Molecular Docking , ADMET and Pharmacokinetic properties predictions of some di-aryl Pyridinamine derivatives as Estrogen Receptor (Er+) Kinase Inhibitors

Figures & data

Figure 1. 3D structure of the 3ERT receptor.

Figure 2. 3D structure of compound 1.

Figure 3. 3D and 2D representations of Compound 3 in the active site of the 3ERT receptor.

Table 1. Docking scores of the analyzed compounds against the 3ERT receptor with Tamoxifen as the reference

Complex	MolDock Score	Rerank Score	E-H bond
1	−134.698	−99.976	−0.425
2	−151.266	−84.518	−2.099
3	−150.523	−119.071	−4.006
4	−149.437	−102.606	−2.358
5	−149.681	−121.819	−4.099
6	−144.918	−115.464	−1.872
7	−145.717	−117.982	−2.500
8	−159.641	−129.307	−3.452
9	−162.781	−135.322	−4.456
10	−144.858	−88.445	−1.315
11	−141.587	−103.625	−1.648
12	−152.327	−125.731	−4.038
13	−143.342	−111.325	−3.047
14	−155.853	−106.063	−2.424
15	−148.410	−115.575	−4.659
16	−138.761	−77.173	−1.247
17	−134.554	−101.087	−1.770
18	−168.434	−122.842	−3.174
19	−133.279	−93.689	−2.361
20	−147.561	−60.473	−2.385
21	−150.714	−124.160	−3.582
22	−143.823	−76.970	−0.482
23	−156.108	−119.832	−2.109
24	−164.822	−135.762	−6.636
25	−138.233	−76.667	−0.846
26	−144.329	−62.473	−5.778
27	−161.015	−132.486	−3.845
28	−146.613	−110.665	−2.414
29	−145.925	−114.010	−2.351
30	−144.240	−118.246	−0.861
31	−170.206	−139.238	−7.918
32	−109.191	−87.9528	−0.692
33	−132.467	−82.1254	0.000
34	−133.818	−50.1614	−4.575
35	−138.83	−109.963	−1.413
36	−128.945	−77.7178	−0.449
37	−134.613	−90.3777	−2.522
38	−136.413	−101.299	−2.893
39	−130.881	80.1516	−4.860
40	−132.395	−104.036	−2.771
41	−142.867	−68.1211	−3.062
42	−138.563	−62.8962	−1.463
43	−140.456	−110.946	−1.170
44	−142.601	−115.129	−3.504
45	−117.116	−82.0994	−1.737
46	−118.791	−80.3251	0.000
47	−129.374	−96.6019	0.000
48	−129.622	−98.3749	0.000
49	−134.004	54.8978	−3.556
50	−147.708	−116.954	−1.021
51	−145.683	−116.258	−0.922
52	−148.662	−116.942	−0.979
53	−144.950	−115.670	0.000
54	−150.696	−119.567	−3.001
55	−154.370	−123.293	−0.689
56	−155.697	−105.297	−5.000
57	−149.291	−100.748	−5.000
Tamoxifen	−145.933	−112.169	0.000

Table 2. Various interactions between the potential hit compounds and the active site of the 3ERT receptor

Complex	Hydrogen Bond Interactions	Electrostatic and Hydrophobic Interactions
3	ARG394, PHE404 and GLY420 Conventional H-bond GLY521 Carbon-Hydrogen bond	GLU353 Pi-anion MET343 Pi-Sulfur LEU346, LEU349, LEU391, ALA350 and LEU525 Pi-alkyl
5	GLY420 and PHE404 Conventional H-bond GLY521, LEU525 and MET528 Carbon-Hydrogen Bond	GLU353 Pi-anion MET343-Pi-Sulfur CYS530, VAL533 and LYS529 Alkyl LEU346, ALA350, LEU349, LEU391 and LEU525 Alkyl
7	VAL534 Conventional H-bond LEU346 and GLU353 C-H bond	MET343 Pi-Sulfur TRP383 Pi-Pi T-Shaped ALA350, LEU387 and LEU391 Alkyl PRO535 and LEU536 Amide-Pi stacked VAL533, LEU536, LEU525, MET522 and ALA350 Pi-alkyl
8	GLY420 and PHE404 Conventional H-bond LEU525 Carbon-Hydrogen bond	ASP351 and GLU353 Pi anion MET343 Pi-Sulfur LEU525 and LYS529 Alkyl LEU525, LEU346, ALA350, LEU349 and LEU391 Pi-alkyl
9	GLU353, GLY420 Conventional H-bond GLY521 Carbon-Hydrogen bond	MET343 Pi-Sulfur MET522, LEU525 and LYS529 Alkyl LEU346, LEU349, ALA350, LEU387 and LEU525 Pi-alkyl
12	ARG394, PHE404 and GLY420 Conventional H-bond GLY521 and GLU380 Carbon-Hydrogen bond	MET343 Pi-Sulfur TRP383 Pi-Pi stacked LEU536 Alkyl TRP383, LEU346, LEU349, ALA350, LEU387 and LEU525 Pi-Alkyl
15	GLU353 and GLY420 Conventional H-bond GLY521 Carbon-Hydrogen bond	MET343 Pi-Sulfur VAL533, LEU536 and LEU539 Alkyl LEU346, LEU349, ALA350, LEU387 and LEU525 Pi-alkyl
18	GLU353 and GLY420 Conventional H-bond GLY521, ASP351, and ALA350 Carbon-Hydrogen bond	LEU346, LEU349, ALA350, LEU387, LEU525 Pi-Alkyl
21	PHE404, GLY420 and LEU346 Conventional H-bond GLY521 Carbon-Hydrogen bond	MET343 Pi-Sulfur LYS529 and VAL533 Alkyl TYR526, LEU349, ALA350, LEU387, LEU346 and LEU525 Pi-Alkyl
23	GLU353 Conventional H-bond GLY420, LYS520, and MET522 Carbon-Hydrogen bond	MET343 Pi- Sulfur TRP383 Pi-Pi Stacked MET522 and LEU525 Alkyl LEU349, LEU387, LEU346, ALA350 and LEU525 Pi-alkyl
24	GLY420, GLU353 Conventional H-bond GLY521 Carbon-Hydrogen bond	ASP351 Pi-anion MET343 Pi-Sulfur LEU536, LEU539 Alkyl Pi-alkyl
27	GLU353 and GLY420 Conventional H-bond GLY521 Carbon-Hydrogen bond	MET343 Pi-Sulfur TRP383 Pi-Pi stacked VAL533 and LEU536 Alkyl LEU346, LEU349, ALA350, LEU387 and LEU525 Pi-alkyl
29	LEU525 Conventional H-bond PRO535 and MET522 Carbon-Hydrogen bond CYS530 Pi-Donor	LYS529 Pi- Cation MET522 and CYS530 Pi-Sulfur TYR526, LYS529, CYS530, VAL533, LYS529, VAL533 and PRO535 Pi-Alkyl
31	LEU536, GLY420 and GLU353 Conventional H-bond VAL534 and VAL533 Carbon-Hydrogen bond	MET343 Pi-Sulfur VAL533 and LEU536 Alkyl LEU525, LEU346, ALA350, LEU349 and LEU387 Pi-alkyl
50	HIS524 Conventional H-bond GLY420 and GLY521 Carbon-Hydrogen bond	GLU353 Pi-Anion MET343 Pi-Sulfur LEU346, LEU387, LEU391, ALA350 and LEU525 Pi-alkyl
51	LEU346 Conventional H-bond	GLU353 Pi-Anion MET343 Pi-Sulfur LEU384, LEU387, MET388, LEU346, LEU349 and LEU391 Alkyl PHE404, MET343, MET421 and LEU525 Pi-alkyl
52	HIS524 Conventional H-bond GLY420 Carbon-Hydrogen bond	GLU353 Pi-Anion MET343 Pi-Sulfur LEU346, LEU349, LEU387, LEU391, ALA350 and LEU525 Pi-Alkyl
54	ARG394 and LEU346 Conventional H-bond	MET343 Pi-Sulfur MET421, LEU525, LEU346 and ALA350 Pi-Alkyl
55	ARG394 and LEU346 Conventional H-bond	MET343 Pi-Sulfur LEU346, LEU349 and LEU391 Alkyl PHE404, MET421, LEU525, LEU346 and ALA350 Pi-Alkyl
Tamoxifen	ASP351 Carbon-Hydrogen bond	MET388, MET421, ILE424, and LEU428 Alkyl ALA350, LEU525, MET421, LEU346 and LEU387 Pi-Alkyl

Figure 4. 3D and 2D representations of Compound 5 in the active site of the 3ERT receptor.

Figure 5. 3D and 2D representations of Compound 7 in the active site of the 3ERT receptor.

Figure 6. 3D and 2D representations of Compound 8 in the active site of the 3ERT receptor.

Figure 7. 3D and 2D representations of Compound 9 in the active site of the 3ERT receptor.

Figure 8. 3D and 2D representations of Compound 12 in the active site of the 3ERT receptor.

Figure 9. 3D and 2D representations of Compound 15 in the active site of the 3ERT receptor.

Figure 10. 3D and 2D representations of Compound 18 in the active site of the 3ERT receptor.

Figure 11. 3D and 2D representations of Compound 21 in the active site of the 3ERT receptor.

Figure 12. 3D and 2D representations of Compound 23 in the active site of the 3ERT receptor.

Figure 13. 3D and 2D representations of Compound 24 in the active site of the 3ERT receptor.

Figure 14. 3D and 2D representations of Compound 27 in the active site of the 3ERT receptor.

Figure 15. 3D and 2D representations of Compound 29 in the active site of the 3ERT receptor.

Figure 16. 3D and 2D representations of Compound 31 in the active site of the 3ERT receptor.

Figure 17. 3D and 2D representations of compound 50 in the binding site of the ER⁺ receptor.

Figure 18. 3D and 2D representations of compound 51 in the active site of the ER⁺ receptor.

Figure 19. 3D and 2D interactions of compound 52 in the binding pocket of the ER⁺ receptor.

Figure 20. 3D and 2D representations of Compound 54 in the active pocket of the ER⁺ receptor.

Figure 21. 3D and 2D interactions of compound 55 with the binding site of the ER⁺ receptor.

Figure 22. 3D and 2D representations of Tamoxifen in the active site of the 3ERT receptor.

Figure 23. RMSD values of the protein and ligand during 1 ns MD simulation.

Figure 24. RMSF values of the backbone protein.

Figure 25. RMSF values of the ligand-protein complex.

Figure 26. Radius of gyration of the ligand-protein complex during 1 ns dynamic simulation.

Figure 27. Ligand-protein contacts during 1 ns simulation studies.

Table 3. Predicted drug-likeness properties of the selected compounds

S/no	Molecular weight	HBA	HBD	mlogP	Synthetic accessibility	Bioavailability score	Lipinski violation	Drug likeness
3	442.51	6	3	2.28	3.16	0.55	0	YES
5	470.56	6	3	2.67	3.40	0.55	0	YES
7	495.57	6	3	2.42	3.33	0.55	0	YES
8	468.55	6	3	2.67	3.25	0.55	0	YES
9	482.57	6	3	2.87	3.36	0.55	0	YES
12	484.55	7	3	1.89	3.41	0.55	0	YES
15	497.59	7	3	2.08	3.55	0.55	0	YES
18	455.51	6	4	1.82	3.13	0.55	0	YES
21	483.56	6	4	2.22	3.37	0.55	0	YES
23	482.57	6	2	2.87	3.38	0.55	0	YES
24	481.55	6	4	2.22	3.22	0.55	0	YES
27	495.57	7	4	2.42	3.33	0.55	0	YES
29	525.64	7	1	2.47	3.80	0.55	1	YES
31	510.59	7	4	1.64	3.52	0.55	1	YES
50	370.36	5	2	1.7	3.19	0.55	0	YES
51	366.42	4	4	2.88	3.43	0.55	0	YES
52	369.38	4	4	2.27	3.35	0.55	0	YES
54	379.37	6	1	1.45	3.90	0.55	0	YES
55	393.4	6	1	1.26	4.00	0.55	0	YES

Table 4. Predicted ADMET properties of the selected compounds

S/no	Absorption Intestinal Human Absorption	Distribution logBB logPS		Metabolism Substrate Inhibitors CYP 2D6 3A4 1A2 2C19 2C9 2D6 3A4							Total clearance	AMES Toxicity
3	86.927	−1.291	−2.344	NO	NO	YES	YES	YES	YES	YES	0.547	NO
5	86.088	−1.393	−2.360	NO	NO	YES	YES	YES	NO	YES	0.667	NO
7	91.487	−1.417	−2.253	NO	NO	NO	YES	YES	NO	YES	0.837	NO
8	88.290	−1.238	−2.144	NO	YES	YES	YES	NO	NO	YES	0.810	NO
9	87.901	−1.260	−2.053	NO	YES	YES	YES	NO	NO	YES	0.763	NO
12	92.229	−1.333	−3.012	NO	YES	YES	YES	NO	NO	YES	0.806	NO
15	90.925	−1.383	−2.474	NO	YES	YES	YES	YES	NO	YES	0.459	NO
18	87.655	−1.259	−2.397	NO	NO	YES	YES	YES	NO	YES	0.442	NO
21	89.169	−1.361	−2.413	NO	NO	NO	YES	YES	NO	YES	0.603	NO
23	91.335	−1.259	−2.201	NO	YES	NO	NO	NO	NO	YES	0.845	NO
24	86.430	−1.396	−2.197	NO	NO	YES	YES	YES	NO	YES	0.801	YES
27	87.262	−1.418	−2.106	NO	NO	YES	YES	YES	NO	YES	0.755	YES
29	93.706	−1.339	−2.413	NO	YES	NO	YES	NO	NO	YES	0.648	NO
31	84.007	−1.351	−2.527	NO	YES	YES	YES	YES	NO	YES	0.387	NO
50	91.204	−0.174	−2.499	NO	YES	YES	NO	NO	NO	YES	0.370	NO
51	94.734	−0.179	−1.849	NO	YES	YES	YES	NO	NO	YES	0.442	YES
52	83.933	−0.998	−2.424	NO	YES	YES	YES	NO	NO	YES	0.278	YES
54	99.312	−0.417	−2.219	NO	YES	YES	YES	YES	NO	YES	0.045	YES
55	98.411	−0.390	−2.216	NO	YES	YES	YES	YES	NO	YES	0.076	YES