Insight into the Interaction of Cationic Porphyrin-Anthraquinone Hybrids with Hsp90: In Silico Analysis

Muhammad Arba, Ruslin Ruslin, Rahmana Emran Kartasasmita, Slamet Ibrahiim, Daryono Hadi Tjahjono


Heat shock protein 90 (Hsp90) is responsible for the correct folding of many cellular proteins. Several Hsp90 inhibitors have been developed for cancer treatment. The present in silico study aimed to evaluate the potential of several porphyrin derivatives conjugated with anthraquinone groups as Hsp90 inhibitors by using simulation of molecular docking and molecular dynamics. The binding mode of porphyrin hybrids to Hsp90, which was examined by using AutoDock 4.2, showed that all six porphyrin compounds fit well in the binding pocket of Hsp90. The pi-cationic interactions with Lys58 were exclusively observed in the interaction of each porphyrin hybrid. Stabilities of porphyrin-Hsp90 complexes were confirmed by 40-ns MD simulation, which was carried out with the help of AMBER16. Prediction of ligand affinity by using the MM-PBSA method showed that all complexes were energetically favorable as indicated by a negative binding free energy. The predicted affinities of tris−H2PyP−AQ, tris−H2PzP−AQ, bis−H2PzP−AQ, and mono−H2PzP−AQ are better than those of geldanamycin, a known inhibitor of Hsp90, which shows the importance of the electrostatic and van der Waals energies for ligand binding.


Hsp90; MM-PBSA; molecular docking; molecular dynamics simulation; porphyrin

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Srinivasan, S.R., Shao, H., Li, X. & Gestwicki, J.E., Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis, Heat Shock Protein Inhibitors. Topics in Medicinal Chemistry, McAlpine S., Edkins A. (eds.), Springer, pp. 131-162, 2015.

Whitesell, L. & Lindquist, S.L., HSP90 and the Haperoning of Cancer, Nature Reviews Cancer, 5(10), pp. 761-772, 2005.

Liang, C. Hao, H. Wu, X. Li, Z. Zhu, J. Lu, C. & Shen, Y., Design and Synthesis of N-(5-Chloro-2,4-Dihydroxybenzoyl)-(R)-1,2,3,4-Tetrahydro isoquinoline-3-Carboxamides as Novel Hsp90 Inhibitors, European Journal of Medicinal Chemistry, 121, pp. 272-282, 2016.

Hanahan, D. & Weinberg, R.A., The Hallmarks of Cancer, Cell, 100(1), pp. 57-70, 2000.

Hanahan, D. & Weinberg, R.A., Hallmarks of Cancer: The Next Generation, Cell, 144(5), pp. 646-674, 2011.

Chatterjee, S. & Burns, T.F., Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach, International Journal of Molecular Sciences, 18(9), pp. 1978-1997, 2017.

Koca, İ., Özgür, A., Er, M., Gümüş, M., Coşkun, K.A. & Tutar, Y., Design and Synthesis of Pyrimidinyl Acyl Thioureas as Novel Hsp90 Inhibitors in Invasive Ductal Breast Cancer and its Bone Metastasis, European Journal of Medicinal Chemistry, 122, pp. 280-290, 2016.

Verma, S., Goyal, S., Jamal, S., Singh, A. & Grover, A., Hsp90: Friends, Clients and Natural Foes, Biochimie, 127, pp. 227-240, 2016.

Neckers, L., Schulte, T.W. & Mimnaugh, E., Geldanamycin as A Potential Anti-cancer Agent: Its Molecular Target and Biochemical Activity, Investigational New Drugs, 17(4), pp. 361-373, 1999.

Özgür, A. & Tutar, Y., Heat Shock Protein 90 Inhibitors in Oncology, Current Proteomics, 11(1), pp. 2-16, 2014.

Proisy, N., Sharp, S.Y., Boxall, K., Connelly, S., Roe, S.M., Prodromou, C., Slawin, A.M.Z., Pearl, L.H., Workman, P. & Moody, C.J.J., Inhibition of Hsp90 with Synthetic Macrolactones: Synthesis and Structural and Biological Evaluation of Ring and Conformational Analogs of Radicicol, Chemistry and Biology, 13(11), pp. 1203-1215, 2006.

Roe, S.M., Prodromou, C., O’Brien, R., Ladbury, J.E., Piper, P.W. & Pearl, L.H., Structural Basis for Inhibition of the Hsp90 Molecular Chaperone by the Antitumor Antibiotics Radicicol and Geldanamycin, Journal of Medicinal Chemistry, 42(2), pp. 260-266, 1999.

Lee, W.H., Lee, J.M., Lim, C., Kim, S. & Kim, S.G., Structural Requirements within Protoporphyrin IX in the Inhibition of Heat Shock Protein 90, Chemico-Biological Interactions, 204(1), pp. 49-57, 2013.

Arba, M., Ihsan, S., Ramadhan, L.O.A.N. & Tjahjono, D.H., In Silico Study of Porphyrin-anthraquinone Hybrids as CDK2 Inhibitor, Computational Biology and Chemistry, 67, pp. 9-14, 2017.

Yuniarti, N., Nugroho, P.A., Asyhar, A., Sardjiman, Ikawati, Z. & Istyastono, E.P., In Vitro and In Silico Studies on Curcumin and Its Analogues as Dual Inhibitors for Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2), ITB Journal of Science, 44A(1), pp. 51-66, 2012.

Levita, J., Istyastono, E.P., Nawawi, A., Mutholib, A., de Esch, I.J.P. & Ibrahim, S., Analyzing the Interaction of Andrographolide and Neoandrographolide, Diterpenoid Compounds from Andrographis Paniculata (Burm.F) Nees, to Cyclooxygenase-2 Enzyme by Docking Simulation, ITB Journal of Science, 41A(2), pp. 110-119, 2009.

Stebbins, C.E., Russo, A. A., Schneider, C., Rosen, N., Hartl, F.U. & Pavletich, N.P., Crystal Structure of An Hsp90-Geldanamycin Complex: Targeting of A Protein Chaperone by An Antitumor Agent, Cell, 89(2), pp. 239-250, 1997.

Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G.A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J., Zheng, G., Sonnenberg, J.L., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery, J.A., Peralta, J.E., Ogliaro, F., Bearpark, M., Heyd, J.J., Brothers, E., Kudin, K.N., Staroverov, V.N., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A., Burant, J.C., Iyengar, S.S., Tomasi, J., Cossi, M., Rega, N., Millam, J.M., Klene, M., Knox, J.E., Cross, J.B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J., Cammi, R., Pomelli, C., Ochterski, J.W., Martin, R.L., Morokuma, K., Zakrzewski, V.G., Voth, G.A., Salvador, P., Dannenberg, J.J., Dapprich, S., Daniels, A.D., Farkas, Foresman, J.B., Ortiz, J.V., Cioslowski, J. & Fox, D.J., Gaussian 09, Revision B.01, Wallingford CT, 2009.

Goodsell, D.S., Morris, G.M. & Olson, A.J., Automated Docking of Flexible Ligands: Applications of Autodock, Journal of Molecular Recognition, 9(1), pp. 1-5, 1996.

Morris, G.M., Goodsell, D.S., Halliday, R.S., Huey, R., Hart, W.E., Belew, R.K. & Olson, A.J., Automated Docking Using a Lamarckian Genetic Algorithm and an Empirical Binding Free Energy Function, Journal of Computational Chemistry, 19(14), pp. 1639-1662, 1998.

Case, D.A., Babin, V., Berryman, J.T., Betz, R.M., Cai, Q., Cerutti, D.S., Cheatham, T.E. III, Darden, T.A., Duke, R.E., Gohlke, H., Goetz, A.W., Gusarov, S., Homeyer, N., Janowski, P., Kaus, J., Kolossváry, I., Kovalenko, A., Lee, T.S., LeGrand, S., Luchko, T., Luo, R., Madej, B., Merz, K.M., Paesani, F., Roe, D.R., Roitberg, A., Sagui, C., Salomon-Ferrer, R., Seabra, G., Simmerling, C.L., Smith, W., Swails, J., Walker, R.C., Wang, J., Wolf, R.M., Wu, X. & Kollman, P.A., AMBER 16, University of California, San Francisco, 2015.

Salomon-Ferrer, R., Goetz, A.W., Poole, D., Grand, S.L. & Walker, R.C., Routine Microsecond Molecular Dynamics Simulations with AMBER - Part II: Particle Mesh Ewald, Journal of Chemical Theory and Computation, 9(9), pp. 3878-3888, 2013.

Maier, J.A., Martinez, C., Kasavajhala, K., Wickstrom, L., Hauser, K.E. & Simmerling, C., ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB, Journal of Chemical Theory and Computation, 11(8), pp. 3696-3713, 2015.

Wang, J., Wolf, R.M., Caldwell, J.W., Kollman, P.A. & Case, D.A., Development and Testing of A General Amber Force Field, Journal of Computational Chemistry, 25(9), pp. 1157-1174, 2004.

Arba, M., Ruslin, Ihsan, S., Tri, S.T. & Tjahjono, D.H., Molecular Modeling of Cationic Porphyrin-Anthraquinone Hybrids as DNA Topoisomerase Iiβ Inhibitors, Computational Biology and Chemistry, 71, pp. 129-135, 2017.

Ryckaert, J.P., Ciccotti, G. & Berendsen, H.J.C., Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of N-Alkanes, Journal of Computational Physics, 23(3), pp. 327-341, 1977.

Darden, T., York, D. & Pedersen, L., Particle Mesh Ewald: An N∙Log(N) Method for Ewald Sums in Large Systems, Journal of Chemical Physics, 98(12), pp. 10089-10092, 1993.

Roe, D.R. & Cheatham, III, T.E., PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data, Journal of Chemical Theory and Computation, 9(7), pp. 3084-3095, 2013.

Humphrey, W., Dalke, A. & Schulten, K., VMD-visual Molecular Dynamics, Journal of Molecular Graphics, 14(1), pp. 33-38, 1996.

Kollman, P.A., Massova, I., Reyes, C., Kuhn, B., Huo, S., Chong, L., Lee, M., Lee, T., Duan, Y., Wang, W., Donini, O., Cieplak, P., Srinivasan, J., Case, D.A. & Cheatam, T.E., Calculating Structures and Free Energies of Complex Molecules: Combining Molecular Mechanics and Continuum Models, Account Chemical Research, 33(12), pp. 889-897, 2000.

Miller, B.R., McGee, T.D., Swails, J.M., Homoeyer, N., Gohlke, H. & Roitberg, A.E., An Efficient Program for End-State Free Energy Calculations, Journal of Chemical Theory and Computation, 8(9), pp. 3314-3321, 2012.

Gopalsamy, A., Shi, M., Golas, J., Vogan, E., Jacob, J., Johnson, M., Lee, F., Nilakantan, R., Petersen, R., Svenson, K., Chopra, R., Tam, M.S., Wen, Y., Ellingboe, J., Arndt, K. & Boschelli F., Discovery of Benzisoxazoles as Potent Inhibitors of Chaperone Heat Shock Protein 90, Journal of Medicinal Chemistry, 51(3), pp. 373-375, 2008.

Genheden, S. & Ryde, U., The MM/PBSA and MM/GBSA Methods to Estimate Ligand-Binding Affinities, Expert Opinion on Drug Discovery, 10(5), pp. 449-461, 2015.



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