Table 1.

Influence of compounds on different structural properties of EGFR exon 20 insertion mutants as ATP competitive inhibitors. The binding free energy is given in Kcal/mol and the distances are in Å.

EGFR Exon 20 Insertion Mutant		D770_N771InsNPG		D770_N771InsSVD		V769_D770InsASV		H773_V774InsH
Inhibitor	Properties	Chain A	Chain B	Chain A	Chain B	Chain A	Chain B	Chain A	Chain B
Erlotinib	Binding Energy of inhibitor	−42.68	−41.12	−66.41	−64.28	−46.87	−61.40	−46.35	−45.27
	Binding Energy of ATP	−32.37	−24.83	−16.17	−27.34	−22.62	−27.44	−20.40	−25.51
	DFG motif and αC-helix orientation *	In	In	In	In	In	In	In	In
	Distance between Lys745 and Glu762	3.0 and 3.0	2.8 and 3.4	2.8 and 3.5	2.8 and 3.7	2.8 and 4.2	2.8 and 3.6	2.8 and 3.2	4.3 and 4.8
	Downward shift of P loop	No	No	No	yes	yes	yes	No	No
Poziotinib	Binding Energy of inhibitor	−59.55	−70.14	−48.17	−61.34	−69.83	−52.96	−60.82	−63.21
	Binding Energy of ATP	−20.56	−25.61	−22.40	−26.60	−33.42	−11.91	−53.86	−33.76
	DFG motif and αC-helix orientation *	In	In	In	In	In	In	In	In
	Distance between Lys745 and Glu762	3.1 and 3.0	3.3 and 3.0	2.9 and 5	2.9 and 3.7	3.5 and 5.6	2.9 and 3.1	2.8 and 4.6	2.8 and 3.3
	Downward shift of P loop	yes	yes	yes	No	No	No	No	No
TAS6417	Binding Energy of inhibitor	−39.31	−43.73	−71.92	−43.88	−54.74	−62.26	−47.06	−57.40
	Binding Energy of ATP	−34.17	−20.42	−32.55	−13.39	−36.68	−35.79	−16.83	−22.77
	DFG motif and αC-helix orientation *	In	In	In	In	In	In	In	In
	Distance between Lys745 and Glu762	2.8 and 3.6	2.8 and 4.2	6.4 and 8.3	3.0 and 3.0	2.8 and 3.9	2.9 and 3.2	4.5 and 6.0	2.9 and 3.3
	Downward shift of P loop	No	yes	No	yes	yes	yes	No	No
CAPE	Binding Energy of inhibitor	−56.48	−46.79	−70.04	−52.52	−63.94	−57.29	−44.17	−35.49
	Binding Energy of ATP	−28.92	−28.82	−20.88	−36.59	−29.20	−17.95	−39.10	−40.25
	DFG motif and αC-helix orientation *	In and Out	In	In	In	In	In	In	In
	Distance between Lys745 and Glu762	10.6 and 12.7	2.9 and 3.0	3.4 and 4.8	2.8 and 3.1	2.8 and 4.2	2.8 and 5.0	3.9 and 4.4	2.8 and 3.5
	Downward shift of P loop	No	yes	No	No	yes	yes	No	No
Wi-A	Binding Energy of inhibitor	−86.90	−46.23	−30.44	−25.60	−53.51	−45.11	−50.64	−42.62
	Binding Energy of ATP	−45.06	−30.59	−56.43	−62.40	−20.97	−38.84	−23.17	−35.66
	DFG motif and αC-helix orientation *	In	In	In	In	In	In	In	In
	Distance between Lys745 and Glu762	7.3 and 9.2	3.2 and 4.2	4.1 and 5.8	4.1 and 5.8	2.8 and 4.6	2.8 and 3.9	4.9 and 6.0	2.8 and 4.3
	Downward shift of P loop	No	No	No	No	yes	yes	No	No
Wi-N	Binding Energy of inhibitor	−48.28	−39.06	−62.79	−58.97	−38.08	−9.87	−35.58	−37.44
	Binding Energy of ATP	−20.17	−26.49	−26.82	−33.29	−60.96	−50.39	−13.47	−33.15
	DFG motif and αC-helix orientation *	In	In	In	In	In	In	In	In
	Distance between Lys745 and Glu762	5.6 and 7.5	2.8 and 3.5	2.8 and 3.1	7.8 and 9.5	2.8 and 4.7	3.2 and 5.0	6.0 and 8.1	2.9 and 3.0
	Downward shift of P loop	No	Yes	No	Yes	Yes	Yes	No	No

* ‘In’ refers to DFG and αC-helix inward conformation; ‘Out’ refers to DFG and αC-helix outward conformation.