3D-QSAR and molecular docking studies of 4-anilinoquinazoline derivatives: a rational approach to anticancer drug design
- 495 Downloads
The present article is an attempt to formulate the three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling of 4-anilinoquinazoline derivatives having promising anticancer activities inhibiting epidermal growth factor (EGFR) kinase. Molecular field analysis was applied for the generation of steric and electrostatic descriptors based on aligned structures. Partial least-squares (PLS) method was applied for QSAR model development considering training and test set approaches. The PLS models showed some interesting results in terms of internal and external predictability against EGFR kinase inhibition for such type of anilinoquinazoline derivatives. Steric and electrostatic field effects are discussed in the light of contribution plot generated. Finally, molecular docking analysis was carried out to better understand of the interactions between EGFR target and inhibitors in this series. Hydrophobic and hydrogen-bond interactions lead to identification of active binding sites of EGFR protein in the docked complex.
KeywordsMurine tumors Anilinoquinazoline derivatives Molecular field analysis Steric and electrostatic descriptors Partial least squares Binding affinity
Unable to display preview. Download preview PDF.
- 2.Ballard P, Bradbury RH, Hennequin LFA, Hickinson DM, Johnson PD, Kettle JG, Klinowska T, Morgentin R, Ogilvie DJ, Olivier A (2005) 5-Substituted 4-anilinoquinazolines as potent, selective and orally active inhibitors of erbB2 receptor tyrosine kinase. Bioorg Med Chem Lett 15: 4226–4229. doi: 10.1016/j.bmcl.2005.06.068 CrossRefPubMedGoogle Scholar
- 3.Rewcastle GW, Denny WA, Bridges AJ, Zhou H, Cody DR, McMichael A, Fry DW (1995) Tyrosine kinase inhibitors. 5. Synthesis and structure–activity relationships for 4-[(phenylmethyl) amino]- and 4-(phenylamino)quinazolines as potent adeonosine-5^ʹ-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor. J Med Chem 38: 3482–3487. doi: 10.1021/jm00018a008 CrossRefPubMedGoogle Scholar
- 4.Gibson KH, Grundy W, Godfrey AA, Woodburn JR, Ashton SE, Curry BJ, Scarlett L, Barker AJ, Brown DS (1997) Epidermal growth factor receptor tyrosine kinase: structure–activity relationships and antitumour activity of novel quinazolines. Bioorg Med Chem Lett 7: 2723–2728. doi: 10.1016/S0960-894X(97)10059-2 CrossRefGoogle Scholar
- 5.Hennequin LFA, Ballard P, Boyle FT, Delouvrie B, Ellston RPA, Halsall CT, Harris CS, Hudson K, Kendrew J, Pease JE, Ross HS, Smith P, Vincent JL (2006) Novel 4-anilinoquinazolines with C-6 carbon-linked side chains: synthesis and structure–activity relationship of a series of potent, orally active, EGF receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett 16: 2672–2676. doi: 10.1016/j.bmcl.2006.02.025 CrossRefPubMedGoogle Scholar
- 7.Bridges AJ, Zhou H, Cody DR, Rewcastle GW, McMichael A, Showalter HDH, Fry DW, Kraker AJ, Denny WA (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: 267–276. doi: 10.1021/jm9503613 CrossRefPubMedGoogle Scholar
- 9.Wold H (1975) Soft modelling by latent variables: the non-linear iterative partial least squares approach. In: Gani J (eds) Perspectives in probability and statistics, papers in honor of Bartlett MS. Academic, LondonGoogle Scholar
- 17.Molecular Design Suite 3.5, VLife Technologies, Pune, India. www.vlifesciences.com
- 18.Halgren TA (1996) Merck molecular force field. III. Molecular geometries and vibrational frequencies. J Comput Chem 17: 553–586. doi: 10.1002/(SICI)1096-987X(199604)17:5/6<553::AID-JCC3>3.0.CO;2-T Google Scholar
- 24.Kubinyi H (eds) (1993) 3D QSAR in drug design. Theory, methods and applications, ESCOM. Science, Leiden, pp, pp 486–502Google Scholar
- 25.Nandi S, Bagchi MC (2009) QSAR of aminopyrido[2,3-d]pyrimidin-7-yl derivatives: anticancer drug design by computed descriptors. J Enzyme Inhib Med Chem. doi: 10.1080/14756360802519327
- 26.Palmer BD, Trumpp-Kallmeyer S, Fry DW, Nelson JM, Showalter HDH, Denny WA (1997) Tyrosine kinase inhibitors. 11. Soluble analogues of pyrrolo- and pyrazoloquinazolines as epidermal growth factor receptor inhibitors: synthesis, biological evaluation, and modeling of the mode of binding. J Med Chem 40: 1519–1529. doi: 10.1021/jm960789h CrossRefPubMedGoogle Scholar