3D-QSAR, molecular docking, ADMET, simulation dynamic, and retrosynthesis studies on new styrylquinolines derivatives against breast cancer

EL-Mernissi, Reda; Alaqarbeh, Marwa; Khaldan, Ayoub; Kara, Mohammed; Al kamaly, Omkulthom; Alnakhli, Anwar M.; Lakhlifi, Tahar; Sbai, Abdelouahid; Ajana, Mohammed Aziz; Bouachrine, Mohammed

doi:10.1515/chem-2024-0041

Figures & Tables

Structure of styrylquinoline derivatives used.

Graphical representation of the observed and predicted activity of training and test sets for CoMSIA models.

Contour maps of CoMSIA analysis: (a) steric field, and (b) electrostatic field.

Contour maps of CoMSIA: (a) HBD field, (b) hydrophobic field, and (c) HBA field.

Re-docking pose with the RMSD value of 1.388 Å (green = original, orange = docked).

RMSD graphs of the complex, protein (Tubulin), and ligands (M1, M2) according to the simulation.

Flexibilities of the protein backbones examined by RMSF values.

(a) and (b) Hydrogen bonds of complex (Tubulin–PredM1) and (Tubulin–PredM2), respectively.

(Tubulin–PredM1) (a) and (Tubulin–PredM1) (b) R
g of the complexes during 100 ns MD simulation. — (Tubulin–PredM1) (a) and (Tubulin–PredM1) (b) R g of the complexes during 100 ns MD simulation.

SASA for 100 ns of the simulations. (a) and (b) represent Tubulin–PredM1 and Tubulin–PredM2, respectively.

The different stages of the prepared compound M1.

Williams plot to evaluate the applicability domain of the model (h* = 0.53 and residual limits = ±2).

PIC50 values of studied compounds

N°	X ₁	pIC₅₀	N°	X ₁	pIC₅₀
1*		5.06	23	—	5.59
2	—	5.12	24	—	4.12
3	—	5.30	25	—	5.02
4*	—	5.05	26*	—	5.02
5	—	4.62	27		5.27
6*	—	4.67	28	—	5.35
7	—	4.64	29	—	5.65
8*		5.16	30	—	5.50
9	—	5.27	31	—	4.23
10	—	5.51	32	—	4.31
11*	—	5.19	33	—	4.55
12	—	4.54	34		5.26
13	—	4.85	35*	—	5.42
14	—	4.57	36	—	5.39
15		5.15	37	—	5.29
16	—	5.47	38	—	4.48
17	—	5.72	39
5.08
18	—	5.36	40	—	5.75
19	—	4.65	41	—	5.61
20		5.62	42	—	5.24
21	—	5.73	43	—	4.96
22	—	5.95

Newly designed molecules and their predicted pIC50

N°	Predicted pIC₅₀	N°	Predicted pIC₅₀
22	5.80	M3	6.42
M1	6.76	M4	6.14
M2	6.65

Result of the Y-randomization test

Iteration	CoMSIA		Iteration	CoMSIA
	q Yrand 2 {q}_{\text{Yrand}}^{2}	r Yrand 2 {r}_{\text{Yrand}}^{2}		q Yrand 2 {q}_{\text{Yrand}}^{2}	r Yrand 2 {r}_{\text{Yrand}}^{2}
1	0.234	0.367	4	0.345	0.356
2	0.453	0.543	5	−0.052	0.121
3	−0.234	0.053	6	0.123	0.321

2D view of the binding conformation for the newly designed compounds (M1, M2, M3, and M4) and compound 22 with the target tubulin–colchicine complex (PDB ID: 4O2B)

N°	2D view	N°	2D view
22		M1
STRM2		M3
M4

Reactions for the synthesis of compound M1

Electronic descriptors for the proposed compounds

N°	Global properties (eV)
	E _LUMO	E _HOMO	µ	η \hspace{0.25em}\eta	χ	ω \omega	∆E _gap
M1	−2.3886	−5.5268	−3.9577	1.5610	3.9577	4.7436	3.1382
M2	−2.1840	−5.2444	−3.7142	1.5302	3.7142	4.5076	3.0604
M3	−2.4756	−5.2085	−3.8420	1.3664	3.8420	5.4014	2.7329
M4	−2.4337	−5.2403	−3.8370	1.4033	3.8370	5.2456	2.8066
22	−2.1739	−5.5301	−3.8520	1.6781	3.8520	4.4210	3.3562

ADMET prediction of the most potent (C22) and the newly designed

Model		Compounds
		22	M1	M2	M3	M4
(A)
Intestinal absorption (human)		83.90	89.95	98.42	86.70	87.23
(D)
VDss (human)		0.35	0. 46	0. 49	0. 56	0. 52
BBB (logBB)		−0.984	−1.08	−1.41	−1.28	−1.45
(M)
Inhibition (CYP)	2C19	+	+	+	+	+
	2D6	−	−	−	—	−
	3A4	+	+	+	+	+
	2C9	+	+	+	+	+
	1A2	−	−	−	−	−
Substrate (CYP)	3A4	+	+	+	+	+
	2D6	−	−	−	−	−
(E)
Clearance		0.62	0.40	0.45	0.65	0.66
(T)
AMES toxicity		−	−	−	−	−

Binding free energies of predicted compounds (kJ/mol)

		Ligands
Energy (kJ/mol)		M1	M2
ΔE _MM	Van der Waal	−151.658 ±38.652	−187.563±32.693
ΔE _MM	Electrostatic	−29.702 ± 41.002	−51.128 ± 30.186
ΔG _Sol	Polar solvation	98.050 ± 33.839	152.559 ± 68.591
ΔG _Sol	ΔG _SASA	−18.464 ± 3.421	−22.222 ± 3.487
Binding (ΔG _bind)		−101.775 ± 26.749	−108.355 ± 77.540

The results obtained

Model	R ²	Q ²	F	S _CV	r ext 2 {r}_{\text{ext}}^{2}	N	Fraction
Model	R ²	Q ²	F	S _CV	r ext 2 {r}_{\text{ext}}^{2}	N	Ster	Acc	Elec	Hyd	Don
CoMSIA	0.97	0.84	224.65	0.09	0.91	5	0.06	0.54	0.09	0.20	0.11

Experimental and predicted values

N°	pIC₅₀	CoMSIA predicted	N°	pIC₅₀	CoMSIA predicted
1*	5.06	5.01	23	5.59	5.75
2	5.12	5.07	24	4.12	4.4
3	5.30	5.25	25	5.02	5.22
4*	5.05	5.15	26*	5.02	5.15
5	4.62	4.86	27	5.27	5.12
6*	4.67	4.79	28	5.35	5.45
7	4.64	4.74	29	5.65	5.62
8*	5.16	5.20	30	5.50	5.63
9	5.27	5.18	31	4.23	4.50
10	5.51	5.47	32	4.31	4.49
11*	5.19	5.08	33	4.55	4.85
12	4.54	4.81	34	5.26	5.27
13	4.85	4.91	35*	5.42	5.37
14	4.57	4.70	36	5.39	5.43
15	5.15	5.20	37	5.29	5.42
16	5.47	5.40	38	4.48	4.71
17*	5.72	5.60	39	5.08	5.33
18	5.36	5.48	40	5.75	5.62
19	4.65	4.76	41	5.61	5.75
20	5.62	5.72	42	5.24	5.13
21	5.73	5.65	43	4.96	5.01
22	5.95	5.85

Interaction types and total score of the newly designed compounds (M1, M2, M3, and M4) and compound 22 with the target tubulin–colchicine complex

N°	Types of interactions			Total score
	Carbon H-bond, Pi-DHB, conventional hydrogen bond	Pi-sigma, amide-Pi stacked, Pi-sulfur, Pi-cation	Pi-alkyl, alkyl
22	Asn349, Asn350	Asn258	Leu248, Cys241	3.45
M1	Asn167, Asn258, Tyr202, Ala317, Lys352, Thr353, Ala354	Leu242, Val238, Leu255, Lys254	Leu252, Ala250, Leu255, Ala354	6.53
M2	Gly237, Val238 ,Lys352 , Asn258	Lys254	Leu255, Cys241, Ile318, Ala250, Lys352	5.74
M3	Gln247, Asn249, Asn350, VaL238	Leu248, Met259	Ala316, Gys241, Leu248	4.43
M4	Thr353, Gln247, Asp251	Leu255, Lys254	Ala250, Lys352	3.67

3D-QSAR, molecular docking, ADMET, simulation dynamic, and retrosynthesis studies on new styrylquinolines derivatives against breast cancer

Figures & Tables

Figure 1

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Figure 4

Figure 5

Figure 6

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Figure 11

Scheme 1

Figure 12

PIC50 values of studied compounds

Newly designed molecules and their predicted pIC50

Result of the Y-randomization test

2D view of the binding conformation for the newly designed compounds (M1, M2, M3, and M4) and compound 22 with the target tubulin–colchicine complex (PDB ID: 4O2B)

Reactions for the synthesis of compound M1

Electronic descriptors for the proposed compounds

ADMET prediction of the most potent (C22) and the newly designed

Binding free energies of predicted compounds (kJ/mol)

The results obtained

Experimental and predicted values

Interaction types and total score of the newly designed compounds (M1, M2, M3, and M4) and compound 22 with the target tubulin–colchicine complex

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