Abstract
Plasmodium falciparum protein kinase 7 (PfPK7) is an important drug target for the development of anti-malarial treatment. In this study, hologram quantitative structure–activity relationship (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of imidazopyridazine derivatives of PfPK7 inhibitors. The best HQSAR model was obtained using atoms, connection, donor, and acceptor as fragment distinction parameter with fragment size (4–7) using a hologram length of 353 and 6 components (q 2 = 0.770, r 2 = 0.964). The receptor-guided alignment has produced better statistical results for both CoMFA (q 2 = 0.590, r 2 = 0.986) and CoMSIA (q 2 = 0.735, r 2 = 0.988). The predictive ability of the developed models was further validated by a test set of eight compounds. HQSAR contribution map identified the presence of phenyl ring and cyclohexane moiety makes positive contribution for activity. Furthermore, CoMFA and CoMSIA contour maps suggested that additional bulky groups in cyclohexane moiety would increase the biological activity of PfPK7 inhibitors. Finally, these QSAR models were used to design new virtual molecules for imidazopyridazine derivatives and the results obtained from this study could be useful for further investigations.
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Anamika, Srinivasan N, Krupa A (2005) A genomic perspective of protein kinases in plasmodium falciparum. Proteins 58:180–189
Bouloc N, Large JM, Smiljanic E, Whalley D, Ansell KH, Edlin CD, Bryans JS (2008) Synthesis and in vitro evaluation of imidazopyridazines as novel inhibitors of the malarial kinase PfPK7. Bioorg Med Chem 18:5294–5298
Cho SJ, Tropsha A (1995) Cross-validated R2-guided region selection for comparative molecular field analysis: a simple method to achieve consistent results. J Med Chem 38:1060–1066
Cramer RD, Patterson DE, Bunce JD (1988) Comparative Molecular-Field Analysis (Comfa). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110:5959–5967
Doerig C (2004) Protein kinases as targets for anti-parasitic chemotherapy. Biochim Biophys Acta 1697:155–168
Doerig C, Billker O, Pratt D, Endicott J (2005) Protein kinases as targets for antimalarial intervention: kinomics, structure-based design, transmission-blockade, and targeting host cell enzymes. Biochim Biophys Acta 1754:132–150
Dorin D, Semblat JP, Poullet P, Alano P, Goldring JPD, Whittle C, Patterson S, Chakrabarti D, Doerig C (2005) PfPK7, an atypical MEK-related protein kinase, reflects the absence of classical three-component MAPK pathways in the human malaria parasite Plasmodium falciparum. Mol Microbiol 55:184–196
Geladi P, Xie YL, Polissar A, Hopke P (1998) Regression on parameters from the three-way decomposition. J Chemom 12:337–354
Hanks SK, Quinn AM, Hunter T (1988) The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241:42–52
Jain AN (2003) Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine. J Med Chem 46:499–511
Jain AN (2006) Scoring functions for protein-ligand docking. Curr Protein Pept Sci 7:407–420
Jones G, Willett P, Glen RC (1995) A genetic algorithm for flexible molecular overlay and pharmacophore elucidation. J Comput Aided Mol Des 9:532–549
Klebe G, Abraham U, Mietzner T (1994) Molecular similarity indexes in a comparative-analysis (comsia) of drug molecules to correlate and predict their biological-activity. J Med Chem 37:4130–4146
Pasha FA, Srivastava HK, Singh PP (2005) QSAR study of estrogens with the help of PM3-based descriptors. Int J Quantum Chem 104:87–100
Pasha FA, Muddassar M, Chung HW, Cho SJ, Cho H (2008) Hologram and 3D-quantitative structure toxicity relationship studies of azo dyes. J Mol Model 14:293–302
Pasha FA, Muddassar M, Srivastava AK, Cho SJ (2010) In silico QSAR studies of anilinoquinolines as EGFR inhibitors. J Mol Model 16:263–277
Pattanaik P, Raman J, Balaram H (2002) Perspectives in drug design against malaria. Curr Top Med Chem 2:483–505
Renslo AR, McKerrow JH (2006) Drug discovery and development for neglected parasitic diseases. Nat Chem Biol 2:701–710
Ridley RG (2002) Antimalarial drug resistance: ramifications, explanations and challenges. Microbes Infect 4:155–156
Ruppert J, Welch W, Jain AN (1997) Automatic identification and representation of protein binding sites for molecular docking. Protein Sci 6:524–533
Singh PP, Srivastava HK, Pasha FA (2004) DFT-based QSAR study of testosterone and its derivatives. Bioorg Med Chem 12:171–177
Srivastava HK, Pasha FA, Singh PP (2005) Atomic softness based QSAR study of testosterone. Int J Quantum Chem 103:237–245
Tong W, Lowis DR, Perkins R, Chen Y, Welsh WJ, Goddette DW, Heritage TW, Sheehan DM (1998) Evaluation of quantitative structure–activity relationship methods for large-scale prediction of chemicals binding to the estrogen receptor. J Chem Inf Comput Sci 38:669–677
Waller CL (2004) A comparative QSAR study using CoMFA, HQSAR, and FRED/SKEYS paradigms for estrogen receptor binding affinities of structurally diverse compounds. J Chem Inf Comput Sci 44:758–765
Wold S, Ruhe A, Wold H, Dunn WJ (1984) The collinearity problem in linear-regression–the partial least-squares (Pls) approach to generalized inverses. SIAM J Sci Stat Comput 5:735–743
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This study was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korean government (MEST) through the Research Center for Resistant Cells (R13-2003-009).
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Madhavan, T., Kothandan, G., Gadhe, C.G. et al. QSAR analysis on PfPK7 inhibitors using HQSAR, CoMFA, and CoMSIA. Med Chem Res 21, 681–693 (2012). https://doi.org/10.1007/s00044-011-9572-x
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DOI: https://doi.org/10.1007/s00044-011-9572-x