Table 1.

Binding energy, glide score and key residue interactions of Arbidol (Umifenovir) and bioisosteric replacement generated analogues with SARS-CoV-2-ACE2, furin and TMPRSS2.

Compound ID	Structure	SARS-CoV-2-ACE2 complex (PDB ID: 6LZG)a			Furin (PDB ID: 5MIM)			TMPRSS2 (homology model, 015393, TMPS2_human)
		ΔG MM-GBSA (kcal/mol)	Glide score (kcal/mol)	Key Interactions	ΔG MM-GBSA (kcal/mol)	Glide score (kcal/mol)	Key Interactions	ΔG MM-GBSA (kcal/mol)	Glide score (kcal/mol)	Key Interactions
Arbidol		−30.36	−2.42	Gly496, Arg403, Tyr505	−14.93	−3.60	Asp154, Hip194	−23.68	−1.71	Tyr226
		−39.99	−3.63	Ser128
A_BR1		−36.75	−3.05	Gly496, Arg403, Tyr505	−27.46	−3.06	Val231, Glu236	−29.93	−1.77	–
		−30.24	−4.54	Glu145, Hip345
A_BR2		−23.39	−2.54	Arg403, Tyr449, Gln493	−9.67	−2.78	Glu257	−33.09	−2.48	Tyr226
		−35.93	−3.27	Hie378, Glh398, Hip401
A_BR3		−28.97	−2.77	Tyr449 Tyr505	−16.62	−2.29	Hip194, Gly255	−27.22	−2.30	Ser228
		−37.13	−3.87	Ser128
A_BR4		−45.34	−5.36	Arg403, Tyr505	−17.50	−3.98	Gly255, Asp258	−28.87	−2.35	Ser228
		−43.65	−5.27	Ala348, Glu375, Hie378, Asp382, Hip401, Tyr510, Arg514
A_BR5		−38.58	−2.86	Glu494	−31.64	−3.94	Asp154, Hip194	−30.44	−2.12	Ser228
		−28.47	−5.01	Hip345, Glu375, Glu402, Arg514
A_BR6		−30.37	−2.26	Arg403, Gly496, Tyr505	−15.74	−4.45	Gly255, Asp258	−16.32	−2.61	Arg165, Tyr226, Hie227, Ser228
		−42.58	−3.92	Ala348, Glh398, Hip401
A_BR7		−29.17	−2.79	Arg403, Gly496, Tyr505	−12.24	−1.50	Asn176, Glh230	−28.32	−2.07	Arg165
		−38.65	−2.84	Asn149
A_BR8		−28.19	−2.38	Arg403, Gly496, Tyr505	−18.50	−0.88	Arg185	−13.64	−2.85	Tyr226, Hie227, Ser228
		−45.75	−3.70	Tyr127, Phe504
A_BR9		−45.44	−4.66	Arg403, Gly496, Tyr505	−19.81	−2.95	Hip194, Gly255	−30.62	−2.16	Ser228
		−41.49	−4.93	Asn149, Arg273
A_BR10		−27.91	−2.95	Arg403, Gly496, Tyr505	−22.79	−3.36	Glu236	−19.18	−2.91	Tyr226, Hie227, Ser228
		−45.27	−3.76	Tyr127, Phe504
A_BR11		−30.42	−2.69	Arg403, Gly496, Tyr505	−11.29	−1.00	Asp154	−27.02	−2.73	Ser163, Tyr226
		−40.01	−3.22	Glu145, Asn149, Arg273
A_BR12		−28.08	−2.06	Arg403, Tyr505, Gly496	−27.37	−3.85	Glu236, Gly255	−19.91	−2.22	Tyr226
		−49.33	−3.81	Ser128
A_BR13		−42.68	−2.25	Arg403, Tyr505	−39.44	−3.55	Asp154, Gly255	−25.65	−2.05	Ser228
		−44.80	−3.07	Asn149, Arg273, Hie505
A_BR14		−30.76	−2.36	Gly496, Tyr505	−31.58	−1.33	Gly255	−37.71	−2.06	–
		−41.25	−3.76	Glh398, Arg514
A_BR15		−28.55	−2.54	Arg403, Gly496, Tyr505	−10.94	−2.89	Hip194, Gly255	−32.45	−2.31	–
		−44.42	−3.00	Tyr127, Arg273
A_BR16		−37.84	−2.53	Arg403, Lys417, Tyr505	−22.32	−2.16	Asn295	−37.34	−2.84	Ser163, Lys223
		−37.64	−3.63	Arg273, Phe504, Tyr515
A_BR17		−37.63	−1.99	Tyr505	−21.96	−2.82	Ash153, Asp154, Hip194	−38.36	−2.03	Ser163, Lys223, Tyr226
		−36.33	−3.04	Arg273, Phe504
A_BR18		−45.52	−5.96	Arg403, Gly496, Asn501, Tyr505	−34.01	−3.92	Asp154, Asp191, Asp228	−35.97	−2.11	Ser228
		−49.50	−6.13	Ala348, Asp382, Hip401
A_BR19		−34.78	−2.85	Arg403, Gln493	−20.91	−3.02	Hip194, Leu227	−26.96	−1.82	–
		−31.25	−5.01	Asp382
A_BR20		−39.84	−1.97	Arg403	−17.96	−2.31	Hip194, Gly255	−15.28	−2.56	Arg165, Tyr226, Ser228
		−47.49	−5.46	Ala348, Asp382, Hip401
A_BR21		−45.83	−5.01	Arg403, Gly496, Tyr505	−7.86	−2.20	Hip194	−28.85	−2.07	Arg165, Tyr226
		−40.46	−5.70	Ser128, Glu145
A_BR22		−37.09	−4.09	Arg403, Tyr453, Tyr505	−22.92	−4.09	Asp154, Hip194	−34.82	−2.38	Tyr226, Ser228
		−37.46	−4.20	Asn149
A_BR23		−29.93	−2.95	Arg403, Gly496, Asn501, Tyr505	−15.22	−2.84	Hip194, Gly255	−30.48	−2.02	Lys224, Tyr226
		−40.03	−3.14	Phe504
A_BR24		−33.17	−3.81	Tyr453	−24.54	−2.97	Gly255, Asp258	−21.82	−1.94	Arg165, Tyr226
		−37.07	−3.79	Ser128
A_BR25		−37.96	−2.53	Arg403, Gln493	−25.41	−2.31	Hip194, Gly255	−30.57	−1.73	Ser228
		−34.77	−3.52	Ala348, Hip374, Asp382, Hip401
A_BR26		−35.17	−2.33	Arg403, Gln493	−16.84	−1.62	–	−23.65	−2.28	Ser163, Arg165, Tyr226
		−33.56	−3.58	Ala348, Asp382, Hip401, Tyr510
A_BR27		−29.25	−2.65	Arg403, Gln493	−38.04	−3.12	Asp154, Hip194	−24.82	−1.72	Ser228
		−30.90	−3.20	Phe274
A_BR28		−42.37	−4.69	Tyr505	−32.52	−5.42	Val231, Gly255	−37.63	−2.20	Ser228
		−40.12	−4.19	Glh398, Hip401, Arg514
A_BR29		−27.77	−1.59	Lys417, Tyr505	−28.13	−4.45	Ash153, Asp154, Hip194	−27.76	−1.88	Arg165, Tyr226, Ser228
		−29.16	−2.72	Arg273, Hip345
A_BR30		−34.54	−2.64	Tyr505	−23.67	−2.12	Asp154, Hip194	−30.13	−2.07	Lys224
		−28.34	−4.26	Hip345, Glu375, Glu403
A_BR31		−36.82	−1.69	Glu484	−32.85	−2.84	Hip194, Gly255	−34.78	−1.70	Ser228
		−27.71	−3.12	Tyr127
A_BR32		−38.82	−4.22	Gly496, Asn501, Tyr505	−25.47	−3.01	Val231, Glu236, Asp264, Tyr308	−34.11	−2.05	Ser228
		−50.11	−5.86	Glu375
A_BR33		−37.68	−2.29	Tyr449	−31.61	−3.62	Glu257	−30.66	−2.01	Tyr226, Ser228
		−24.69	−4.28	Glu145
A_BR34		−35.77	−1.83	Tyr505	−34.86	−3.78	Hip194, Gly255	−29.16	−1.94	Ser228
		−26.87	−3.36	Asp382
A_BR35		−39.17	−2.47	Tyr449	−28.38	−3.05	Asp154, Leu227	−32.69	−1.71	Tyr226, Ser228
		−41.66	−2.55	Asn149, Phe504
A_BR36		−37.36	−1.94	Glu494	−32.14	−2.79	Gly255	−38.34	−2.09	–
		−38.54	−2.78	Asn149

Parent drug.

Bio-isosteric replacement 1.

Bio-isosteric replacement 2.

Bio-isosteric replacement 3.

Bio-isosteric replacement 4.

Bio-isosteric replacement 5.

Bio-isosteric replacement 6.

^aSARS-CoV-2 (Chain B) scores given in upper row, ACE2 (Chain A) scores given in lower row.