Table 1 The list of TNFα, TNFR1 and TNFα-TNFR1 complex and their best lead molecules interactions, binding energies, smiles, bond angles, bond lengths and number of hydrogen bonds

ZINC09609430

N-[1-(2,5-dioxabicyclo[4.4.0]deca-7,9,11-trien-8-yl)ethyl]-3-[7-(4-fluorophenyl)-2,4,8-trimethyl-1,5

Cc1c(c(n2c(n1)c(c(n2)C)c3ccc(cc3)F)C)CCC(=O)N[C@H](C)c4ccc5c(c4)OCCO5

− 9.2

Gly¹²¹ CH–HN

107.21

3.17

01

ZINC49467549

N-[2-[3-(4-methyl-2-phenyl-thiazol-5-yl)-6-oxo-pyridazin-1-yl]ethyl]-2-(1-naphthyloxy)acetamide

Cc1c(sc(n1)c2ccccc2)c3ccc(=O)n(n3)CCNC(=O)COc4cccc5c4cccc5

− 9.0

Ile⁵⁸, Leu¹²⁰, Gly¹²¹ and Tyr¹⁵¹

–

–

–

ZINC13113075

(2R)-2-[[5-[(1S)-1-(4-fluorophenoxy)ethyl]-1,3,4-oxadiazol-2-yl]sulfanyl]-1-(2-methyl-1H-indol-3-yl)

Cc1c(c2ccccc2[nH]1)C(=O)[C@@H](C)Sc3nnc(o3)[C@H](C)Oc4ccc(cc4)F

− 8.8

Tyr¹⁵¹ CO–OC

98.29

3.29

01

ZINC39907639

2-[(3,4-dimethoxyphenyl)methyl]-1-[2-(1-naphthyloxy)ethyl]benzimidazole

COc1ccc(cc1OC)Cc2nc3ccccc3n2CCOc4cccc5c4cccc5

− 8.5

Ile⁵⁸, Leu¹²⁰, Gly¹²¹ and Tyr¹⁵¹

–

–

–

ZINC25251930

1-[[(R)-(3-methoxyphenyl)-(1-methylimidazol-2-yl)methyl]amino]-3-methyl-pyrido[1,2-a]benzimidazole-4

cc1cc(n2c3ccccc3nc2c1C#N)N[C@H](c4cccc(c4)OC)c5nccn5C

− 8.1

Ile⁵⁸ CO–NC

3.16

17.87

03

Leu¹²⁰ CO–NH

3.31

39.97

Gly¹²¹ CN–OC

2.99

111.96

307 (Query)

6,7-dimethyl-3-[(methyl{2-[methyl({1-[3-(trifluoro methyl)phenyl]-1H-indol-3-yl}methyl)amino]ethyl}amino)methyl]-4H-chromen-4-one

Cn(ccn(c)cc1=c[n](c2=cc(=cc=c2)c(f)(f)f)c3=cc=cc=c13)cc4=coc5=cc(=c(c)c=c5c4=o)c

− 6.8

Ile⁵⁸, Leu¹²⁰, Gly¹²¹ and Tyr¹⁵¹

–

–

–

ZINC02968981

N-benzyl-2-[[2-(4-nitrophenyl)-[1, 2, 4]triazolo[1,5-c]quinazolin-5-yl]thio]acetamide

c1ccc(cc1)CNC(=O)CSc2nc3ccccc3c4n2nc(n4)c5ccc(cc5)[N+](=O)[O–]

− 10.1

Lys⁷⁵ CO–ON

Gln⁸² CO–ON

Gln⁸² CN–ON

Arg¹⁰⁴ CN–OC

Tyr¹⁰⁶ CO–OC

112.42

97.99

101.92

109.87

149.80

3.25

3.35

3.16

2.84

3.20

05

ZINC09544246

2-[[5-(1H-indol-3-yl)-1,3,4-oxadiazol-2-yl]sulfanyl]-N-(3-sulfamoylphenyl)-acetamide

c1ccc2c(c1)c(c[nH]2)c3nnc(o3)SCC(=O)Nc4cccc(c4)S(=O)(=O)N

− 9.8

Glu⁵⁶ CN–OC

Glu⁵⁶ CO–NH

Ser⁵⁷ CO–NH

Ser⁵⁹ CO–OC

Cys⁷⁰ CN–OC

Cys⁷³ CO–NH

Ser⁷⁴ CO–NH

167.25

106.92

119.86

124.31

109.30

150.85

105.01

2.93

2.06

3.34

2.90

3.06

3.24

3.19

07

ZINC58047088

N-[(4-fluorophenyl)methyl]-2-[(3-methyl-2-oxo-[1, 2, 4]triazino[2,3-c]quinazolin-6-yl)sulfanyl]acetami

Cc1c(=O)nc2c3ccccc3nc(n2n1)SCC(=O)NCc4ccc(cc4)F

− 9.5

Ser⁷⁴ CO–NH

Asn¹¹⁰ CO–NH

131.62

123.93

3.07

3.01

02

ZINC72021182

2-(4-chlorobenzoyl)-N-[2-[(2-hydroxybenzoyl)amino]ethyl]benzamide

c1ccc(c(c1)C(=O)c2ccc(cc2)Cl)C(=O)NCCNC(=O)c3ccccc3O

− 9.3

Arg¹⁰⁴ CN–OH

85.81

2.98

01

ZINC08704414

2-(methylBLAHyl)sulfanyl-N-(p-tolylmethyl)propanamide

Cc1ccc(cc1)CNC(=O)[C@@H](C)Sc2nc3ccccc3c4n2nc(n4)C

− 9.1

Ser⁷⁴ CO–NH

Lys⁷⁵ CO–NH

Arg⁷⁷ CN–OC

Asn¹¹⁰ CO–NH

55.03

30.27

101.39

111.93

3.13

3.11

3.02

3.37

04

ZINC33832439 (query)

1-Hydroxy-3-methoxy-6-methyl-8-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)anthracene-9,10-dione

Cc1cc2c(c(c1)O[C@H]3[C@@H]([C@H]([C@@H]([C@H](O3)CO)O)O)O)C(=O)c4c(cc(cc4O)OC)C2=O

− 7.6

Arg⁷⁷ CN–OC

Cys⁹⁶ CN-OH

Cys⁹⁶ CO–OH

Arg¹⁰⁴ CN—OH

Arg¹⁰⁴ CN–OH

Arg¹⁰⁴ CN—OH

Tyr¹⁰⁶ CO–OH

Asn¹¹⁰ CO–OH

111.69

106.76

151.20

92.64

120.04

107.99

58.49

3.01

3.09

2.70

3.31

2.81

3.00

3.16

08

ZINC05462670

Chaetochromin B

C[C@@H]1[C@H](Oc2cc3c(c(cc(c3c4c5cc6c(c(c5c(cc4O)O)O)C(=O)[C@@H]([C@@H](O6)C)C)O)O)c(c2C1=O)O)C

− 10.0

Ser⁷⁴ CO–OH

Thr⁹⁴ CO–OH

Glu¹⁰⁹ CO–OC

Asn¹¹⁰ CO–OH

72.63

27.39

121.49

45.29

3.19

2.93

3.36

2.73

04

ZINC35681945

N2-[(2R)-2-(dimethylamino)-2-(2-methoxyphenyl)ethyl]-N4-(4-ethoxyphenyl)-5-nitro-pyrimidine-2,4,6-tr

CCOc1ccc(cc1)Nc2c(c(nc(n2)NC[C@@H](c3ccccc3OC)[NH+](C)C)N)[N+](=O)[O–]

− 9.7

Lys⁷⁵ CO–NH

Gln⁸² CO–ON

Gln⁸² CN–ON

Asp⁹³ CO–NH

Arg¹⁰⁴ CN–OC

Asn¹¹⁰ CO–NH

76.93

114.27

111.31

155.37

95.38

129.41

3.32

3.08

3.38

2.89

3.20

2.79

06

ZINC23553920

6-[[4-allyl-5-(2-methoxyphenyl)-1,2,4-triazol-3-yl]sulfanylmethyl]-N′-(2-ethylphenyl)-1,3,5-triazine

CCc1ccccc1Nc2nc(nc(n2)N)CSc3nnc(n3CC=C)c4ccccc4OC

− 9.5

Ser⁷⁴ CO–OC

Thr⁹⁴ CO–NH

Thr⁹⁴ CO–NH

75.40

46.06

52.19

3.49

3.12

3.20

03

ZINC05328058

DNC011371

C[C@H]1CC(=O)c2c(cc3c(c2O)c(cc(c3c4c5cc6c(c(c5c(cc4O)O)O)C(=O)C[C@@H](O6)C)O)O)O1

− 8.9

Ser⁷⁴ CO–OH

Gln⁸² CO–OC

Pro⁹⁰ CO–OH

Asn⁹² CN–OH

Cys⁹⁶ CN–OH

49.49

103.84

73.92

29.76

65.40

2.80

3.48

3.24

2.97

2.95

05

ZINC17206695

(2Z)-2-(2,5-dimethoxyphenyl)imino-6-[(3R,5S)-3,5-dimethyl-1-piperidyl]-5-nitro-1H-pyrimidin-4-amine

C[C@@H]1C[C@@H](CN(C1)c2c(c(nc(n2)Nc3cc(ccc3OC)OC)N)[N+](=O)[O–])C

− 8.5

Ser⁷⁴ CO–NH

Ser⁷⁴ CO–NH

Asn⁹³ CO–NH

Asn¹¹⁰ CN–ON

Asn¹¹⁰ CN–NO

Ser¹⁴⁷ OC–OC

55.45

30.72

47.81

102.70

54.86

2.81

3.20

2.73

2.81

3.35

06

ZINC08214556 (query)

Erythrosine sodium (USP)

c1ccc2c(c1)C(=O)OC23c4cc(c(c(c4Oc5c3cc(c(c5I)O)I)I)O)I

− 7.2

Thr⁹⁴ CO–OC

Asn¹¹⁰ CN–OC

120.52

102.30

3.05

3.20

02