1)Rules for Breaking Down Drug Molecules Into Fragments

1)Rules for Breaking Down Drug Molecules Into Fragments

Supporting information

1)Rules for breaking down drug molecules into fragments:

a)the fragments must satisfy “TheRuleOfThree”10;

b)the breakdown into fragments must not create new ionogenic groups, since the presence of such groups may critically alter the nature of ligand binding;

c)the breakdown into fragments must be done with the splitting of as few bonds as possible so that the reconstruction of the original drug structure is still feasible;

d)the fragments must be relatively stable structures; they must not contain highly active functional groups that would complicate the experimental work;

e)a drug molecule is broken down into two or more non-overlapping fragments; if such breakdown creates fragments that are too small to be used in molecular docking, only the larger fragments are docked:

2)An illustration of molecular docking of known drugs and their fragments into the target proteins. The docking results are denoted by «+» - correct, «-» - incorrect docking). Each fragment has the number of hydrogen bonds with the target protein HB, metal coordination Me, the degree of Van-der-Waals interaction on a three-tier scale VdW, and the occupancy rate of the active center by a V, in %.

PDB ID / Drug name / Protein target name / Drug structure / Fragment
1azm / Acetazolamide / Carboanhydrase /
+ / -
1fwe / Acetohydroxamic acid / Urease /
+ / -
2v0z / Aliskiren / Renin / + /
+
HB 1
Me -
VdW 2
V 50%

+
HB 7
Me –
VdW 1
V 50%

-
HB 5
Me –
VdW 1
V 25%

-
HB 0
Me 0
VdW 1
V 25%
1cae / Aminocaproic acid / Plasminogen /
+ /
+
HB 5
Me -
VdW 0
V 75%
1dwc / Argatroban / Thrombin /
+ /
-
HB 2
Me –
VdW 1
V 25%

+
HB 6
Me –
VdW 1
V 50%
1hwk / Atorvastatin / HMG-CoA reductase /
+ /
+
HB 6
Me –
VdW 0
V 25%

+
HB 1
Me –
VdW 1
V 75%
1uzf / Captopril / ACE /
+ /
+
HB 3
Me –
VdW 1
V 50%

+
HB 0
Me +
VdW 0
V 25%
1ITU / Cilastatin fragment / Dipeptidase /
+ /
+
HB 2
Me –
VdW 1
V 50%

+
HB 3
Me +
VdW 0
V 50%
1qkt / Conjugated estrogens / Estrogen receptors /
+ /
+
HB 2
Me –
VdW 2
V 50%

-
HB 0
Me –
VdW 2
V 50%
2ien / Darunavir / HIV-1 protease /
- /
-
HB 2
Me –
VdW 0
V 15%

-
HB 1
Me –
VdW 0
V 15%
2GQG / Dasatinib / ABL1 /
+ /
+
HB 2
Me –
VdW 1
V 50%

+
HB 2
Me –
VdW 2
V 25%

-
HB 0
Me –
VdW 0
V 15%

-
HB 3
Me –
VdW 0
V 15%
1m2z / Dexamethasone / Glucocorticoid receptor /
+ /
+
HB 4
Me –
VdW 1
V 50%

+
HB 2
Me –
VdW 1
V 50%
3ERD / Diethylstilbestrol / Estrogen receptor alpha /
+ /
+
HB 2
Me –
VdW 1
V 50%
1m17 / Erlotinib / EGFR /
+ /
-
HB 2
Me –
VdW 0
V 25%

+
HB 2
Me –
VdW 2
V 50%
1hwi / Fluvastatin / HMG-CoA reductase /
+ /
+
HB 7
Me –
VdW 0
V 25%

-
HB 0
Me 0
VdW 1
V 50%
1w6r / Galantamine / AChE /
+ /
-
HB 2
Me 0
VdW 1
V 50%

+
HB 1
Me –
VdW 1
V 25%
2itz / Gefitinib / EGFR /
+ /
+
HB 1
Me –
VdW 0
V 25%

+
HB 1
Me –
VdW 1
V 50%
2hyy / Imatinib / ABL1 /
+ /
+
HB 2
Me –
VdW 1
V 25%

+
HB 2
Me –
VdW 1
V 50%

-
HB 0
Me –
VdW 1
V 25%
3I3K / Ketoconazole / 14 alpha demethylase /
- / -
1o86 / Lisinopril / ACE /
+ /
+
HB 4
Me 0
VdW 1
V 25%

-
HB 2
Me +
VdW 0
V 25%
2w8y / Mifepristone / Progesterone receptor /
+ /
-
HB 0
Me –
VdW 0
V 15%

-
HB 0
Me 0
VdW 1
V 25%
1ffy / Mupirocin / Ile-TRNA synthetase /
- / -
1meh / Mycophenolic acid / IMPDH /
+ /
+
HB 2
Me –
VdW 1
V 25%
1SQN / Norethindrone / Progesterone receptor /
+ /
+
HB 2
Me –
VdW 1
V 50%

-
HB 0
Me –
VdW 1
V 50%
3d90 / Norgestrel / Progesterone receptor /
+ /
+
HB 2
Me –
VdW 1
V 50%

-
HB 0
Me –
VdW 1
V 50%
1j3j / Pyrimethamine / DHFR /
+ /
+
HB 3
Me –
VdW 1
V 50%
2qxs / Raloxifene / Estrogen receptor /
+ /
+
HB 3
Me 0
VdW 1
HB 50%

+
HB 2
Me –
VdW 1
V 25%
3d91 / Remikiren / Renin /
+ /
+
HB 5
Me –
VdW 1
V 25%

+
HB 2
Me 0
VdW 1
V 25%
1zgy / Rosiglitazone / PPAR /
+ /
+
HB 3
Me –
VdW 0
V 50%

-
HB 1
Me –
VdW 0
V 25%
1hwl / Rosuvastatin / HMG-CoA reductase /
+ /
+
HB 7
Me –
VdW 0
V 25%

+
HB 1
Me –
VdW 2
V 50%
1tbf / Sildenafil / PDE5 /
+ /
+
HB 4
Me –
VdW 1
V 25%
1x70 / Sitagliptin / DPP 4 /
+ /
+
HB 3
Me –
VdW 2
V 25%

-
HB 0
Me -
VdW 0
V 25%
1uwh / Sorafenib / Braf /
+ /
+
HB 2
Me –
VdW 2
V 25%

+
HB 2
Me –
VdW 2
V 25%
2ab2 / Spironolactone / Mineralocorticoid receptor /
+ /
+
HB 2
Me –
VdW 1
V 25%

-
HB 0
Me –
VdW 1
V 25%
3g0e / Sunitinib / KIT /
+ /
-
HB 0
Me –
VdW 0
V 25%

+
HB 2
Me –
VdW 1
V 50%
1xoz / Tadalafil / PDE5 /
+ /
-
HB 1
Me –
VdW 0
V 15%

+
HB 0
Me –
VdW 1
V 15%

-
HB 1
Me –
VdW 1
V 50%
2w3a / Trimethoprim / DHFR /
+ /
+
HB 4
Me –
VdW 1
V 25%

-
HB 0
Me –
VdW 1
V 50%
1xp0 / Vardenafil / PDE5 /
- / -
1t69 / Vorinostat / HDAC8 /
- / -

3)The inhibition of PARP1 by the found fragment structures.

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