O uso da Inteligência Artificial na predição de flavonoides inibidores do Vírus Sincicial Respiratório

Lopes, B. R. P.; Albertini, T. T.; Costa, M. F.; Ferreira, A. S.; Toledo, K. A.; Rocha, J. C.

B. R. P. Lopes

Universidade Estadual Paulista – UNESP, Faculdade de Ciências e Letras, Departamento de Ciências Biológicas, Assis, SP, Brasil

https://orcid.org/0000-0003-3360-898x

T. T. Albertini

Universidade Estadual Paulista – UNESP, Faculdade de Ciências e Letras, Departamento de Ciências Biológicas, Assis, SP, Brasil

Universidade Estadual Paulista – UNESP, Faculdade de Ciências e Letras, Laboratório de Matemática Aplicada, Assis, SP, Brasil

https://orcid.org/0000-0001-9979-6325

M. F. Costa

Universidade Estadual Paulista – UNESP, Faculdade de Ciências e Letras, Departamento de Ciências Biológicas, Assis, SP, Brasil

Universidade Estadual Paulista – UNESP, Instituto de Biociências Letras e Ciências Exatas, Pós-graduação em Microbiologia, São José do Rio Preto, SP, Brasil

https://orcid.org/0000-0003-1237-0538

A. S. Ferreira

Universidade Estadual Paulista – UNESP, Faculdade de Ciências e Letras, Departamento de Ciências Biológicas, Assis, SP, Brasil

Universidade Estadual Paulista – UNESP, Faculdade de Ciências e Letras, Laboratório de Matemática Aplicada, Assis, SP, Brasil

https://orcid.org/0000-0003-0998-650X

K. A. Toledo ^**e-mail: karina.toledo@unesp.br

Universidade Estadual Paulista – UNESP, Faculdade de Ciências e Letras, Departamento de Ciências Biológicas, Assis, SP, Brasil

Universidade Estadual Paulista – UNESP, Instituto de Biociências Letras e Ciências Exatas, Pós-graduação em Microbiologia, São José do Rio Preto, SP, Brasil

https://orcid.org/0000-0001-7212-6794

J. C. Rocha

Universidade Estadual Paulista – UNESP, Faculdade de Ciências e Letras, Departamento de Ciências Biológicas, Assis, SP, Brasil

Universidade Estadual Paulista – UNESP, Faculdade de Ciências e Letras, Laboratório de Matemática Aplicada, Assis, SP, Brasil

https://orcid.org/0000-0002-0094-2634

*e-mail: karina.toledo@unesp.br

Flavones ^ classification flavonoids classes.		Flavans**
CID^* * CID = compound identification from PubChem site.	Name	CID*	Name
14005	Quercetin pentaacetate1	932	Naringenin³
64982	Baicalin² 2 Wang et al. (2012)	9064	Cianidanol³
72344	Nobiletin²	10621	Hesperidin³
114776	Isoorientin²	65084	Gallocatechin³
124034	Swertisin²	68071	Pinocembrin³
155692	Spinosin²	161557	Ampelopsin³
162350	Isovitexin²	165506	4'-Hydroxyflavanone³
188323	Cirsimaritin²	442428	Naringin³
261859	Gardenin A²	503737	Liquiritin⁴ 4 Ma et al. (2001)
442659	Swertiajaponin³ 3 Chung et al. (2013)	11669392	7-O-Galloyltricetiflavan⁵ 5 Li et al. (2006)
3084961	Oroxindin³	11999968	7,4'-Di-O-galloyltricetiflavan⁵
5271991	Ganhuangenin³	12309904	Isookanin⁶ 6 Song et al. (2016)
5280343	Quercetin¹
5280443	Apigenin³
5280445	Luteolin³	Isoflavonoids**
5280862	Isokaempferide³	CID*	Name
5281600	Amentoflavone³	124052	Glabridin⁷ 7 Kaul et al. (1985)
5281605	Baicalein³	187808	Glycitin⁷
5281607	Chrysin³	480783	6,8-Diprenylgenistein⁷
5281616	Galangin³	5280373	Biochanin⁸ 8 Ma et al. (2002)
5281628	Hispidulin³	5280448	Calycosin⁸
5281672	Myricetin³	5280961	Genistein⁸
5281697	Scutellarein³	5281704	Afrormosin⁵
5281703	Wogonin³	5281708	Daidzein⁵
5281954	Tectochrysin³	5281812	Texasin⁹
5318997	Icariin³	5282074	Hydroxygenistein⁹ 9 Shi et al. (2016)
5320315	Oroxylin A³	5481948	Semilicoisoflavone B⁹
5320438	Pectolinarigenin³
5481982	Baohuoside II³
10005544	10-O-Methylquercetin tetraacetate³
11726019	Isothymonin³	Aurone**
16681753	10',5',6,7-tetramethoxyflavone³	CID*	Name
44144321	Quercetin-10-rham(4)-gluc³	5281295	Sulfuretin⁴

^*
CID = compound identification from PubChem site.
^**
classification flavonoids classes.
References: ¹Lopes et al. (2020)LOPES, B.R.O., COSTA, M.F., RIBEIRO, A.G., LIMA, C.S., CARUSO, I.P., ARAÚJO, G.C., KUBO, L.H., IACOVELLI, F., FALCONI, M., DESIDERI, A., OLIVEIRA, J., REGASINI, L.O., de SOUZA, F.P. and TOLEDO, K.A., 2020. Quercetin pentaacetate inhibits in vitro human respiratory syncytial virus adhesion. Virus Research, vol. 276, pp. 197805. http://dx.doi.org/10.1016/j.virusres.2019.197805. PMid:31712123.
http://dx.doi.org/10.1016/j.virusres.201...
²
Wang et al. (2012)WANG, Y., CHEN, M., ZHANG, J., ZHANG, X.L., HUANG, X.J., WU, X., ZHANG, Q.W., LI, Y.L. and YE, W.C., 2012. Flavone C-Glycosides from the Leaves of Lophatherum Gracile and Their in Vitro Antiviral Activity. Planta Medica, vol. 78, no. 1, pp. 46-51. http://dx.doi.org/10.1055/s-0031-1280128. PMid:21870321.
http://dx.doi.org/10.1055/s-0031-1280128...
³
Chung et al. (2013)CHUNG, D.H., MOORE, B.P., MATHARU, D.S., GOLDEN, J.E., MADDOX, C., RASMUSSEN, L., SOSA, M.I., ANANTHAN, S., WHITE, E.L., JIA, F., JONSSON, C.B. and SEVERSON, W.E., 2013. A cell based high-throughput screening approach for the discovery of new inhibitors of respiratory syncytial virus. Virology Journal, vol. 10, no. 1, pp. 19. http://dx.doi.org/10.1186/1743-422X-10-19. PMid:23302182.
http://dx.doi.org/10.1186/1743-422X-10-1...
⁴
Ma et al. (2001)MA, S.C., BUT, P.P.H., OOI, V.E.C., HE, Y.H., LEE, S.H.S., LEE, S.F. and LIN, R.C., 2001. Antiviral amentoflavone from selaginella sinensis. Biological & Pharmaceutical Bulletin, vol. 24, no. 3, pp. 311-312. http://dx.doi.org/10.1248/bpb.24.311. PMid:11256492.
http://dx.doi.org/10.1248/bpb.24.311...
⁵
Li et al. (2006)LI, Y., LEUNG, K.T., YAO, F., OOI, L.S.M. and OOI, V.E.C., 2006. Antiviral flavans from the leaves of pithecellobium clypearia. Journal of Natural Products, vol. 69, no. 5, pp. 833-835. http://dx.doi.org/10.1021/np050498o. PMid:16724853.
http://dx.doi.org/10.1021/np050498o...
⁶
Song et al. (2016)SONG, M., GAO, M.H., HUANG, W.H., MAN-MEI, L., HUA, L., YAO-LAN, L., XIAO-QI, Z. and WEN-CAI, Y., 2016. Flavonoids from the seeds of hovenia acerba and their in vitro antiviral activity. Journal of Pharmaceutical and Biomedical Sciences, vol. 6, no. 6, pp. 401-409.
⁷
Kaul et al. (1985)KAUL, T.N., MIDDLETON JUNIOR, E. and OGRA, P.L., 1985. Antiviral effect of flavonoids on human viruses. Journal of Medical Virology, vol. 15, no. 1, pp. 71-79. http://dx.doi.org/10.1002/jmv.1890150110. PMid:2981979.
http://dx.doi.org/10.1002/jmv.1890150110...
⁸
Ma et al. (2002)MA, S.C., DU, J., BUT, P.P.H., DENG, S.L., ZHANG, Y.W., OOI, V.E.C., XU, H.X., LEE, S.H.S. and LEE, S.F., 2002. Antiviral chinese medicinal herbs against respiratory syncytial virus. Journal of Ethnopharmacology, vol. 79, no. 2, pp. 205-211. http://dx.doi.org/10.1016/S0378-8741(01)00389-0. PMid:11801383.
http://dx.doi.org/10.1016/S0378-8741(01)...
⁹
Shi et al. (2016)SHI, H., REN, K., LV, B., ZHANG, W., ZHAO, Y., TAN, R.X. and LI, E., 2016. Baicalin from scutellaria baicalensis blocks Respiratory Syncytial Virus (RSV) infection and reduces inflammatory cell infiltration and lung injury in mice. Scientific Reports, vol. 6, no. 1, pp. 35851. http://dx.doi.org/10.1038/srep35851. PMid:27767097.
http://dx.doi.org/10.1038/srep35851...

Source	Abbr.	Definition	Type	Unit	ANN Structure
DOI	CID	Identification in PubChem	String	None	Not Input
SDF file	AB	Cartesian 3D Position	(R) Number	Å	Input
SDF file	BB	Connections Between Atoms	(N) Number	Covalent Bond	Input
Open Babel	MW	Molecular Mass	(R) Number	g/mol	Input
Open Babel	NA	Total N. Atoms	(N) Number	Atoms	Input
Open Babel	NB	Total N. Bonds	(N) Number	Covalent Bond	Input
Open Babel	NR	N. of Chemical Rings	(W) Number	None	Input
Open Babel	LP	Log(10) of Partition Coefficient	(R) Number	None	Input
Open Babel	PSA	Polar Surface Area	(R) Number	Å^2	Input
Open Babel	BS	Energy of Bonds Stretching	(R) Number	Kcal/mol	Input
Open Babel	AB	Energy in Angle Between Atoms Bonded	(R) Number	Kcal/mol	Input
Open Babel	SB	Energy of Stretch Bending	(R) Number	Kcal/mol	Input
Open Babel	TE	Energy of Torsional Rotation Between Atoms	(R) Number	Kcal/mol	Input
Open Babel	OPB	Energy of Bending Outside of the Plan	(R) Number	Kcal/mol	Input
Open Babel	VDWE	Van der Waals Energy	(R) Number	Kcal/mol	Input
Open Babel	EE	Molecular Surface Charge	(R) Number	Kcal/mol	Input
Open Babel	TE	Sum of all OBprop Energy in F.F.	(R) Number	Kcal/mol	Input
DOI	S	hRSV Strain	(N) Number	None	Input
DOI	PFU	Particle Forming Units	(R) Number	N. particles/mL	Input
DOI	T	Type of Assay	(N) Number	None	Input
DOI	C	Concentration of Assay	(R) Number	μg/ml	Input
ARN	E	Have Effect	(W) Number	None	Output
ARN	NE	Don't Have Effect	(W) Number	None	Output

Data set	ANN	Hidden layer						Training	Output
		1		2		3
		N	T.F.	N	T.F.	N	T.F.
Total	TT1	189	purelin	371	radbas	78	satlin	trainscg	satlin
	TT2	173	purelin	246	radbas	73	hardlim	trainscg	purelin
	TT3	228	logsig	117	radbas	67	tansig	trainrp	logsig
Empirical	E1	47	radbas	86	tansig	46	tribas	trainrp	tansig
	E2	122	logsig	79	logsig	81	tribas	trainrp	logsig
	E3	241	tansig	54	logsig	23	tansig	trainrp	tansig
Theoretical	T1	139	logsig	79	tribas	56	logsig	trainrp	purelin
	T2	389	purelin	166	radbas	45	satlin	trainscg	tansig
	T3	332	purelin	173	radbas	38	satlin	trainscg	satlin

Data set	AIs	Training		Simulation
Data set	AIs	Active	Inactive	Active	Inactive
Total	TT1	83.0	92.5	77.6	87.2
	TT2	78.6	93.0	72.0	87.8
	TT3	85.8	89.2	84.4	84.7
Empirical	E1	91.4	87.6	84.4	84.5
	E2	82.8	91.6	75.6	89.7
	E3	79.3	94.0	71.1	92.9
Theoretical	T1	97.2	99.3	99.0	97.6
	T2	96.5	99.2	97.5	96.9
	T3	97.7	96.6	95.5	93.6

Data set	AIs	Agreement
Data set	AIs	inactivity	activity
Total	TT1–3	713	31
Theoretical	T1–3	471	132
Empirical	E1–3	500	348

Prediction	CID	Class	Treatment ^* * The numbers for antiviral treatment indicate the kind of antiviral assay was predicted by the AI (1 for pre-treatment; 2 for virucidal; 3 for post-treatment and 4 for screening).	AI agreement (%)	ZINC ID	Antiviral activity in literature
ACTIVE	71307295	Flavan	3	88.8	14642741
	5379096	Flavone	2	88.8	14779854	Papilomavirus¹ 1 Kumar et al. (2015)
	10449654	Flavone	3	88.8	14762971
	485522	Flavone	4	77.7	6483423
	629964	Flavone	4	77.7	2585767
	5318869	Flavone	3	77.7	5732364	Sars-Cov-2² 2 Leal et al. (2021) , Picornavirus²
	5320399	Flavone	1	77.7	2392262
	5458461	Flavone	4	77.7	1763468	Influenza³ 3 Walther et al. (2016) , Herpes simplex⁴ 4 Likhitwitayawuid et al. (2006)
	5746354	Isoflavone	3	88.8	14762971
	5321398	Isoflavone	2	77.7	1792763	Influenza⁵ 5 Liu et al. (2008) , Sars-Cov⁶ 6 Yu et al. (2012)
INACTIVE	11483087	Flavanone	2	100	14728393	HIV⁷ 7 Esposito et al. (2013)
	440735	Flavanone	2	100	58116	Sars-Cov-2⁸ 8 Deshpande et al. (2020)
	73202	Flavanone	4	100	14806381
	5280681	Flavone	4	100	5998596	Hepatitis B⁹ 9 Lin et al. (2005) , Poliovirus¹⁰ 10 Robin et al. (2001)
	5318761	Flavone	4	100	49823026
	71437113	Flavone	2	100	85867362
	15382687	Flavone	4	100	15271731
	5281617	Flavone	2	100	5732375	Sars-Cov-2¹¹ 11 Nouadi et al. (2021) , African swine fever virus¹² 12 Hakobyan et al. (2019)
	56776173	Flavone	2	100	67903379
	5281801	Isoflavone	2	100	6092209	HIV¹³ 13 Tewtrakul et al. (2007) , HCV¹⁴ 14 Lee et al. (2018) , Rhinovirus¹⁵ 15 Choi et al. (2010)

^*
The numbers for antiviral treatment indicate the kind of antiviral assay was predicted by the AI (1 for pre-treatment; 2 for virucidal; 3 for post-treatment and 4 for screening).
Abbreviations: HIV, human immunodeficiency virus; HCV, hepatitis C virus.
References:
¹
Kumar et al. (2015)KUMAR, S., JENA, L., MOHOD, K., DAF, S. and VARMA, A.K., 2015. Virtual screening for potential inhibitors of high-risk human papillomavirus 16 E6 protein. Interdisciplinary Sciences, Computational Life Sciences, vol. 7, no. 2, pp. 136-142. http://dx.doi.org/10.1007/s12539-015-0008-z. PMid:26199214.
http://dx.doi.org/10.1007/s12539-015-000...
²
Leal et al. (2021)LEAL, C.M., LEITÃO, S.G., SAUSSET, R., MENDONÇA, S.C., NASCIMENTO, P.H.A., CAIO, C.F., ESTEVES, M.E.A., LEAL DA SILVA, M., GONDIM, T.S., MONTEIRO, M.E.S., TUCCI, A.R., FINTELMAN-RODRIGUES, N., SIQUEIRA, M.M., MIRANDA, M.D., COSTA, F.N., SIMAS, R.C. and LEITÃO, G.G., 2021. Flavonoids from siparuna cristata as potential inhibitors of SARS-CoV-2 replication. Revista Brasileira de Farmacognosia, vol. 31, no. 5, pp. 658-666. http://dx.doi.org/10.1007/s43450-021-00162-5. PMid:34305198.
http://dx.doi.org/10.1007/s43450-021-001...
³
Walther et al. (2016)WALTHER, E., XU, Z., RICHTER, M., KIRCHMAIR, J., GRIENKE, U., ROLLINGER, J.M., KRUMBHOLZ, A., SALUZ, H.P., PFISTER, W., SAUERBREI, A. and SCHMIDTKE, M., 2016. Dual acting neuraminidase inhibitors open new opportunities to disrupt the lethal synergism between streptococcus pneumoniae and influenza virus. Frontiers in Microbiology, vol. 7, pp. 357. http://dx.doi.org/10.3389/fmicb.2016.00357. PMid:27047471.
http://dx.doi.org/10.3389/fmicb.2016.003...
⁴
Likhitwitayawuid et al. (2006)LIKHITWITAYAWUID, K., CHAIWIRIYA, S., SRITULARAK, B. and LIPIPUN, V., 2006. Antiherpetic flavones from the heartwood of artocarpus gomezianus. Chemistry & Biodiversity, vol. 3, no. 10, pp. 1138-1143. http://dx.doi.org/10.1002/cbdv.200690115. PMid:17193228.
http://dx.doi.org/10.1002/cbdv.200690115...
⁵
Liu et al. (2008)LIU, A.L., WANG, H.D., LEE, S.M.Y., WANG, Y.T. and DU, G.H., 2008. Structure-activity relationship of flavonoids as influenza virus neuraminidase inhibitors and their in vitro anti-viral activities. Bioorganic & Medicinal Chemistry, vol. 16, no. 15, pp. 7141-7147. http://dx.doi.org/10.1016/j.bmc.2008.06.049. PMid:18640042.
http://dx.doi.org/10.1016/j.bmc.2008.06....
⁶
Yu et al. (2012)YU, M.S., LEE, J., LEE, J.M., KIM, Y., CHIN, Y.W., JEE, J.G., KEUM, Y.S. and JEONG, Y.J., 2012. Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, NsP13. Bioorganic & Medicinal Chemistry Letters, vol. 22, no. 12, pp. 4049-4054. http://dx.doi.org/10.1016/j.bmcl.2012.04.081. PMid:22578462.
http://dx.doi.org/10.1016/j.bmcl.2012.04...
⁷
Esposito et al. (2013)ESPOSITO, F., SANNA, C., DEL VECCHIO, C.D., CANNAS, V., VENDITTI, A., CORONA, A., BIANCO, A., SERRILLI, A.M., GUARCINI, L., PAROLIN, C., BALLERO, M. and TRAMONTANO, E., 2013. Hypericum Hircinum L. components as new single-molecule inhibitors of both HIV-1 reverse transcriptase-associated DNA polymerase and ribonuclease H activities. Pathogens and Disease, vol. 68, no. 3, pp. 116-124. http://dx.doi.org/10.1111/2049-632X.12051. PMid:23821410.
http://dx.doi.org/10.1111/2049-632X.1205...
⁸
Deshpande et al. (2020)DESHPANDE, R.R., TIWARI, A.P., NYAYANIT, N. and MODAK, M., 2020. In silico molecular docking analysis for repurposing therapeutics against multiple proteins from SARS-CoV-2. European Journal of Pharmacology, vol. 886, pp. 173430. http://dx.doi.org/10.1016/j.ejphar.2020.173430. PMid:32758569.
http://dx.doi.org/10.1016/j.ejphar.2020....
⁹
Lin et al. (2005)LIN, Y.L., SHEN, C.C., HUANG, Y.J. and CHANG, Y.Y., 2005. Homoflavonoids from ophioglossum petiolatum. Journal of Natural Products, vol. 68, no. 3, pp. 381-384. http://dx.doi.org/10.1021/np0401819. PMid:15787440.
http://dx.doi.org/10.1021/np0401819...
¹⁰
Robin et al. (2001)ROBIN, V., IRURZUN, A., AMOROS, M., BOUSTIE, J. and CARRASCO, L., 2001. Antipoliovirus flavonoids from psiadia dentata. Antiviral Chemistry & Chemotherapy, vol. 12, no. 5, pp. 283-291. http://dx.doi.org/10.1177/095632020101200503. PMid:11900347.
http://dx.doi.org/10.1177/09563202010120...
¹¹
Nouadi et al. (2021)NOUADI, B., EZAOUINE, A., MESSAL, M.E., BLAGHEN, M., BENNIS, F. and CHEGDANI, F., 2021. Prediction of anti-COVID 19 therapeutic power of medicinal moroccan plants using molecular docking. Bioinformatics and Biology Insights, vol. 15, pp. 11779322211009199. http://dx.doi.org/10.1177/11779322211009199. PMid:33888980.
http://dx.doi.org/10.1177/11779322211009...
¹²
Hakobyan et al. (2019)HAKOBYAN, A., ARABYAN, E., KOTSINYAN, A., KARALYAN, A., SAHAKYAN, H., ARAKELOV, V., NAZARYAN, K., FERREIRA, F. and ZAKARYAN, H., 2019. Inhibition of african swine fever virus infection by Genkwanin. Antiviral Research, vol. 167, pp. 78-82. http://dx.doi.org/10.1016/j.antiviral.2019.04.008. PMid:30991087.
http://dx.doi.org/10.1016/j.antiviral.20...
¹³
Tewtrakul et al. (2007)TEWTRAKUL, S., SUBHADHIRASAKUL, S., CHEENPRACHA, S. and KARALAI, C., 2007. HIV-1 protease and HIV-1 integrase inhibitory substances from eclipta prostrata. Phytotherapy Research, vol. 21, no. 11, pp. 1092-1095. http://dx.doi.org/10.1002/ptr.2252. PMid:17696192.
http://dx.doi.org/10.1002/ptr.2252...
¹⁴
Lee et al. (2018)LEE, W.P., LAN, K.L., LIAO, S.X., HUANG, Y.H., HOU, M.C. and LAN, K.H., 2018. Inhibitory effects of amentoflavone and orobol on daclatasvir-induced resistance-associated variants of hepatitis C virus. The American Journal of Chinese Medicine, vol. 46, no. 4, pp. 835-852. http://dx.doi.org/10.1142/S0192415X18500441. PMid:29737209.
http://dx.doi.org/10.1142/S0192415X18500...
¹⁵
Choi et al. (2010)CHOI, H.J., BAE, E.Y., SONG, J.H., BAEK, S.H. and KWON, D.H., 2010. Inhibitory effects of orobol 7-O-d-Glucoside from Banaba (Lagerstroemia Speciosa L.) on human rhinoviruses replication. Letters in Applied Microbiology, vol. 51, no. 1, pp. 1-5. http://dx.doi.org/10.1111/j.1472-765X.2010.02845.x. PMid:20497313.
http://dx.doi.org/10.1111/j.1472-765X.20...

[1] *e-mail: karina.toledo@unesp.br

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O uso da Inteligência Artificial na predição de flavonoides inibidores do Vírus Sincicial Respiratório

Resumo