Aminopurine derivatives as putative SopE inhibitors

Figures & data

Figure 1. Crystal structure of the GEF domain of SopE in complex with Cdc42, shown in cartoon representation (PDB id: 1gzs:A,B). Switch regions of Cdc42 are shown in red and purple. Critical GAGA loop residues are shown in yellow.

Figure 2. Schematic workflow of VS and docking of SopE.

Figure 3. (A) Binding modes of all fragments superimposed at the binding site of SopE in stick representation. (B) Pharmacophore site points as spheres located on the binding site of SopE, determined by E-pharm. Top six sites based on energetic contribution are labeled. All site points are colored and labeled according to their feature type (donor, acceptor, hydrophobic or ring).

Table 1. Pharmacophore features and ranks by E-pharm. Numbers in feature labels are indices which are automatically assigned during feature generation.

Rank	Feature label	Score	X	Y	Z	Type
1	D995	−1.80	−42.79	58.44	53.22	D
2	A708	−1.70	−30.15	57.8	55.76	A
3	N1548	−1.59	−35.87	53.23	58.95	N
4	D1296	−1.52	−31.51	48.41	53.15	D
5	A42	−1.49	−32.33	53.73	56.24	A
6	D1091	−1.29	−34.84	51.76	54.15	D
7	R2124	−0.98	−42.51	61.08	52.86	R
8	A62	−0.98	−34.14	58.86	54.35	A
9	R2224	−0.95	−41.82	59.85	57.27	R
10	R2233	−0.90	−39.8	58.26	53.84	R
11	D939	−0.90	−39.2	58.7	57.22	D
12	R1961	−0.81	−28.68	56.67	57.28	R
13	R2033	−0.77	−35.52	52.49	56.7	R
14	A81	−0.70	−43.29	56.69	55.55	A
15	D930	−0.70	−29.96	57.53	48.45	D
16	D937	−0.70	−31.93	54.98	52.91	D
17	H1450	−0.70	−31.37	55.91	55.68	H
18	D1282	−0.70	−37.06	56.69	52.44	D
19	R2142	−0.53	−29.74	52.3	54.63	R
20	D999	−0.34	−35.34	56.55	56.15	D
21	R2236	−0.20	−33.94	56.87	54.72	R

Table 2. Docking results of top 20 hits in kcal/mol. ZINC IDs and strain corrected GlideScores for proposed inhibitors are indicated by (*).

#	Title	Glide score	Bound energy	Free energy	Strain energy	Strain penalty	Strain GlideScore	Glide Emodel
1	ZINC03860635	−8.171	16.182	5.816	10.365	1.591	−6.580	−34.444
2	ZINC10274669	−7.948	59.025	26.953	32.072	7.018	−0.930	−57.122
3	ZINC00370772*	−7.681	49.776	45.792	3.984	0.000	−7.681*	−37.519
4	ZINC09214236	−7.567	64.928	64.928	0.000	0.000	−7.567	−33.284
5	ZINC03874923	−7.567	11.363	−5.676	17.039	3.260	−4.307	−50.343
6	ZINC17005625	−7.499	68.736	61.171	7.565	0.891	−6.608	−37.686
7	ZINC17020721*	−7.489	62.430	62.415	0.015	0.000	−7.489*	−38.399
8	ZINC19910989*	−7.456	16.478	13.041	3.437	0.000	−7.456*	−60.893
9	ZINC05033974	−7.410	67.590	54.666	12.924	2.231	−5.179	−44.115
10	ZINC09214236*	−7.330	65.940	64.687	1.253	0.000	−7.330*	−36.937
11	ZINC00375097	−7.324	11.928	11.737	0.191	0.000	−7.324	−39.996
12	ZINC05033974*	−7.274	64.699	63.128	1.572	0.000	−7.274*	−41.142
13	ZINC00388310	−6.960	13.084	10.852	2.232	0.000	−6.960	−43.441
14	ZINC00754304	−6.949	45.244	38.999	6.245	0.561	−6.388	−52.592
15	ZINC09214236	−6.863	69.688	64.003	5.685	0.421	−6.442	−32.037
16	ZINC19910989	−6.841	13.163	8.705	4.459	0.115	−6.726	−57.662
17	ZINC00097607	−6.763	19.312	13.621	5.691	0.423	−6.340	−37.690
18	ZINC39345243	−6.749	55.915	46.046	9.869	1.467	−5.282	−51.248
19	ZINC00155974	−6.700	16.180	14.826	1.353	0.000	−6.700	−41.773
20	ZINC17076964	−6.573	40.677	32.146	8.531	1.133	−5.44	−51.235

Table 3. ADME and druglikeness properties of the selected ligands by QikProp.

Molecule*	SASA†	FOSA‡	FISA¶	QPlogHERG§	QplogS||	QPlogPo/w#	% Human oral absorption$
ZINC00370772	415.4	108.6	223.4	−5.653	−1.21	−1.102	54.1
ZINC17020721	463.4	139.2	217.8	−6.036	−2.13	−1.049	55.4
ZINC19910989	694.2	97.3	212.7	−5.439	−4.56	3.187	68.5
ZINC09214236	441.4	160.4	197.5	−5.492	−1.77	−0.975	59.2
ZINC05033974	502.7	221.9	201.7	−5.692	−2.65	0.372	55.7

*ZINC IDs.

†Total solvent accessible surface area in Ų using a probe with a 1.4 Å radius (acceptable range: 300–1000).

‡Hydrophobic component of the SASA (acceptable range: 0–750).

¶Hydrophilic component of the SASA (acceptable range: 7–330).

§Predicted IC50 value for blockage of HERG K+ channels (acceptable range: below −5).

||Predicted aqueous solubility, S in mol/dm⁻³ (acceptable range: −2–6.5).

#Predicted octanol/water partition coefficient (acceptable range: −6.5–0.5).

$Predicted human oral absorption on 0 to 100% scale (<25% is poor and >80% is high).

Figure 4. (A)–(E) Glide XP binding modes of proposed molecules S1–S5 at SopE binding site. SopE is shown in ribbon representation. Ligands and SopE residues interacting with the ligand are shown in stick representation, colored by atom type. Hydrogen bonds between ligands and SopE are indicated by black dashed lines. (F) Binding mode overlay of five proposed molecules. SopE binding site is in surface representation and ligands are in stick representation, colored by molecule.

Table 4. Summary of H-bond interactions between and proposed molecules of SopE. “+” sign indicates presence of a hydrogen bond and number of signs indicates the number of hydrogen bonds between ligand and a particular SopE residue.

		Residue
Database title/ligand	2D structure	Ala117	Lys121	Asp124	Gly168	Asn170	Lys198
ZINC00370772/S1		+	+	+	+
ZINC17020721/S2		+			+	+	++
ZINC19910989/S3		+	+		+		++
ZINC09214236/S4				+	+		+
ZINC05033974/S5			+		++		++

Figure 5. (A)–(E) IFD binding modes of proposed molecules S1–S5 at SopE binding site. SopE is shown in ribbon representation. Ligands and SopE residues interacting with the ligand are shown in stick representation, colored by atom type. Hydrogen bonds between ligands and SopE are indicated by black dashed lines. (F) Binding mode overlay of five proposed molecules. SopE binding site is in surface representation and ligands are in stick representation, colored by the molecule.

Table 5. IFD Score of proposed molecules in kcal/mol. Docking score of the best pose is presented for each ligand.

Database title	Ligand	IFD Score	GlideScore
ZINC00370772	S1	−7.87	−7.681
ZINC17020721	S2	−7.42	−7.489
ZINC19910989	S3	−4.54	−7.456
ZINC09214236	S4	−7.09	−7.330
ZINC05033974	S5	−8.69	−7.274

Table 6. Docking results of proposed SopE inhibitors to SopE2 in kcal/mol.

Database title	Ligand	GlideScore	Interacting residue on GAGA loop
ZINC00370772	S1	−4.58	Gly166, Ala169
ZINC19910989	S3	−3.81	Gly166, Ala169
ZINC05033974	S5	−2.92	Ala169