we enumerated the libraries using clustering, PAINS filtering, physicochemical characterization and SAR matching.

Results: We generated a focused library of compounds towards Bcl-2 interface, screened the 8270 compounds and identified top hits for seven families upon fine filtering with PAINS algorithm, features, SAR mapping, synthetic accessibility and similarity search. Our approach retrieved a set of 50 lead compounds.

Conclusion: Finding rational approach meeting the needs of drug discovery process for PPI targets is the need of the hour which can be fulfilled by an extended scaffold hopping approach resulting in focused PPI targeting by providing novel leads with better potency.

Keywords: Scaffold hopping, Hierarchical virtual screening, Protein-protein interactions, Bcl-2, High-throughput screening, Inhibition.

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[1]
Hughes, J.P.; Rees, S.; Kalindjian, S.B.; Philpott, K.L. Principles of early drug discovery. Br. J. Pharmacol., 2011, 162(6), 1239-1249.
[http://dx.doi.org/10.1111/j.1476-5381.2010.01127.x] [PMID: 21091654]
[2]
Sun, H.; Tawa, G.; Wallqvist, A. Classification of scaffold-hopping approaches. Drug Discov. Today, 2012, 17(7-8), 310-324.
[http://dx.doi.org/10.1016/j.drudis.2011.10.024] [PMID: 22056715]
[3]
Russ, A.P.; Lampel, S. The druggable genome: An update. Drug Discov. Today, 2005, 10(23-24), 1607-1610.
[http://dx.doi.org/10.1016/S1359-6446(05)03666-4] [PMID: 16376820]
[4]
Müller, G. Medicinal chemistry of target family-directed masterkeys. Drug Discov. Today, 2003, 8(15), 681-691.
[http://dx.doi.org/10.1016/S1359-6446(03)02781-8] [PMID: 12927511]
[5]
Böhm, H.J.; Flohr, A.; Stahl, M. Scaffold hopping. Drug Discov. Today. Technol., 2004, 1(3), 217-224.
[http://dx.doi.org/10.1016/j.ddtec.2004.10.009] [PMID: 24981488]
[6]
Schneider, G. Scaffold-hopping: How far can you jump? QSAR Comb. Sci., 2006, 25(12), 1162-1171.
[http://dx.doi.org/10.1002/qsar.200610091]
[7]
Schneider, G.; Neidhart, W.; Giller, T.; Schmid, G. “Scaffold-Hopping” by Topological Pharmacophore Search: A contribution to virtual screening. Angew. Chem. Int. Ed. Engl., 1999, 38(19), 2894-2896.
[http://dx.doi.org/10.1002/(SICI)1521-3773(19991004)38:19<2894:AID-ANIE2894>3.0.CO;2-F] [PMID: 10540384]
[8]
Brown, N.; Jacoby, E. On scaffolds and hopping in medicinal chemistry. Mini Rev. Med. Chem., 2006, 6(11), 1217-1229.
[http://dx.doi.org/10.2174/138955706778742768] [PMID: 17100633]
[9]
Kumar, A.; Zhang, K.Y. Hierarchical virtual screening approaches in small molecule drug discovery. Methods, 2015, 71, 26-37.
[http://dx.doi.org/10.1016/j.ymeth.2014.07.007] [PMID: 25072167]
[10]
Delbridge, A.R.; Grabow, S.; Strasser, A.; Vaux, D.L. Thirty years of BCL-2: Translating cell death discoveries into novel cancer therapies. Nat. Rev. Cancer, 2016, 16(2), 99-109.
[http://dx.doi.org/10.1038/nrc.2015.17] [PMID: 26822577]
[11]
Degen, J.; Wegscheid-Gerlach, C.; Zaliani, A.; Rarey, M. On the art of compiling and using ‘drug-like’ chemical fragment spaces. ChemMedChem, 2008, 3(10), 1503-1507.
[http://dx.doi.org/10.1002/cmdc.200800178] [PMID: 18792903]
[12]
Kanakaveti, V.; Sakthivel, R.; Rayala, S.K.; Gromiha, M.M. Importance of functional groups in predicting the activity of small molecule inhibitors for Bcl-2 and Bcl-xL. Chem. Biol. Drug Des., 2017, 90(2), 308-316.
[http://dx.doi.org/10.1111/cbdd.12952] [PMID: 28112863]
[13]
Abreu, R.M.; Froufe, H.J.; Daniel, P.O.; Queiroz, M.J.; Ferreira, I.C. ChemT, an open-source software for building template-based chemical libraries. SAR QSAR Environ. Res., 2011, 22(5-6), 603-610.
[http://dx.doi.org/10.1080/1062936X.2011.604097] [PMID: 21846264]
[14]
O’Boyle, N.M.; Banck, M.; James, C.A.; Morley, C.; Vandermeersch, T.; Hutchison, G.R. Open Babel: An open chemical toolbox. J. Cheminform., 2011, 3, 33.
[http://dx.doi.org/10.1186/1758-2946-3-33] [PMID: 21982300]
[15]
Agrafiotis, D.K.; Rassokhin, D.N.; Lobanov, V.S. Multidimensional scaling and visualization of large molecular similarity tables. J. Comput. Chem., 2001, 22(5), 488-500.
[http://dx.doi.org/10.1002/1096-987X(20010415)22:5%3C488:AID-JCC1020%3E3.0.CO;2-4]
[16]
Baell, J.B.; Holloway, G.A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem., 2010, 53(7), 2719-2740.
[http://dx.doi.org/10.1021/jm901137j] [PMID: 20131845]
[17]
RDKit Cheminformatics and machine learning software, 2013.(Available at: . http://www.rdkit.org
[18]
Stumpfe, D.; Bajorath, J. Similarity Searching. Wiley Interdiscip. Rev. Comput. Mol. Sci., 2011, 1, 260-282.
[http://dx.doi.org/10.1002/wcms.23]
[19]
Willett, P.; Barnard, J.M.; Downs, G.M. Chemical similarity searching. J. Chem. Inf. Comput. Sci., 1998, 38, 983-996.
[http://dx.doi.org/10.1021/ci9800211]
[20]
Bender, A.; Jenkins, J.L.; Scheiber, J.; Sukuru, S.C.K.; Glick, M.; Davies, J.W. How similar are similarity searching methods? A principal component analysis of molecular descriptor space. J. Chem. Inf. Model., 2009, 49(1), 108-119.
[http://dx.doi.org/10.1021/ci800249s] [PMID: 19123924]
[21]
Sousa, F.; Fernandes, P.A.; Ramos, M.J. Protein – Ligand docking: Current status and future. proteins: Struct Func. Genet, 2006, 65, 15-26.
[PMID: 16862531]
[22]
Bissantz, C.; Folkers, G.; Rognan, D. Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. J. Med. Chem., 2000, 43(25), 4759-4767.
[http://dx.doi.org/10.1021/jm001044l] [PMID: 11123984]
[23]
Krovat, E.M.; Steindl, T.; Langer, T. Recent advances in docking and scoring. Curr. Comput.-. Aided Drug Des., 2005, 1, 93-102.
[http://dx.doi.org/10.2174/1573409052952314]
[24]
Durant, J.L.; Leland, B.A.; Henry, D.R.; Nourse, J.G. Reoptimization of MDL keys for use in drug discovery. J. Chem. Inf. Comput. Sci., 2002, 42(6), 1273-1280.
[http://dx.doi.org/10.1021/ci010132r] [PMID: 12444722]
[25]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[http://dx.doi.org/10.1002/jcc.21334] [PMID: 19499576]
[26]
Petros, A.M.; Medek, A.; Nettesheim, D.G.; Kim, D.H.; Yoon, H.S.; Swift, K.; Matayoshi, E.D.; Oltersdorf, T.; Fesik, S.W. Solution structure of the antiapoptotic protein bcl-2. Proc. Natl. Acad. Sci. USA, 2001, 98(6), 3012-3017.
[http://dx.doi.org/10.1073/pnas.041619798] [PMID: 11248023]
[27]
Touré, B.B.; Miller-Moslin, K.; Yusuff, N.; Perez, L.; Doré, M.; Joud, C.; Michael, W.; DiPietro, L.; van der Plas, S.; McEwan, M.; Lenoir, F.; Hoe, M.; Karki, R.; Springer, C.; Sullivan, J.; Levine, K.; Fiorilla, C.; Xie, X.; Kulathila, R.; Herlihy, K.; Porter, D.; Visser, M. The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions. ACS Med. Chem. Lett., 2013, 4(2), 186-190.
[http://dx.doi.org/10.1021/ml300321d] [PMID: 24900652]
[28]
Perez, H.L.; Banfi, P.; Bertrand, J.; Cai, Z.W.; Grebinski, J.W.; Kim, K.; Lippy, J.; Modugno, M.; Naglich, J.; Schmidt, R.J.; Tebben, A.; Vianello, P.; Wei, D.D.; Zhang, L.; Galvani, A.; Lombardo, L.J.; Borzilleri, R.M. Identification of a phenylacylsulfonamide series of dual Bcl-2/Bcl-xL antagonists. Bioorg. Med. Chem. Lett., 2012, 22(12), 3946-3950.
[http://dx.doi.org/10.1016/j.bmcl.2012.04.103] [PMID: 22608961]
[29]
Souers, A.J.; Leverson, J.D.; Boghaert, E.R.; Ackler, S.L.; Catron, N.D.; Chen, J.; Dayton, B.D.; Ding, H.; Enschede, S.H.; Fairbrother, W.J.; Huang, D.C.; Hymowitz, S.G.; Jin, S.; Khaw, S.L.; Kovar, P.J.; Lam, L.T.; Lee, J.; Maecker, H.L.; Marsh, K.C.; Mason, K.D.; Mitten, M.J.; Nimmer, P.M.; Oleksijew, A.; Park, C.H.; Park, C.M.; Phillips, D.C.; Roberts, A.W.; Sampath, D.; Seymour, J.F.; Smith, M.L.; Sullivan, G.M.; Tahir, S.K.; Tse, C.; Wendt, M.D.; Xiao, Y.; Xue, J.C.; Zhang, H.; Humerickhouse, R.A.; Rosenberg, S.H.; Elmore, S.W. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med., 2013, 19(2), 202-208.
[http://dx.doi.org/10.1038/nm.3048] [PMID: 23291630]
[30]
Kanakaveti, V.; Anoosha, P.; Sakthivel, R.; Rayala, S.K.; Gromiha, M.M. Influence of amino acid mutations and small molecules for targeted inhibition of proteins involved in cancer. Curr. Top. Med. Chem., 2019, 19(6), 957-466.
[http://dx.doi.org/10.2174/1568026619666190304143354] [PMID: 30836917]
[31]
Cao, Y.; Charisi, A.; Cheng, L.C.; Jiang, T.; Girke, T.; Chemmine, R. A compound mining framework for R. Bioinformatics, 2008, 24(15), 1733-1734.
[http://dx.doi.org/10.1093/bioinformatics/btn307] [PMID: 18596077]
[32]
Lama, D.; Modi, V.; Sankararamakrishnan, R. Behavior of solvent-exposed hydrophobic groove in the anti-apoptotic Bcl-XL protein: Clues for its ability to bind diverse BH3 ligands from MD simulations. PLoS One, 2013, 8(2)e54397
[http://dx.doi.org/10.1371/journal.pone.0054397] [PMID: 23468841]
[33]
Aboalhaija, N.H.; Zihlif, M.A.; Taha, M.O. Discovery of new selective cytotoxic agents against Bcl-2 expressing cancer cells using ligand-based modeling. Chem. Biol. Interact., 2016, 250, 12-26.
[http://dx.doi.org/10.1016/j.cbi.2016.03.006] [PMID: 26954606]

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