Protein-coding gene interaction network prediction of bioactive plant compound action against SARS-CoV-2: a novel hypothesis using bioinformatics analysis

SANTOS SOBRINHO, ELIANE M.; SANTOS, HÉRCULES O.; MARTINS, ERNANE R.; FONSECA, FRANCINE SOUZA ALVES DA; FARIAS, LUCYANA C.; AGUILAR, CHARLES M.; PEREIRA, ULISSES A.; NICOLAU JUNIOR, NILSON; GOMES, MATHEUS S.; SOUZA, CINTYA N. DE; RAVNJAK, JOÃO MATHEUS A.; PORTO, RAPHAEL R.; ALMEIDA, ANNA CHRISTINA DE

doi:10.1590/0001-3765202220201380

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HEALTH SCIENCES • An. Acad. Bras. Ciênc. 94 (suppl 3) • 2022 • https://doi.org/10.1590/0001-3765202220201380 copy

Protein-coding gene interaction network prediction of bioactive plant compound action against SARS-CoV-2: a novel hypothesis using bioinformatics analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

This study aimed to verify the action of bioactive compounds from Brazilian plants on the leader genes involved in the SARS-CoV-2 pathway. The main human genes involved were identified in GeneCards and UNIPROT platforms, and an interaction network between leader genes was established in the STRING database. To design chemo-biology interactome networks and elucidate the interplay between genes related to the disease and bioactive plant compounds, the metasearch engine STITCH 3.1 was used. The analysis revealed that SMAD3 and CASP3 genes are leader genes, suggesting that the mechanism of action of the virus on host cells is associated with the molecular effects of these genes. Furthermore, the bioactive plant compounds, such as ascorbate, benzoquinone, ellagic acid, and resveratrol was identified as a promising adjuvant for the treatment inhibiting CASP3-mediated apoptosis. Bioactive plant compounds were verified as the main pathways enriched with KEGG and related to viral infection, assessments/immune/infections, and cell proliferation, which are potentially used for respiratory viral infections. The best-ranked molecule docked in the CASP3 binding site was rutin, while the SMAD3 binding site was resveratrol. In conclusion, this work identified several bioactive compounds from Brazilian plants showing potential antiviral functions that can directly or indirectly inhibit the new coronavirus.

Key words
CASP-3; cerrado plant; coronavirus; COVID-19; medicinal plant; SMAD

TARGET PROTEIN: CASP3
Bioactive compounds	Action/effects			Action/Types
Bioactive compounds	Upregulation	Downregulation	Unspecified	Activation	Inhibition	Transcriptional regulation	Binding
Angelicin	x			x
Apigenin	x			x
Ascorbic acid		x			x
Benzoquinone	x	x		x	x
β-elemene			x
Catechol	x			x
Ellagic acid	x	x	x	x	x	x
Eugenol	x			x
Flavanone	x			x
Gallic acid	x		x	x		x
γ-tocopherol
Isoquercitrin			x
Kaempferol			x
Luteolin	x			x
Lycopene			x
Oleanolic acid	x		x	x		x
Oleic acid			x
Quercetin	x		x	x		x
Resveratrol	x	x	x	x	x	x
Rutin	x			x
Safrole	x		x	x		x
Salicylate	x			x
Scopoletin			x
Sitosterol	x			x
Thymol	x			x
TARGET PROTEIN: SMAD3
Ellagic acid							x
Resveratrol			x			x

	Ascorbic acid	Benzoquinone	Ellagic acid	Resveratrol
Description*	A six-carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant.	1,4-Benzoquinone, commonly known as para-quinone, is a chemical compound with the formula C6H4O2. In a pure state, it forms bright-yellow crystals with a characteristic irritating odor, resembling that of chlorine, bleach, and hot plastic. This six-membered ring compound is the oxidized derivative of 1,4-hydroquinone. The molecule is multifunctional: it exhibits properties of a ketone, forming an oxime; an oxidant, forming the dihydroxy derivative; and an alkene, undergoing addition reactions, especially those typical for Î±,Î²-unsaturated ketones. 1,4-Benzoquinone is sensitive toward both strong mineral acids and alkali, which cause condensation and decomposition of the compound.	Ellagic acid is a natural phenol antioxidant found in numerous fruits and vegetables. The antiproliferative and antioxidant properties of ellagic acid have prompted research into its potential health benefits. It has been fraudulently marketed as having the ability to prevent and treat several human maladies, including cancer, but such claims have not been proven.	Resveratrol (3,5,4’-trihydroxystilbene) is a polyphenolic phytoalexin. It is a stilbenoid, a derivate of stilbene, and is produced in plants with the help of the enzyme stilbene synthase. It exists as two structural isomers: cis-(Z) and trans-(E), with the trans-isomer shown in the top image. The trans-form can undergo isomerisation to the cis- form when heated or exposed to ultraviolet irradiation.
Structure*
Plants	Scientific name: Annona coriacea Mart.	Scientific name: Ourateahexasperma (A.St.-Hil.) Baill.	Scientific name: Cochlospermumregium (Mart. ex Schrank) Pilg.	Scientific name: Ourateahexasperma(A.St.-Hil.) Baill.
	Popular name: Pinha, araticum, cabeça-de-negro, pinha-miúda		Popular name: Algodão bravo,algodão-do-campo,algodão-do-mato,algodão-do-campo
	Scientificname: Annonasylvatica A.St.-Hil.		Scientific name: Terminaliaargentea Mart. &Zucc.
	Popular name: Araticum, articum	Popular name: Cabelo-de-negro	Popular name: Capitão-do-mato,capitão-do-campo,Pau-de-bicho	Popular name: Cabelo-de-negro
	Scientific name: Eugenia punicifolia(Kunth.) DC.		Scientificname: Mesosphaerumsuaveolens (L.) Kuntze
	Popular name: murta, muta		Popular name: bamburral
* Source: STRING DATABASE

KEGG PATHWAYS
Pathway ID	Pathway description	Observed gene count	False discovery rate	Matching proteins in network (labels)
5161	Hepatitis B	5	1.41e-05	CASP3, CREBBP, EP300, JUN, SMAD4
5200	Pathways in cancer	6	1.41e-05	CASP3, CREBBP, EP300, JUN, SMAD4, XIAP
4350 TGF-beta signaling pathway		4	3.12e-05	CREBBP, EP300, SMAD4, SP1
5166	HTLV-I infection	5	7.35e-05	CREBBP, EP300, JUN, SMAD4, XIAP
4310	Wnt signaling pathway	4	0.000178	CREBBP, EP300, JUN, SMAD4
5016	Huntington s disease	4	0.000356	CASP3, CREBBP, EP300, SP1
5168	Herpes simplex infection	4	0.000356	CASP3, CREBBP, EP300, JUN
5203	Viral carcinogenesis	4	0.000356	CASP3, CREBBP, EP300, JUN
BIOLOGICAL PROCESS (GO)
Pathway ID	Pathway description	Observed gene count	False discovery rate	Matching proteins in network (labels)
GO.0007166	cell surface receptor signaling pathway	12	4.86e-07	CASP3, CREBBP, EP300, JUN, SKI, SKIL, SMAD3, SMAD4, SP1, TGFBR1, UBC, XIAP
GO.0007165	signal transduction	11	0.00311	CASP3, CREBBP, JUN, SKI, SKIL, SMAD3, SMAD4, SP1, TGFBR1, UBC, XIAP
GO.0071363	cellular response to growth factor stimulus	10	7.59e-09	CASP3, EP300, JUN, SKI, SKIL, SMAD3, SMAD4, SP1, TGFBR1, UBC
GO.0007167	enzyme-linked receptor protein signaling pathway	9	2.83e-06	CASP3, JUN, SKI, SKIL, SMAD3, SMAD4, SP1, TGFBR1, UBC
GO.0007179	transforming growth factor-beta receptor signaling pathway	8	4.38e-10	JUN, SKI, SKIL, SMAD3, SMAD4, SP1, TGFBR1, UBC
GO.0090092	regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	7	1.56e-07	SKI, SKIL, SMAD3, SMAD4, TGFBR1, UBC, XIAP
GO.0017015	regulation of transforming growth factor-beta receptor signaling pathway	6	1.56e-07	SKI, SKIL, SMAD3, SMAD4, TGFBR1, UBC
GO.0009952	anterior/posterior pattern specification	5	9.86e-05	EP300, SKI, SMAD3, SMAD4, TGFBR1
GO.0060395	SMAD protein signal transduction	4	3.37e-05	JUN, SKI, SMAD3, SMAD4
MOLECULAR FUNCTION (GO)
Pathway ID	Pathway description	Observed gene count	False discovery rate	Matching proteins in network (labels)
GO.0005515	protein binding	10	0.0438	CREBBP, EP300, JUN, SKI, SKIL, SMAD3, SMAD4, SP1, TGFBR1, UBC
GO.0000988	transcription factor activity, protein binding	7	5.26e-05	CREBBP, EP300, JUN, SKI, SKIL, SMAD3, SMAD4
GO.0046332	SMAD binding	6	6.47e-09	JUN, SKI, SKIL, SMAD3, SMAD4, TGFBR1
GO.0001085	RNA polymerase II transcription factor binding	5	6.15e-06	CREBBP, EP300, JUN, SMAD3, SP1
GO.0001102	RNA polymerase II activating transcription factor binding	4	1.38e-05	CREBBP, EP300, JUN, SMAD3
GO.0070412	R-SMAD binding	3	0.000145	JUN, SMAD3, SMAD4
CELLULAR COMPONENT (GO)
Pathway ID	Pathway description	Observed gene count	False discovery rate	Matching proteins in network (labels)
GO.0031981	nuclear lumen	10	0.00449	CASP3, CREBBP, JUN, SKI, SKIL, SMAD3, SMAD4, SP1, UBC, XIAP
GO.0005654	nucleo plasm	8	0.0446	CASP3, JUN, SKI, SKIL, SMAD4, SP1, UBC, XIAP
GO.0005667	transcription factor complex	6	5.61e-05	CREBBP, EP300, JUN, SKI, SMAD3, SMAD4
GO.0000790	nuclear chromatin	5	0.000438	CREBBP, JUN, SMAD3, SMAD4, SP1
GO.0071141	SMAD protein complex	2	0.00132	SMAD3, SMAD4
PFAM PROTEINS DOMAINS
Pathway ID	Pathway description	Observed gene count	False discovery rate	Matching proteins in network (labels)
PF03166	MH2 domain	2	0.0103	SMAD3, SMAD4
PF03165	MH1 domain	2	0.0128	SMAD3, SMAD4
INTERPRO PROTEINS DOMAINS AND FEATURES
Pathway ID	Pathway description	Observed gene count	False discovery rate	Matching proteins in network (labels)
IPR001132	SMAD domain, Dwarfin-type	2	0.00732	SMAD3, SMAD4
IPR013019	MAD homology, MH1	2	0.00732	SMAD3, SMAD4
IPR013790	Dwarfin	2	0.00732	SMAD3, SMAD4
IPR003619	MAD homology1, Dwarfin-type	2	0.011	SMAD3, SMAD4
IPR017855	SMAD domain-like	2	0.011	SMAD3, SMAD4
IPR008984	SMAD/FHA domain	2	0.0335	SMAD3, SMAD4

CASP3
Molecule	ChemPLP score
Angelicin	34,0
Apigenin	47,2
Ascorbic acid	28,8
Benzoquinone	-
β-elemene	47,3
Catechol	-
Ellagic acid	55,6
Eugenol	-
Flavonone	-
Gallic acid	41,4
γ-tocopherol	-
Isoquercitrin	66,3
Kaempferol	54,2
Luteolin	47,6
Lycopene	-
Oleanolic acid	82,2
Oleic acid	69,2
Quercetin	72,2
Resveratrol	65,5
Rutin	92,0
Safrole	48,9
Salicylate	55,6
Scopoletin	48,7
Sitosterol	-
Thymol	52,0

SMAD3
Molecule	ChemPLP score
Resveratrol	65,8
Ellagic acid	50,2

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[1] Correspondence to: Anna Christina de Almeida E-mail: aca2006@ica.ufmg.br