Hydrogen Bond Stability of Quinazoline Derivatives Compounds in Complex against EGFR using Molecular Dynamics Simulation


Herlina Rasyid(1*), Bambang Purwono(2), Thomas S Hofer(3), Harno Dwi Pranowo(4)

(1) Austrian-Indonesian Centre (AIC) for Computational Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(2) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(3) Theoretical Chemistry Division, Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 52, 6020 Innsbruck, Austria
(4) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(*) Corresponding Author


Lung cancer was a second common cancer case due to the high cigarette smoking activity both in men and women. One of protein receptor which plays an important role in the growth of the tumor is Epidermal Growth Factor Receptor (EGFR). EGFR protein is the most frequent protein mutation in cancer and promising target to inhibit the cancer growth. In this work, the stability of the hydrogen bond as the main interaction in the inhibition mechanism of cancer will be evaluated using molecular dynamics simulation. There were two compounds (A1 and A2) as new potential inhibitors that were complexed against the EGFR protein. The dynamic properties of each complexed were compared with respect to erlotinib against EGFR. The result revealed that both compounds had an interaction in the main catalytic area of protein receptor which is at methionine residue. Inhibitor A1 showed additional interactions during simulation time but the interactions tend to be weak. Inhibitor A2 displayed a more stable interaction. Following dynamics simulation, binding free energy calculation was performed by two scoring techniques MM/GB(PB)SA method and gave a good correlation with the stability of the complex. Furthermore, potential inhibitor A2 had a lower binding free energy as a direct consequence of the stability of hydrogen bond interaction.


hydrogen bond; quinazoline; MD simulations; MM/GB(PB)SA

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[1] Madhusudan, S., and Ganesan, T.S., 2004, Tyrosine kinase inhibitors in cancer therapy, Clin. Biochem., 37 (7), 618–635.

[2] Vallbohmer, D., and Lenz, H.J., 2005, Epidermal growth factor receptor as a target for chemotherapy, Clin. Colorectal Cancer, 5 (Suppl 1), S19–27.

[3] Baselga, J., 2002, Why the epidermal growth factor receptor? The rationale for cancer therapy, Oncologist, 7 (Suppl 4), 2–8.

[4] Ismail, R.S.M., Ismail, N.S.M., Abuserii, S., and El Ella, D.A.B., 2016, Recent advances in 4-aminoquinazoline based scaffold derivatives targeting EGFR kinases as anticancer agents, Future J. Pharm. Sci., 2 (1), 9–19.

[5] Stamos, J., Sliwkowski, M.X., and Eigenbrot, C., 2002, Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor, J. Biol. Chem., 277 (48), 46265–46272.

[6] Solca, F., Dahl, G., Zoephel, A., Bader, G., Sanderson, M., Klein, C., Kraemer, O., Himmelsbach, F., Haaksma, E., and Adolf, G.R., 2012, Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker, J. Pharmacol. Exp. Ther., 343 (2), 342–350.

[7] Jedhe, G.S., Paul, D., Gonnade, R.G., Santra, M.K., Hamel, E., Nguyen, T.L., and Sanjayan, G.J., 2013, Correlation of hydrogen-bonding propensity and anticancer profile of tetrazole-tethered combretastatin analogues, Bioorg. Med. Chem. Lett., 23 (16), 4680–4684.

[8] Amin, K.M., Georgey, H.H., and Awadallah, F.M., 2011, EGFR tyrosine kinase targeted compounds: Synthesis, docking study, and in vitro antitumor activity of some new quinazoline and benzo[d]isothiazole derivatives, Med. Chem. Res., 20 (7), 1042–1053.

[9] Tu, Y., Ouyang, Y., Xu, S., Zhu, Y., Li, G., Sun, C., Zheng, P., and Zhu, W., 2016, Design, synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors, Bioorg. Med. Chem., 24 (7), 1495–1503.

[10] Lü, S., Zheng, W., Ji, L., Luo, Q., Hao, X., Li, X., and Wang, F., 2013, Synthesis, characterization, screening and docking analysis of 4-anilinoquinazoline derivatives as tyrosine kinase inhibitors, Eur. J. Med. Chem., 61, 84–94.

[11] Ahmed, M., Sadek, M.M., Abouzid, K.A., and Wang, F., 2013, In silico design: Extended molecular dynamic simulations of a new series of dually acting inhibitors against EGFR and HER2, J. Mol. Graphics Modell., 44, 220–231.

[12] Ahmed, M., Sadek, M.M., Serrya, R.A., Kafafy, A.H.N., Abouzid, K.A., and Wang, F., 2013, Assessment of new anti-HER2 ligands using combined docking, QM/MM scoring and MD simulation, J. Mol. Graphics Modell., 40, 91–98.

[13] Alonso, H., Bliznyuk, A.A., and Gready, J.E., 2006, Combining docking and molecular dynamic simulations in drug design, Med. Res. Rev., 26 (5), 531–568.

[14] Rasyid, H., Armunanto, R., and Purwono, B., 2017, Study of quinazoline derivative compound as anticancer on EGFRWT protein using quantitative structure-activity relationship (QSAR), Int. J. Pharm. Sci. Rev. Res., 42 (1), 44–49.

[15] Case, D.A., Betz, R.M., Botello-Smith, W., Cerutti, D.S., Cheatham, T.E., Darden, T.A., Duke, R.E., Giese, T.J., Gohlke, H., Goetz, A.W., Homeyer, N., Izadi, S., Janowski, P., Kaus, J., Kovalenko, A., Lee, T.S., LeGrand, S., Li, P., Lin, C., Luchko, T., Luo, R., Madej, B., Mermelstein, D., Merz, K.M., Monard, G., Nguyen, H., Nguyen, H.T., Omelyan, I., Onufriev, A., Roe, D.R., Roitberg, A., Sagui, C., Simmerling, C.L., Swails, J., Walker, R.C., Wang, J., Wolf, R.M., Wu, X., Xiao, L., York, D.M., and Kollman, P.A., 2016, AMBER 2016, University of California, San Fransisco.

[16] Humprey, M.C., Dalke, A., and Schulten, K., 1996, VMD: Visual molecular dynamics, J. Mol. Graphics, 14 (1), 33–38.

[17] 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, Jr., 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, Ö., Foresman, J.B., Ortiz, J.V., Cioslowski, J., and Fox, D.J., 2009, Gaussian 09, Revision A.02, Gaussian, Inc., Wallingford CT.

[18] Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E., and Ferrin, T.E., 2004, UCSF Chimera – A visualization system for exploratory research and analysis, J. Comput. Chem., 25 (13), 1605–1612.

[19] Rasyid, H., Purwono, B., and Armunanto, R., 2017, Molecular docking analysis on epidermal growth factor receptor wild type (EGFRWT) with quinazoline derivative compounds as tyrosine kinase inhibitors, KMUTNB Int. J. Appl. Sci. Technol., 10 (4), 293–299.

[20] Maier, J., Martinez, C., Kasavajhala, K., Wickstrom, L., Hauser, K., and Simmerling, C., 2015, ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB, J. Chem. Theory Comput., 11 (8), 3696–3713.

[21] Wang, J., Wolf, R.M., Caldwell, J.W., Kollman, P.A., and Case, D.A., 2004, Development and testing of a general AMBER force field, J. Comput. Chem., 25 (9), 1157–1174.

[22] Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W., and Klein, M.L., 1983, Comparison of simple potential functions for simulating liquid water, J. Chem. Phys., 79, 926–935.

[23] Rewcastle, G.W., Palmer, B.D., Bridges, A.J., Showalter, H.D.H., Sun, L., Nelson, J., McMichael, A., Kraker, A.J., Fry, D.W., and Denny, W.A., 1996, Tyrosine kinase inhibitors. 9. Synthesis and evaluation of fused tricyclic quinazoline analogues as ATP site inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor, J. Med. Chem., 39 (4), 918–928.

[24] Patel, H., Pawara, R., Ansari, A., and Surana, S., 2017, Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance, Eur. J. Med. Chem., 142, 32–47.

[25] Wang, S., Song, Y., and Liu, D., 2017, EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance, Cancer Lett., 385, 51–54.

[26] Cheng, H., Nair, S.K., and Murray, B.W., 2016, Recent progress on third generation covalent EGFR inhibitors, Bioorg. Med. Chem. Lett., 26, 1861–1868.

[27] Bridges, A.J., Zhou, H., Cody, D.R., Rewcastle, G.W., McMichael, A., Showalter, H.D.H., Fry, D.W., Kraker, A.J., and Denny, W.A, 1996, Tyrosine kinase inhibitors. 8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor, J. Med. Chem., 39 (1), 267–276.

[28] Jeffrey, G.A., and Saenger, W., 1991, Hydrogen Bonding in Biological Structure, 1st ed., Springer-Verlag Berlin Heidelberg.

DOI: https://doi.org/10.22146/ijc.39567

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