Structure Activity Relationship and Target Relationship Analysis Based of Formal Concept

Supplementary Materials

Structural and Activity Profile Relationships between Drug Scaffolds

Ye Hu, and Jürgen Bajorath*

Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and

Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität Bonn, Dahlmannstr. 2, D-53113

Bonn, Germany.

Supplementary Figures S1-S4

Supplementary Tables S1-S2

1 Figure S1. Distribution of structural relationships for bioactive scaffolds.

100 90 ≥ 5 Relationships MMP RECAP Sub CSK

s 80 d l % Bioactive scaffolds 54.6 20.3 14.2 45.5 o

f 70 f a

c 60 s

e 50 v i t

c 40 a o i 30 B

% 20 10 0 0 1 2 3 4 5 [6,10] [11,20] >20 # Relationships per bioactive scaffold

MMP RECAP Sub CSK

For each type of structural relationships, the percentage of bioactive scaffolds forming increasing numbers of relationships is reported. In addition, for each type of structural relationships, the proportion of scaffolds involved in at least five relationships is given in a table insert.

2 Figure S2. Proportion of different structural relationships for bioactive scaffolds.

Union (MMP, RECAP, Sub, CSK): 1,150,457 pairs s r

i 100 a p

d l 80 o f f a c

s 60 51.7 e

v 44.5 i t

c 40 a o i B 20 % 6.3 9.4 0 MMP RECAP Sub CSK

Different types of structural relationships were combined by determining the union of pairs involved in these relationships (given at the top). For each type, the proportion (black bar) is shown.

3 Figure S3. Promiscuity of structurally related bioactive scaffolds.

s 90 r i

a 80 p

l 70 o f

f 60 a c s

50 e v

i 40 t c

a 30 o i

% 10 0 0 1 2 [3,5] [6,10] >10 ∆Promiscuity

MMP RECAP Sub CSK

For bioactive scaffolds, the number of scaffold pairs forming different types of structural relationships and having increasing differences in the degree of scaffold-based promiscuity

(∆Promiscuity) is reported.

4 Figure S4. Activity profile comparison.

s 90 r i

a 80 p

l 70 o f

f 60 a c s

50 e v

i 40 t c

a 30 o i

% 10 0 Identical Distinct Overlapping

MMP RECAP Sub CSK

For bioactive scaffolds, the number of scaffold pairs forming different types of structural relationships and having identical, distinct, or overlapping activity profiles is reported.

5 Table S1. Target profile for a representative drug scaffold with a high mean RDF value.

Target ID Target name 1 Gamma-aminobutyric acid receptor subunit rho-3 2 Gamma-aminobutyric acid receptor subunit pi 3 Gamma-aminobutyric acid receptor subunit delta 4 Cytochrome P450 3A4 5 Cytochrome P450 2C8 6 Cytochrome P450 2C9 7 Gamma-aminobutyric acid receptor subunit alpha-1 8 Gamma-aminobutyric acid receptor subunit beta-1 9 Gamma-aminobutyric acid receptor subunit gamma-2 10 Cytochrome P450 3A5 11 Gamma-aminobutyric acid receptor subunit rho-1 12 Cytochrome P450 3A7 13 Gamma-aminobutyric acid receptor subunit beta-3 14 Gamma-aminobutyric acid receptor subunit rho-2 15 Translocator protein 16 Gamma-aminobutyric acid receptor subunit alpha-5 17 Cytochrome P450 2C19 18 Gamma-aminobutyric acid receptor subunit alpha-3 19 Gamma-aminobutyric acid receptor subunit alpha-2 20 Gamma-aminobutyric acid receptor subunit beta-2 21 Gamma-aminobutyric acid receptor subunit alpha-4 22 Gamma-aminobutyric acid receptor subunit epsilon 23 Gamma-aminobutyric acid receptor subunit alpha-6 24 Gamma-aminobutyric acid receptor subunit gamma-1 25 Gamma-aminobutyric acid receptor subunit gamma-3 26 Gamma-aminobutyric acid receptor subunit theta

For the drug scaffold shown in Figure 8b that yielded a high mean RDF value of 0.80, its target profile is provided.

6 Table S2. Target profile for a representative drug scaffold with a low mean RDF value.

Target ID Target name 1 Serum albumin 2 Estrogen receptor 3 Multidrug resistance protein 1 4 Cytochrome P450 3A4 5 Cytochrome P450 2C8 6 Cytochrome P450 2D6 7 Cytochrome P450 2C9 8 Cyclic AMP-responsive element-binding protein 1 9 Alpha-1-acid glycoprotein 2 10 Cytochrome P450 3A5 11 Prostaglandin G/H synthase 1 12 Cytochrome P450 3A7 13 Mu-type opioid receptor 14 Delta-type opioid receptor 15 Kappa-type opioid receptor 16 Solute carrier organic anion transporter family member 1A2

For the drug scaffold shown in Figure 8c that yielded a low mean RDF value of 0.33, its target profile is provided.