Exploring MIA-QSARs for farnesyltransferase inhibitory effect of antimalarial compounds refined by docking simulations
Author(s)
Omar Deeb*,
Sherin Alfalah,
Matheus P. Freitas,
Elaine F. F. da Cunha,
Teodorico C. Ramalho
ABSTRACT
Two series of farnesyltransferase (FTase) inhibitors were grouped and their antimalarial activi-ties modeled by means of multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR). A reliable model was achieved, with r2 for calibration, external prediction and leave-one-out cross-validation of 0.96, 0.87 and 0.83, respectively. Therefore, biological activities of congeners can be estimated using the QSAR model. The bioactivities of new compounds based on the miscellany of substructures of the two classes of FTase inhibitors were predicted using the MIA-QSAR model and the most promising ones were submitted to ADME (absorption, distribution, metabolism and excretion) and docking evaluation. Despite the smaller interaction energy of the two most promising, predicted compounds in comparison to the two most active compounds of the data set, one of the proposed structures did not violate any Lipinski’s rule of five. Therefore, it is either a potential drug or may drive synthesis of similar, improved compounds.
Two series of farnesyltransferase (FTase) inhibitors were grouped and their antimalarial activi-ties modeled by means of multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR). A reliable model was achieved, with r2 for calibration, external prediction and leave-one-out cross-validation of 0.96, 0.87 and 0.83, respectively. Therefore, biological activities of congeners can be estimated using the QSAR model. The bioactivities of new compounds based on the miscellany of substructures of the two classes of FTase inhibitors were predicted using the MIA-QSAR model and the most promising ones were submitted to ADME (absorption, distribution, metabolism and excretion) and docking evaluation. Despite the smaller interaction energy of the two most promising, predicted compounds in comparison to the two most active compounds of the data set, one of the proposed structures did not violate any Lipinski’s rule of five. Therefore, it is either a potential drug or may drive synthesis of similar, improved compounds.
Cite this paper
Deeb, O. , Alfalah, S. , Freitas, M. , Cunha, E. and Ramalho, T. (2012) Exploring MIA-QSARs for farnesyltransferase inhibitory effect of antimalarial compounds refined by docking simulations. Journal of Biophysical Chemistry, 3, 58-71. doi: 10.4236/jbpc.2012.31008.
Deeb, O. , Alfalah, S. , Freitas, M. , Cunha, E. and Ramalho, T. (2012) Exploring MIA-QSARs for farnesyltransferase inhibitory effect of antimalarial compounds refined by docking simulations. Journal of Biophysical Chemistry, 3, 58-71. doi: 10.4236/jbpc.2012.31008.
References
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Jour- nal of Medicinal Chemistry, 49, 3315-3321. doi:10.1021/jm051197e [27] Golbraikh, A. and Tropsha, A. (2002) Beware of q2! Journal of Molecular Graphics and Modelling, 20, 269-276. doi:10.1016/S1093-3263(01)00123-1 [28] Eastman, R.T., White, J., Hucke, O., Bauer, K., Yokoyama, K., Nallan, L., Chakrabarti, D., Verlinde, C.L., Gelb, M.H., Rathod, P.K. and Van Voorhis, W.C. (2005) Resistance to a protein farnesyltransferase inhibitor in Plasmodium falciparum. Journal of Biological Chemistry, 280, 13554-13559. doi:10.1074/jbc.M413556200 [29] Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J. (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 23, 3-25. doi:10.1016/S0169-409X(96)00423-1 [30] Molinspiration Cheminformatics, Bratislava, Slovak Republic. http://www.molinspiration.com [31] Friesner, R.A., Banks, J.L., Murphy, R.B., Halgren, T.A., Klicic, J.J., Mainz, D.T., Repasky, M.P., Knoll, E.H., Shaw, D.E., Shelley, M., Perry, J.K., Francis, P. and Shenkin, P.S.A. (2004) New approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of Medicinal Chemistry, 47, 1739-1749. doi:10.1021/jm0306430
[1] US Global Health Policy. http://www.globalhealthfacts.org [2] Li, Y., Zhu, Y.-M., Jiang, H.-J., Pan, J.-P., Wu, G.-S., Wu, J.-M., Shi, Y.-L., Yang, Y.-L. and Wu, B.A. (2000) Synthesis and antimalarial activity of artemisinin derivatives containing an amino group. Journal of Medicinal Chemistry, 43, 1635-1640. doi:10.1021/jm990552w [3] Mekonnen, B., Weiss, E., Katz, E., Ma, J., Ziffer, H. and Kyle, D.E. (2000) Synthesis and antimalarial activities of base-catalyzed adducts of 11-azaartemisinin. Bioorganic & Medicinal Chemistry, 8, 1111-1116. doi:10.1016/S0968-0896(00)00049-3 [4] Winstanley, P.A. (2000) Chemotherapy for falciparum malaria: The armoury, the problems and the prospects. Parasitology Today, 16, 146-153. doi:10.1016/S0169-4758(99)01622-1 [5] Coy, D.F. (2004) Ferriprotoporphyrin IX, phospholipids, and the antimalarial actions of quinoline drugs. Life Sciences, 74, 1957-1972. doi:10.1016/j.lfs.2003.10.003 [6] Agarwal, A., Srivastava, K., Puri, S. and Chauhan, P. (2005) Antimalarial activity of 2,4,6-trisubstituted pyri- midines. Bioorganic & Medicinal Chemistry Letters, 15, 1881-1883. [7] Equbal, T., Silakari, O. and Ravikumar, M. (2008) Exploring three-dimensional quantitative structural activity relationship (3D-QSAR) analysis of SCH 66336 (Sarasar) analogues of farnesyltransferase inhibitors. European Jour- nal of Medicinal Chemistry, 43, 204-209. doi:10.1016/j.ejmech.2007.02.013 [8] Puntambekar, D.S., Giridhar, R. and Yadav, M.R. (2008) Insights into the structural requirements of farnesyltransferase inhibitors as potential anti-tumor agents based on 3D-QSAR CoMFA and CoMSIA models. European Jour- nal of Medicinal Chemistry, 43, 142-154. doi:10.1016/j.ejmech.2007.02.003 [9] Xie, A., Sivaprakasam, P. and Doerksen, R.J. (2006) 3D-QSAR analysis of antimalarial farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold. Bioorganic & Medicinal Chemistry, 14, 7311-7323. doi:10.1016/j.bmc.2006.06.041 [10] Xie, A., Odde S. and Prasanna, R.J. (2009) Doerksen, Imidazole-containing farnesyltransferase inhibitors: 3D quantitative structure-activity relationships and molecular docking. Journal of Computer-Aided Molecular Design, 23, 431-448. doi:10.1007/s10822-009-9278-z [11] Srivastava, M., Singh, H. and Naik, P.K. (2009) Quantitative structure-activity relationship (QSAR) of the artemisinin: The development of predictive in vitro antimalarial activity model. Journal of Chemometrics, 23, 618- 635. [12] Deshpande, S., Solomon, V.R., Katti, S.B. and Prabhakar, Y.S. (2009) Topological descriptors in modelling antimalarial activity: N(1)-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl) piperazine as prototype. Journal of Enzyme Inhibition and Medicinal Chemistry, 24, 94-104. doi:10.1080/14756360801915377 [13] Freitas, M.P., Brown, S.D. and Martins, J.A. (2005) MIA- QSAR: A simple 2D image-based approach for quantitative structure-activity relationship analysis. Journal of Molecular Structure, 738, 149-154. doi:10.1016/j.molstruc.2004.11.065 [14] Freitas, M.P. (2006) MIA-QSAR modelling of anti-HIV-1 activities of some 2-amino-6-arylsulfonylbenzonitriles and their thio and sulfinyl congeners. Organic & Biomolecular Chemistry, 4, 1154-1159. doi:10.1039/b516396j [15] Freitas, M.P. (2007) Multivariate QSAR: From classical descriptors to new perspectives. Current Computer-Aided Drug Design, 3, 235-239. [16] Freitas, M.P. (2008) Multivariate image analysis applied to QSAR: Evaluation to a series of potential anxiolytic agents. Chemometrics and Intelligent Laboratory Systems, 91, 173-176. doi:10.1016/j.chemolab.2007.11.002 [17] Pinheiro, J.R., Bitencourt, M., da Cunha, E.F.F., Ramalho, T.C. and Freitas, M.P. (2008) Novel anti-HIV cyclotriazadisulfonamide derivatives as modeled by ligand- and receptor-based approaches. Bioorganic & Medicinal Che- mistry, 16, 1683-1690. doi:10.1016/j.bmc.2007.11.020 [18] Goodarzi, M. and Freitas, M.P. (2010) MIA-QSAR modelling of activities of a series of AZT analogues: Bi- and multilinear PLS regression. Molecular Simulation, 36, 267-272. doi:10.1080/08927020903278001 [19] Gupta, M.K. and Prabhakar, Y.S. (2008) QSAR study on tetrahydroquinoline analogues as plasmodium protein farnesyltransferase inhibitors: A comparison of rationales of malarial and mammalian enzyme inhibitory activities for selectivity. European Journal of Medicinal Chemistry, 43, 2751-2767. doi:10.1016/j.ejmech.2008.01.025 [20] Puntambekar, D., Giridhar, R. and Yadav, M.R. (2006) 3D-QSAR studies of farnesyl transferase Inhibitors: A comparative molecular field analysis approach. Bioorganic & Medicinal Chemistry Letters, 16, 1821-1827. doi:10.1016/j.bmcl.2006.01.019 [21] Freitas, M.P., da Cunha, E.F.F., Ramalho, T.C. and Goodarzi, M. (2008) Multimode methods applied on MIA descriptors in QSAR. Current Computer-Aided Drug Design, 4, 273-282. [22] ACD/ChemSketch (2009) Version 12.01, Advanced Che- mistry Development, Inc., Toronto. [23] Hast, M.A., Fletcher, S., Cummings, C.G., Pusateri, E.E., Blaskovich, M.A., Rivas, K., Gelb, M.H., Van Voorhis, W.C., Sebti, S.M., Hamilton, A.D. and Beese, L.S. (2009) Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase. Chemistry & Biology, 16, 181-192. doi:10.1016/j.chembiol.2009.01.014 [24] SpartanPro 1.0.1 Wavefunction, (Irvine, 2001). [25] Dewar, M.J.S., Zoebisch, E.G., Healy, E.F. and Stewart, J.J.P. (1985) Development and use of quantum mechanical molecular models. 76. AM1: A new general purpose quantum mechanical molecular model. Journal of the American Chemical Society, 107, 3902-3909. doi:10.1021/ja00299a024 [26] Thomsen, R. and Christensen, M.H. (2006) MolDock: A new technique for highaccuracy molecular docking. Jour- nal of Medicinal Chemistry, 49, 3315-3321. doi:10.1021/jm051197e [27] Golbraikh, A. and Tropsha, A. (2002) Beware of q2! Journal of Molecular Graphics and Modelling, 20, 269-276. doi:10.1016/S1093-3263(01)00123-1 [28] Eastman, R.T., White, J., Hucke, O., Bauer, K., Yokoyama, K., Nallan, L., Chakrabarti, D., Verlinde, C.L., Gelb, M.H., Rathod, P.K. and Van Voorhis, W.C. (2005) Resistance to a protein farnesyltransferase inhibitor in Plasmodium falciparum. Journal of Biological Chemistry, 280, 13554-13559. doi:10.1074/jbc.M413556200 [29] Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J. (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 23, 3-25. doi:10.1016/S0169-409X(96)00423-1 [30] Molinspiration Cheminformatics, Bratislava, Slovak Republic. http://www.molinspiration.com [31] Friesner, R.A., Banks, J.L., Murphy, R.B., Halgren, T.A., Klicic, J.J., Mainz, D.T., Repasky, M.P., Knoll, E.H., Shaw, D.E., Shelley, M., Perry, J.K., Francis, P. and Shenkin, P.S.A. (2004) New approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of Medicinal Chemistry, 47, 1739-1749. doi:10.1021/jm0306430