Ginger components as new leads for the design and development of novel multi-targeted anti-Alzheimer’s drugs: a computational investigation

Figures & data

Figure 1 Chemical structure of potential bioactive phytochemicals from Zingiber officinale.

Abbreviation: Ac, acetyl.

Table 1 Various mechanisms associated with ginger

Serial number	Ginger compound or extract	Mechanisms of action	Reference
1	6-Shogaol	Inhibition of lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX) gene expression in macrophages	^Citation14
2	6-Shogaol	Inhibition of nitric oxide (NO) and the expression of iNOS induced by LPS	^Citation17
3	6-Shogaol	Neuroprotective effects in vivo in transient global ischemia via the inhibition of microglia	^Citation17
4	6-Shogaol	Protects neurons by increasing acetyltransferase and choline transport expression through a brain-derived neurotrophic factor escalation	^Citation34
5	6-Gingerol	Inhibits the production of proinflammatory cytokines in murine peritoneal macrophage	^Citation16
6	[6]-Gingerol	Inhibits COX-2 expression by blocking the activation of p38 mitogen-activated protein (MAP) kinase and NF-κB in phorbol ester-stimulated mouse skin	^Citation40
7	Gingerol	Attenuates β-amyloid-induced oxidative cell death	^Citation19
8	Zerumbone	Inhibitors of acetylcholinesterase (anti-AChE)	^Citation33
9	Zingerone	Acts as an antioxidant by inhibiting the formation of peroxynitrite (ONOO)	^Citation35
10	Zingerone	Increases superoxide dismutase activity and scavenges superoxide radical	^Citation36
11	Gingerols and diarylheptanoids	Inhibits prostaglandin and leukotriene biosynthesis	^Citation37
12	Extract of Zingiber officinale	Inhibited the production of NO and proinflammatory cytokines in LPS-stimulated BV-2 microglial cells via the NF-κB pathway	^Citation15
13	Extract of Zingiber officinale	Improves memory impairment in focal cerebral ischemic rats and mitigates brain damage	^Citation38
14	Extract of Zingiber officinale	Scavenges free radicals in quinic acid-induced lipid peroxidation	^Citation39
15	Extract of Zingiber officinale	Ginger varieties inhibit acetylcholinesterase activities in vitro with the white ginger causing higher AChE inhibition than the red ginger	^Citation21
16	Extract of Zingiber officinale	The authors indicated that ginger hexane extract significantly inhibited the excessive production of NO, prostaglandin E2, TNF-α, and IL-1β in LPS-stimulated BV-2 cells	^Citation32

Abbreviation: NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells.

Table 2 Protein targets with anti-Alzheimer’s effect or target enzymes of drug design selected for docking studies

S. no	Name of the targets	PDB code	Experimental		Docking predicted
			Ki a	pKi	Ki a	pKi
1	Acetylcholinesterase (AChE)	4EY5^Citation50	0.008^Citation51	7.62	0.0154	7.81
2	Butyrylcholinesterase (BuChE)	4B0P^Citation52	44^Citation52	4.36	40.01	4.39
3	β-Site amyloid precursor protein cleaving enzyme (BACE-1)	4DJU^Citation53	3.6^Citation53	5.44	2.49	5.60
4	Glycogen-synthase-kinase-3β (GSK-3β)	1Q5K^Citation54	0.77^Citation55	6.11	0.996	6.00
5	TNF-α converting enzyme (TACE)	2FV5^Citation56	0.00056^Citation57	9.25	0.000448	9.35
6	c-Jun N-terminal kinase (JNK)	3G9N^Citation58	1.8^Citation58	5.74	0.5929	6.23
7	Nitric oxide synthase (NOS)	1QWC^Citation59	7.3^Citation60	5.14	3.43	5.46
8	Human carboxylesterase (hCE-1)	1MX1^Citation61	100^Citation61	4.00	10.69	4.97
9	N-methyl-D-aspartate (NMDA)	1PBQ^Citation62	0.54^Citation62	6.27	3.69	5.43
10	Cyclooxygenase-1 (COX-1)	1EQG^Citation63	9^Citation64	5.05	6.76	5.17
11	Cyclooxygenase-2 (COX-2)	3QMO^Citation65	0.92^Citation66	6.04	0.2928	6.53
12	Phosphodiesterase-5 (PD-5)	1UDT^Citation67	0.0018^Citation68	8.74	0.00192	8.72
13	Angiotensin converting enzyme (ACE)	3BKL^Citation69	0.679^Citation69	6.17	0.5312	6.27

Note:

a Data given in μM.

Abbreviations: PDB, protein data bank; K_i, inhibition constant; pK_i, negative logarithm of inhibition constant.

Table 3 Results obtained after docking of ginger compounds (1–12) with various protein targets

PDB code	Docking results	Ginger compounds
		1	2	3	4	5	6	7	8	9	10	11	12
4EY5	ΔGb a	−8.51	−9.25	−6.21	−8.14	−9.07	−9.92	−9.66	−10.89	−8.67	−9.48	−9.21	−8.68
	Ki b	0.58	0.17	28.19	1.08	0.23	53.35f	82.36f	10.38f	0.44	0.11	0.18	0.44
	RMSDc	2.33	4.22	1.01	1.89	4.04	4.22	4.71	4.07	4.23	3.58	1.69	2.25
	HBd	1	1	1	3	2	2	3	5	2	4	2	5
	π-inte	–	–	–	2	2	–	2	2	5	5	2	–
2FV5	ΔGb a	−8.60	−8.85	−6.80	−8.39	−8.66	−9.30	−9.47	−8.92	−8.63	−9.68	−9.84	−9.20
	Ki b	0.49	0.33	10.43	0.71	0.45	0.15	0.11	0.29	0.47	80.25f	61.76f	0.18
	RMSDc	0.67	2.25	4.73	1.56	0.98	1.79	1.69	2.33	2.32	2.35	1.85	2.26
	HBd	2	2	2	2	3	3	2	4	4	5	6	4
	π-inte	–	1	–	1	–	–	–	–	–	–	–	–
4B0P	ΔGb a	−7.78	−8.36	−6.15	−7.55	−7.82	−8.38	−8.81	−8.10	−8.26	−8.73	−9.72	−9.70
	Ki b	1.99	0.74	31.08	2.93	1.85	0.72	0.35	1.15	0.88	0.40	74.44f	77.61f
	RMSDc	3.12	3.61	5.36	2.87	3.37	1.41	2.22	1.78	1.63	1.67	1.54	1.24
	HBd	–	1	1	1	–	2	–	–	1	1	1	–
	π-inte	–	1	–	–	–	2	–	1	2	1	2	3
1QWC	ΔGb a	−7.99	−8.12	−6.36	−7.42	−6.89	−7.59	−8.11	−7.92	−7.82	−6.98	−9.61	−9.02
	Ki b	1.39	1.12	21.93	3.66	8.88	2.73	1.14	1.57	1.86	7.63	90.09f	0.25
	RMSDc	7.83	8.22	8.41	7.23	6.67	6.60	6.08	5.80	6.85	7.28	7.21	7.62
	HBd	1	–	1	1	–	1	1	1	2	6	3	2
	π-inte	2	3	2	2	3	3	–	2	3	3	–	5
1UDT	ΔGb a	−7.79	−7.97	−5.81	−7.13	−6.94	−7.54	−8.40	−9.21	−7.61	−7.27	−9.12	−8.60
	Ki b	1.96	1.45	55.27	5.98	8.13	2.99	0.69	0.18	2.64	4.69	0.21	0.49
	RMSDc	3.19	4.17	5.51	3.01	1.33	1.65	5.58	2.14	5.76	5.56	2.48	1.38
	HBd	2	1	1	2	1	2	1	4	4	5	3	4
	π-inte	1	–	–	1	–	–	–	1	1	–	–	–
1PBQ	ΔGb a	−7.25	−7.15	−5.51	−6.85	−7.30	−8.30	−7.94	−7.25	−7.77	−7.97	−9.13	−9.21
	Ki b	4.85	5.77	90.94	9.52	4.45	0.83	1.51	4.82	2.01	1.43	0.20	0.18
	RMSDc	4.69	5.14	0.63	4.13	4.50	3.87	4.30	2.39	2.90	3.69	3.93	3.34
	HBd	–	–	3	–	–	–	–	–	1	–	2	3
	π-inte	–	–	1	–	1	1	1	2	–	–	–	1
3QMO	ΔGb a	−8.38	−8.13	−6.02	−7.79	−8.34	−8.02	−8.13	−6.69	−7.57	−7.86	−7.85	−9.43
	Ki b	0.72	1.09	38.96	1.95	0.77	1.31	1.10	12.54	2.83	1.72	1.76	0.12
	RMSDc	2.80	2.32	2.55	2.10	2.11	2.33	4.25	1.64	2.17	1.95	0.74	2.07
	HBd	1	1	1	2	1	2	2	5	4	4	4	4
	π-inte	–	–	–	–	–	–	–	–	–	–	1	1
1MX1	ΔGb a	−7.12	−6.53	−5.30	−6.20	−6.89	−8.00	−8.13	−6.91	−7.77	−8.03	−8.34	−7.72
	Ki b	6.00	16.31	0.13g	28.43	8.89	1.37	1.10	8.59	2.00	1.31	0.77	2.20
	RMSDc	1.76	3.45	3.57	1.92	2.35	6.05	1.71	3.50	2.05	5.32	3.63	1.76
	HBd	1	1	1	4	4	3	2	–	3	4	3	2
	π-inte	–	–	–	–	–	–	–	1	–	–	–	–
1EQG	ΔGb a	−7.31	−7.55	−5.83	−7.39	−8.23	−7.70	−7.97	−8.07	−7.22	−7.37	−8.36	−8.80
	Ki b	4.35	2.92	53.68	3.80	0.93	2.29	1.44	1.22	5.08	3.94	0.75	0.35
	RMSDc	1.83	2.25	3.96	0.85	3.64	1.12	1.99	1.95	3.73	1.73	1.31	1.57
	HBd	1	1	1	5	2	2	1	2	5	2	5	3
	π-inte	–	–	–	–	–	–	–	–	1	–	–	–
1Q5K	ΔGb a	−7.14	−6.33	−5.50	−6.17	−5.52	−7.63	−7.28	−6.36	−6.43	−6.43	−7.26	−6.77
	Ki b	5.82	23.01	93.21	30.23	89.54	2.56	4.63	21.80	19.19	19.51	4.79	10.91
	RMSDc	1.92	1.27	3.15	0.90	2.39	1.40	1.77	3.40	2.21	1.10	1.24	3.05
	HBd	2	–	1	1	2	3	2	4	5	2	4	4
	π-inte	–	1	1	1	–	–	1	–	–	1	1	–
4DJU	ΔGb a	−6.39	−6.26	−5.09	−5.72	−5.75	−7.49	−7.49	−6.06	−5.73	−6.44	−6.86	−7.35
	Ki b	20.88	25.58	0.19g	64.39	60.84	3.23	3.24	35.84	62.83	18.91	9.35	4.12
	RMSDc	3.18	2.39	5.18	3.92	1.75	1.77	1.36	0.76	4.40	1.66	3.35	4.83
	HBd	2	1	2	2	2	2	4	2	5	3	5	4
	π-inte	–	–	–	–	–	1	–	2	–	–	–	–
3BKL	ΔGb a	−5.68	−6.94	−4.71	−5.42	−5.82	−6.56	−7.04	−5.63	−6.30	−6.78	−7.47	−7.56
	Ki b	68.88	8.20	0.35g	0.11g	54.29	15.65	6.96	75.02	24.15	10.70	3.37	2.85
	RMSDc	1.83	1.79	4.83	2.09	1.15	1.63	4.29	3.44	3.70	2.78	5.35	5.01
	HBd	1	3	2	2	3	2	3	4	3	5	6	8
	π-inte	–	–	–	–	1	–	–	2	–	–	–	–
3G9N	ΔGb a	−6.82	−6.73	−5.61	−6.56	−5.94	−6.78	−6.86	−6.40	−6.46	−6.79	−6.97	−7.33
	Ki b	9.99	11.65	77.76	15.56	44.44	10.72	9.31	20.32	18.44	10.53	7.78	4.25
	RMSDc	0.79	2.10	4.07	2.30	0.42	1.61	0.52	2.35	3.07	0.93	3.40	2.07
	HBd	1	1	1	2	1	2	3	2	3	3	3	3
	π-inte	–	–	–	–	–	–	–	–	–	–	–	–

Notes:

a Binding free energy (kcal/mol)

b docking predicted inhibition constant in μM

c root mean square deviation in Å

d number of hydrogen bond interactions

e number of π-interactions

f data presented in mM

g data presented in nM.

Abbreviations: PDB, protein data bank; RMSD, root mean square deviation; HB, hydrogen bond; K_i, inhibition constant.

Figure 2 The validation of accuracy and performance of AutoDock 4.2.

Notes: The native and docked-ligands of AChE, blue and sky blue (A); TACE, pink and sky blue (B); BuChE, dark magenta and dark orange (C); NOS, light steel blue and purple (D); PDE-5, gold and pale green (E); NMDA, magenta and turquoise (F); COX-2, red and green (G); hCE-1, medium turquoise and khaki (H); COX-1, brown and fuchsia (I); GSK-3, blue and green (J); BACE-1, red and medium sea green (K); ACE, maroon and green (L); JNK, orange and sky blue (M) respectively.
Abbreviations: AChE, acetylcholinesterase; TACE, TNF-α converting enzyme; BuChE, butyrylcholinesterase; NOS, nitric oxide synthase; PDE-5, phosphodiesterase-5; NMDA, N-methyl-D-aspartate; COX, cyclooxygenase; hCE-1, human carboxylesterase-1; GSK, glycogen-synthase-kinase-3β; BACE, β-site amyloid precursor protein cleaving enzyme; ACE, angiotensin-converting enzyme; JNK, c-Jun N-terminal kinase.

Figure 3 Plot between experimentally reported and docking predicted activities of native co-crystallized ligands of all 13 targets.

Abbreviation: pK_i, negative logarithm of inhibition constant.

Figure 4 Plot between docked targets and negative logarithmic values of docking predicted K_i of ginger compounds.

Abbreviations: AChE, acetylcholinesterase; TACE, TNF-α converting enzyme; BuChE, butyrylcholinesterase; NOS, nitric oxide synthase; PDE-5, phosphodiesterase-5; NMDA, N-methyl-D-aspartate; COX, cyclooxygenase; GSK, glycogen-synthase-kinase-3β; BACE, β-site amyloid precursor protein cleaving enzyme; ACE, angiotensin converting enzyme; JNK, c-Jun N-terminal kinase; hCE-1, human carboxylesterase-1; pK_i, negative logarithm of inhibition constant.

Figure 5 Suggested pharmacophore model of ginger compounds for eliciting anti-Alzheimer’s effects.

Figure 6 3D structures of proteins showing the binding sites (left), and main residues involved in the ligand–protein (right) interaction of compound 8 and AChE (A, B), compound 11 and TACE (C, D), compound 11 and BuChE (E, F), and compound 11 and NOS (G, H).

Abbreviations: AChE, acetylcholinesterase; TACE, TNF-α converting enzyme; BuChE, butyrylcholinesterase; NOS, nitric oxide synthase.

Figure 7 An overview of the structural requirements of ginger compounds for their interaction with different target receptors associated with Alzheimer’s disease.

Abbreviations: BuChE, butyrylcholinesterase; NOS, nitric oxide synthase; NMDA, N-methyl-D-aspartate; COX, cyclooxygenase; GSK, glycogen-synthase-kinase-3β; BACE, β-site amyloid precursor protein cleaving enzyme; ACE, angiotensin converting enzyme; JNK, c-Jun N-terminal kinase; Ac, acetyl.

Figure 8 The lowest energy configuration of docking result of compound 7 with binding pocket of acetylcholinesterase.

Notes: The amino acids (blue) are shown as stick while compound 7 is presented as ball and stick style in olive green color. Dashed lines in green indicate H-bonds while π–π interaction is shown as orange line. Oxygens are in red and polar hydrogens in light gray color.

Figure 9 The docked compound 7 (yellow) and native Huperzine A (blue) in the binding pocket of human acetylcholinesterase.

Table 4 Physicochemical parameters for good oral bioavailability of ginger compounds (1–12)

Compound	%ABSa	TPSA (Å^2)b	MWc	miLogPd	HBDe	HBAf	n-ROTBg	Violation of Lipinski’s rule
Rule	–	–	<500	≤5	<5	<10	≤10	≤1
1	92.95	46.53	276.37	4.34	1	3	9	0
2	87.06	63.60	290.35	3.06	1	4	9	0
3	92.95	46.53	194.23	1.51	1	3	4	0
4	85.97	66.76	294.39	3.21	2	4	10	0
5	85.99	66.76	350.49	5.23	2	4	14	0
6	76.89	93.06	372.41	2.24	2	6	10	1
7	82.78	75.99	356.41	3.32	2	5	9	0
8	75.32	97.62	448.55	4.30	3	7	14	0
9	74.71	99.38	376.44	2.61	4	6	10	0
10	68.82	116.45	390.43	2.13	4	7	10	0
11	71.53	108.61	390.43	2.33	4	7	6	0
12	74.71	99.38	360.40	2.51	4	6	5	0

Notes:

a Percentage of absorption (%ABS)

b topological polar surface area (TPSA)

c molecular weight (MW)

d logarithm of partition coefficient between n-octanol and water (miLogP)

e number of hydrogen bond donors (HBD)

f number of hydrogen bond acceptors (HBA)

g number of rotatable bonds (n-ROTB).

Table 5 Drug-likeness/scores and toxicity calculations of ginger compounds based on Osiris property explorer

Compound	Solubility	Drug-likeness	Drug score	Mutagenic	Tumorigenic	Irritant	Reproductive effect
1	−3.42	−14.48	0.22	Red	Green	Green	Green
2	−3.44	−16.52	0.24	Green	Green	Red	Green
3	−2.03	−2.22	0.31	Green	Green	Red	Green
4	−3.25	−7.78	0.4	Green	Green	Green	Green
5	−4.33	−15.79	0.27	Green	Green	Green	Green
6	−3.35	−6.82	0.39	Green	Green	Green	Green
7	−3.47	−3.48	0.38	Green	Green	Green	Green
8	−3.81	−3.6	0.3	Green	Green	Green	Green
9	−3.25	0.23	0.61	Green	Green	Green	Green
10	−3.01	2.51	0.77	Green	Green	Green	Green
11	−2.89	2.26	0.77	Green	Green	Green	Green
12	−2.87	1.27	0.74	Green	Green	Green	Green

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