Molecular docking and dynamics simulations of bioactive terpenes from Catharanthus roseus essential oil targeting breast cancer

Nayila, Iffat; Sharif, Sumaira; Ullah, Riaz; Alotaibi, Amal; Shah, Syed Ali Raza; Bibi, Maira; Hameed, Saima; Iqbal, Aasma

doi:10.1515/chem-2025-0169

Figures & Tables

GC-MS chromatogram of Catharanthus roseus EO.

2D interaction of terpenes with surrounding amino acids of estrogen receptor: (a) ER-gamma-terpinene, (b) ER-terpinen-4-ol, (c) ER-terpinolene, (d) ER-limonene, (e) ER-2-carene, and (f) ER-incensole acetate.

2D interaction of terpenes with surrounding amino acids of progesterone receptor: (a) PR-gamma-terpinene, (b) PR-terpinen-4-ol, (c) PR-terpinolene, (d) PR-limonene, (e) PR-2-carene, and (f) PR-incensole acetate.

2D interaction of terpenes with surrounding amino acids of HER2 receptor: (a) HER2-gamma-terpinene, (b) HER2-terpinen-4-ol, (c) HER2-terpinolene, (d) HER2-limonene, (e) HER2-2-carene, and (f) HER2 - incensole acetate.

3D images of selected terpenes with interacting amino acid residues: (a) ER-gamma terpinene, (b) ER-terpinen-4-ol, (c) ER-terpinolene, (d) ER-limonene, (e) ER-2-carene, (f) ER-incensole acetate, (g) PR-gamma-terpinene, (h) PR-terpinen-4-ol, (i) PR-terpinolene, (j) PR-limonene, (k) ER-2-carene, (l) ER-incensole acetate, (m) HER2-gamma-terpinene, (n) HER2-terpinen-4-ol, (o) HER2-terpinolene, (p) HER2-limonene, (q) ER-2-carene, and (r) ER-incensole acetate.

Two-dimensional LigPlot demonstration of top docked ligands interacting with amino acid residues of receptor protein: Interaction of gamma terpinene with ER, interaction of limonene with ER, interaction of gamma terpinene with incensole acetate, interaction of gamma terpinen with HER2, and interaction of terpinen-4-ol with HER2. Red dotted lines specify the hydrophobic interactions while green residues denote the hydrogen bonds involved in the interaction.

The radar-like representation of the drug-likeness of the tested terpene compounds: (a) gamma terpinene, (b) terpinen-4-ol, (c) terpinolene, (d) limonene, (e) 2-carene, and (F) incensole acetate. LIPO (Lipophility): −0.5 < XLOGP3 < +5.0. SIZE: 150 g/mol < MV < 500 g/mol. POLAR (Polarity): 20 Å2 < TPSA < 130 Å2.

Boiled-egg model of selected terpenes for brain penetration and absorption in the GI tract. The BBB is thought to be passively crossed by molecules in the yolk of boiled eggs.

RMSD plot vs time (ns): (a) RMSD of estrogen with gamma terpinene (7,461) and estrogen with limonene (22,311) and (b) RMSD of HER2 with gamma terpinene (7,461) and HER2 with terpinen-4-ol (5,325,830).

(a) RMSF of ER with gamma terpinene (7,461) and ER with limonene (22,311) and (b) RMSF values of HER2 with gamma terpinene (7,461) and HER2 with terpinen-4-ol (5,325,830).

Rg vs time (ns) plot: (a) ER with gamma terpinen (7,461), ER with limonene (22,311). (b) HER2 with gamma terpinen (7,461) and HER2 with terpinen-4-ol (5,325,830).

PCA analysis of ER docked trajectories with gamma terpinene (a) and limonene (b). The corresponding eigen value’s total % of mean square displacements is used to calculate the logged deviations in the residue location for each direction. The steady color transition from blue to white to red indicates periodic jumps between the structural conformations derived from simulated trajectories.

PCA analysis of HER2 receptor docked simulated MD trajectories with gamma terpinene (a) and terpinen-4-ol (b). The corresponding value of mean square displacements is used to calculate the logged deviations in the residue location for each direction.

Dynamic cross correlation for ER complexed with (a) gamma terpinene and (b) limonene. HER2 receptor complex with (c) gamma terpinene and (d) terpinen-4-ol. (Residues are numbered from 1 to 200 as in crystal structure). During 100 ns simulation interval, the crusade of residues displays dynamic positive correlation in cyan blue color and a negative correlation in cyan pink color.

(a) MTT test for cytotoxicity and (b) IC50 concentration of selected terpene compounds. P values indicated as *(0.05), **(0.001), and ***(0.0001).

ADMET properties of terpenes phytocompounds reported in C_ roseus EO

ADMET parameters	Gamma terpinene	Terpinen-4-ol	Terpinolene	Limonene	2-Carene	Incensole acetate
Aq. solubility (mg/mol)	4.33	2.54	3.41	3.31	4.51	4.65
BBB penetration	Yes	Yes	Yes	Yes	Yes	Yes
Bioavailability	0.55	0.55	0.55	0.55	0.55	0.55
VDss	Moderate	Low	Moderate	High	High	Low
Lipinski violation	0	0	0	0	1	1
Gastrointestinal (GI) absorption	Low	High	Low	Low	Low	Low
CYP3A4 inhibitor	No	No	No	No	No	No
Log S (ESOL)mg/mol	4.33	−2.78	−3.5	−3.5	−2.48	−3.26
Bioavailability	0.55	0.52	0.55	0.55	0.55	0.56
CNS permeability (log PS)	−2.762	−2.9883	−3.542	−2.994	−3.775	−3.551
CYP1A2 inhibitor	No	No	No	No	No	No
CYP2C19 inhibitor	No	No	No	No	No	No
Total clearance (log mL/min/kg)	1.343	1.247	1.225	0.433	0.552	0.732
Renal OCT2 substrate	No	No	No	No	No	No

Assessment of the toxicity properties of terpenes phytocompounds reported in C_ roseus EO

Toxicity parameters	Gamma terpinene	Terpinen-4-ol	Terpinolene	Limonene	2-carene	Incensole acetate
AMES toxicity	Nontoxic	Nontoxic	Nontoxic	Nontoxic	Nontoxic	Nontoxic
Hepatotoxicity	No	No	No	No	No	Yes
Carcinogen	Noncarcinogen	Noncarcinogen	Noncarcinogen	Noncarcinogen	Noncarcinogen	Noncarcinogen
Biodegradation	Not readily biodegradable	Not readily biodegradable	Not readily biodegradable	Not readily biodegradable	Not readily biodegradable	Not readily biodegradable
hERG-1 inhibitor	Weak inhibitor	Weak inhibitor	Weak inhibitor	Weak inhibitor	Weak inhibitor	Weak inhibitor
HIA	HIA+	HIA+	HIA+	HIA+	HIA+	HIA+

Molecular interaction profile of breast cancer receptors with terpene hit phytocompounds identified from C_ roseus EO

Receptor	Compound	Vander Waals interaction	No. of H bonds	H-bond length (Å)	Hydrogen bond residues	Pi–Pi interaction	Docking score (kcal/mol)
Estrogen	Gamma-terpinene	THR227, GLY 259	4	1.722	LYS 197, GLY 259, TYR 193, LEU 173	PHE 229, TRP 53	−6.9
				1.451
				2.311
				1.321
	Terpinen-4-ol	LYS 197, ARG 130, GLY 259, PHY 229	1	1.97	TYR 193	TRP 53	−6.3
	Terpinolene	LEU 428, GLY 321	2	2.711	MET 38, LEU 391, ALA 35, GLY 390	LEU 428, MET 388	−6.1
	Terpinolene	LEU 428, GLY 321	2	2.177	MET 38, LEU 391, ALA 35, GLY 390	LEU 428, MET 388	−6.1
	Limonene	LUE 349, ARG394, ALA 350	1	2.19	ALA350, LEU391, GLY390, ARG 394	MET 388, LEU 387, LEU 391	−6.5
	2-Carene	TRP 383, ARG 394, LEU 349	1	1.069	ALA 351, TRP 383, GLU 353	ALA 350, LEU 387	−6.3
	Incensole -acetate	LEU384, MET388, PHE 404, GLY 521	3	2.196	ALA 354, MET 388, LEU 375	—	−8.0
				2.160
				2.178
Progesterone	Gamma-terpinene	LEU 797, TYR890, CYS 891, PHE 905	2	1.875	ASN719, PHE 895	PHE 794, LEU715, MET 801	−6.2
	Gamma-terpinene	LEU 797, TYR890, CYS 891, PHE 905	2	1.421	ASN719, PHE 895	PHE 794, LEU715, MET 801	−6.2
	Terpinen-4-ol	GLU723, LEU726, ASN719, GLU 721	4	1.919	LEU726, GLY 722	MET 759	−6.3
	Terpinolene	ASN719, PHE 794, LEU 715	1	1.8997	CYS 891	TYR890, LEU887, PHE 905, MET 801	−6.3
	Limonene	PHE 778, LEU 718, ASN719, MET 801	5	2.54	ASN719, MET801, CYS891, THR894, PHE 905	LEU715, PHE 905, TYR890, VAL 903	−6.2
	2-Carene	LEU 718, THR 894	—	—	LEU 715, ASN 719, TAR 894	VAL 903	−6.3
	Incensole -acetate	MET 759, LEU 887, TYR 890	3	1.91	GLY 722, GLY 724, CYS 891	—	−4.6
				2.46
				2.08
HER2	Gamma terpinene	LEU 866, ARG 868	4	1.849	ALA730, LYS 853, GLY804, ASP 863	LEU852, VAL734, LYS 753	−6.8
				1.613
				2.088
	Terpinen-4-ol	—	4	1.770	SER 783, MET774, LYS 753, THR 798	VAL734 LYS 753	−7.1
	Terpinen-4-ol	—	4	2.652	SER 783, MET774, LYS 753, THR 798	VAL734 LYS 753	−7.1
	Terpinolene	THR862, MET774, ASP 863, GLU770, SER 783	3	1.797	ALA730, LYS 753, THR798, ASP 863	VAL734, LEU796, PHE 864, ALA 751	−6.6
	Terpinolene	THR862, MET774, ASP 863, GLU770, SER 783	3	2.058	ALA730, LYS 753, THR798, ASP 863	VAL734, LEU796, PHE 864, ALA 751	−6.6
	Limonene	THR798, ASP 863, THR 862	3	1.794	ALA730, LYS 753, ASP 863	ALA 751, VAL 734	−6.6
	Limonene	THR798, ASP 863, THR 862	3	1.849	ALA730, LYS 753, ASP 863	ALA 751, VAL 734	−6.6
	2-Carene	SER 783, THR798, ASP 863, LYS 753	4	1.613	LYS 753, SER 783, MET 774, ASP 613	PHE 864, MET 774, LEU 785	−6.6
				1.770
				2.435
				1.7842
	Incensole -acetate	—	4	1.797	ALA 730, LYS 753, LEU 806	—	−3.4
				1.746
				2.058

Molecular docking and dynamics simulations of bioactive terpenes from Catharanthus roseus essential oil targeting breast cancer

Figures & Tables

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ADMET properties of terpenes phytocompounds reported in C_ roseus EO

Assessment of the toxicity properties of terpenes phytocompounds reported in C_ roseus EO

Molecular interaction profile of breast cancer receptors with terpene hit phytocompounds identified from C_ roseus EO

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