Molecular Docking Study: Application to the Epidermal Growth Factor Receptor ^†

Abstract

With the development of computer tools over the past 20 years, molecular modeling, and more precisely molecular docking (molecular docking), has very quickly entered the field of pharmaceutical research. Our work consists of studying the inhibition of the enzyme EGFR (1M17) involved in cancer with deferent inhibitors derived from quinazoline and quinoline by molecular docking. Ligands L_1 and L_2 are the best ligands for inhibiting the activity of 1M17 since they form a stable complex with this enzyme by better binding to the active site. The results obtained show that ligands L1 and L2 have weak interactions with the active site residue EGFR (1M17), which stabilize the complexes formed with these ligands, allow better binding at the level of the active site, and give an RMSD of L_1 [1.9563 Å] and of L_2 [1.2483 Å]. All the newly designed compounds passed the pharmacokinetic analysis (ADME–TOX) (adsorption, distribution, metabolism, excretion, and other physicochemical tests), passed the drug-likeness test, and also adhered to the Lipinski rule of five.

1. Introduction

Skin cancer ranks among the most common types of cancer worldwide, posing significant challenges in both diagnosis and treatment. The most prevalent non-melanoma skin cancers, basal cell carcinoma and squamous cell carcinoma, frequently develop due to extended exposure to ultraviolet light [1,2,3].

This research seeks to conduct a molecular docking analysis to discover potential drug target agents derived from quinazoline and quinoline [4]. These compounds are recognized for their anti-cancer properties, including their capacity to inhibit key pathways involved in cell proliferation and survival [5]. The focus is on the Epidermal Growth Factor Receptor (EGFR), a crucial element in skin cancer, to explore how these agents can interact with and inhibit the receptor’s activity [6].

Detailed insights for this docking study are provided by the crystal structure of the EGFR tyrosine kinase domain, as recorded in the Protein Data Bank (PDB) entry 1M17 (https://www.rcsb.org/ (accessed on 4 September 2024)). This structure, in complex with the inhibitor erlotinib [7], reveals the binding interactions and conformational changes within EGFR [6]. Utilizing these structural data, the research aims to identify and optimize quinazoline and quinoline derivatives to effective effectively target EGFR, potentially leading to enhanced therapeutic options for skin cancer patients [7,8,9].

Finally, to reduce the failure rate of drug candidates, the implementation of ADME (absorption, distribution, metabolism, and elimination)-Tox (toxicity) filters for chemo- therapies in any screening process gave good pharmacokinetic performance and bioavailability, as well as excellent results.

2. Materials and Methods

A series of 213 derivative compounds [10,11,12] of quinazoline and quinoline with reported biological activities IC₅₀ in µM was prepared using Marvin Sketch (https://www.chemaxon.com (accessed on 6 September 2024)), converted to 3D and optimized, and other software programs were used to find optimal high-affinity compounds, which were studied by molecular docking and ADME-T, and their EGFR inhibitory activities were tested with MOE [13].

3. Results and Discussion

3.1. Molecular Docking

The results of the molecular docking of quinazoline and quinoline derivatives indicate that the complexes formed by the ligands L1 (code S148), L2 (code S177), L3 (code S198), L4 (S140), L5 (S143), L6 (S138), L7 (S161), L8 (S150), L9 (S164), and L10 (S136) exhibit the lowest possible energy compared to other ligands, including the complex formed by the reference ligand in 1M17 (

Table 1. Docking score and interactions between compounds and 1M17 active sites.

No of Ligands	IC50 (µM)	S-Score (kcal mol)	RMSD (Å)	Bonds Between the Compounds Atoms and the Active Site Residues
				Compound Atoms	Receptor Atoms	Interaction Type	Distance (Å)
L1	0.016	−9.0419	1.9563	N10	OD2	H-donor	2.98
				S18	CA	H-acceptor	3.83
				N25	NZ	H-acceptor	3.71
L2	0.011	−9.0158	1.2483	CL69	OD2	H-donor	3.33
				CL70	O	H-donor	3.05
				N43	CA	H-acceptor	3.63
L3	0.015	−9.0054	1.6614	N12	NZ	H-acceptor	3.19
				6-ring	CD	pi-H	3.90
				6-ring	CD	pi-H	4.33
				6-ring	CA	pi-H	3.54
L4	0.030	−8.8247	1.4567	CL67	OD1	H-donor	3.09
				N12	OG1	H-acceptor	3.28
L5	0.031	−8.7421	1.5109	6-ring	CG1	pi-H	3.82
				6-ring	CD	pi-H	3.94
				6-ring	N	pi-H	4.00
L6	0.020	−8.6277	2.0115	N10	OD1	H-donor	3.51
				O23	OD2	H-donor	3.16
				N47	N	H-acceptor	3.47
				6-ring	CD1	pi-H	4.25
L7	0.024	−8.3984	1.9097	CL55	O	H-donor	3.05
L8	0.026	−8.3727	1.6572	N 24	N	H-acceptor	3.42
				6-ring	CB	pi-H	3.71
L9	0.007	−8.1837	1.7923	6-ring	CB	pi-H	3.74
				6-ring	CB	pi-H	4.65
L10	0.034	−8.1624	1.4415	6-ring	N	pi-H	4.05
L_Ref	0.020	−8.0480	1.4130	N44	N	H-acceptor	3.13

).

These results suggest that these ten ligands possess optimal values. Notably, the ligands L1 and L2 show the most promising inhibition of 1M17. Figure 1 demonstrates the 2D interactions of these ligands, highlighting how they form stable complexes with the enzyme by binding effectively to the active site.

3.2. Evaluation ADME-TOX

The ADME proprieties of the best compounds are summarized in

Table 2. ADMET features of best selected compounds.

Category			L_148	L_177	L_198	L_140	L_143	L_Ref
Physicochemical properties	Molecular weight (MW g/mol) < 500		614.16	590.50	494.38	465.30	467.92	393.4
	Heavy atoms		43	41	32	30	33	29
	Rotatable bonds		12	12	9	7	9	10
	H-bond acceptors < 10		6	6	5	5	6	6
	H-bond donors < 5		2	2	2	2	2	1
	TPSA 140 (Å2)		124.81	99.51	90.28	96.27	90.28	74.73
Drug-likeness	Lipinski violation		Yes	Yes	Yes	Yes	Yes	Yes
	Veber violation		No	No	Yes	No	Yes	Yes
	Ghose violation		No	No	No	Yes	Yes	Yes
	Muegge violations		No	No	Yes	No	Yes	Yes
	Egan violations		No	No	Yes	Yes	Yes	Yes
	Bioavailability		0.55	0.55	0.55	0.55	0.55	0.55
	Consensus log Po/w < 5		5.26	5.48	3.86	3.40	4.10	3.20
	Log S (ESOL)		−7.22	−7.22	−5.52	−5.24	−5.37	−4.11
Pharmacokinetics	GI absorption		Low	Low	High	High	High	High
	BBB permeability		No	No	No	No	No	Yes
	P-gp substrate		Yes	Yes	No	No	No	No
	CYP inhibitor	1A2	No	No	No	Yes	No	Yes
		2C19	Yes	Yes	Yes	Yes	Yes	Yes
		2C9	Yes	No	Yes	Yes	Yes	Yes
		2D6	No	Yes	Yes	Yes	Yes	Yes
		3A4	No	No	Yes	Yes	Yes	Yes
	Log Kp (cm/s)		−5.55	−5.27	−6.12	−6.23	−5.93	−6.35
Toxicity		Oral rat acute toxicity LD50 (mol/kg)	2.426	3.033	2.531	2.386	2.641	2 368
		Hepatotoxicity	Inactive	Inactive	Inactive	Inactive	Inactive	active
		Carcinogenicity	Inactive	Inactive	Inactive	Inactive	Inactive	Inactive
		Cytotoxicity	Inactive	Inactive	Inactive	Inactive	Inactive	active
		Mutagenicity	Active	Inactive	Inactive	Inactive	Inactive	active
		Immunotoxicity	Inactive	Inactive	active	Active	active	active
		Ames toxicity	No	No	No	No	No	No
		Skin sensitization	No	No	No	No	No	No
		hERG I inhibition	No	No	No	No	No	No
		hERG II inhibition	Yes	Yes	Yes	Yes	Yes	Yes

to ensure compliance with the Lipinski, Veber, and Egan rules, which describe various physicochemical properties of the calculated ligand molecules. All these molecules follow the rules of Lipinski, Ghose, Veber, and Egan. Finally, toxicity prediction results indicated that none of the compounds was toxic. We can confirm that these compounds do not cause oral bioavailability issues, have good properties compared to drugs for both targets (natural ligands), and have the potential to be selected as oral drugs against this disease.

4. Conclusions

In the present study, we have concentrated on the molecular interactions between Epidermal Growth Factor Receptor (EGFR) and quinazoline and quinoline derivatives, exploring their potential as future inhibitors. Using molecular docking techniques, we aimed to better understand the mechanism of inhibition of these enzymes. Our findings indicate that the values obtained are optimal for all ten selected ligands. Notably, ligands L1 and L2 stand out as the most effective inhibitors of 1M17 activity. These ligands form stable complexes with the enzyme, achieving superior binding to the active site compared to other ligands. This enhanced binding affinity suggests that L148 and L177 could serve as promising candidates for the development of new therapeutic agents targeting EGFR.