Protein Kinase Inhibitor Design by Targeting the Asp-Phe-Gly (DFG) Motif: The Role of the DFG Motif in the Design of Epidermal Growth Factor Receptor Inhibitors

Abstract

The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example. Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif. Indeed, introduction of an N,N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a. Structural studies confirmed this N,N-dimethylamino tail moved toward the DFG motif to form a salt bridge with the side chain of Asp831. That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g, and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly.

Apoptosis induction by an analog of curcumin (BDMC-A) in human laryngeal carcinoma cells through intrinsic and extrinsic pathways

“…In addition to its presumed interaction with the MET769 residue, BDMC-A was found to be able to undergo an additional H-bond interaction with the DFG loop of the ASP831 residue. Recently, furano-pyrimidine EGFR kinase inhibitors were shown to specifically interact with this DFG loop and to modify the kinase activity [54,55]. Additionally, we found that BDMC-A exhibits higher docking and free binding energy scores compared to curcumin.…”

The design and discovery of water soluble 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multitargeted receptor tyrosine kinase inhibitors and microtubule targeting antitumor agents

“…This is similar to the vertical and horizontal bound conformations observed for other furo[2,3- d ]pyrimidines in crystal structures with RTKs. 50 The energy difference between the best docked horizontal pose of 11 was within 2 kcal/mol of the lowest energy vertical docked pose in both VEGFR-2 crystal structure and the PDGFR-β homology model. The horizontal pose conformationally orients the phenyl ring of the aniline group towards the 5-position of the furo[2,3- d ]pyrimidine as demonstrated by a 1 H NMR study (see below).…”

Statistical analysis of EGFR structures’ performance in virtual screening

“…The choice of any one should be fine, though the selection of chain A was a little arbitrary. At the time of analysis 49 EGFR structures of kinase domain were obtained: 1M14, 1M17,[17] 1XKK,[18] 2EB2, 2EB3, 3UG1, 3UG2, 3VJN, 3VJO,[19] 2GS2, 2GS7,[20] 2ITN, 2ITO, 2ITP, 2ITQ, 2ITT, 2ITU, 2ITV, 2ITW, 2ITX, 2ITY, 2ITZ, 2J6M,[21] 2JIT, 2JIU,[9] 2RF9, 2RFD, 2RFE,[22] 2RGP,[23] 3BEL,[24] 3GT8,[25] 3LZB,[26] 3POZ,[27] 3W2O, 3W2R, 3W2S,[28] 3W32, 3W33,[29] 4HJO,[7] 4I1Z, 4I20, 4I21, 4I22, 4I23,[8] 4JQ7, 4JQ8, 4JR3, 4JRV,[30] 4LI5. [31]…”