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Identifying potential drug targets in the kinomes of two monogenean species Cover

Identifying potential drug targets in the kinomes of two monogenean species

Helminthologia
Volume 61 (2024): Issue 2 (June 2024)
By: ,  ,  ,   and    
Open Access
|Jul 2024
Figures & tables

Figures & Tables

Fig. 1.

Bioinformatic pipeline for the identification, classification, and selection of potential drug targets. A) Pipeline for the identification and classification of monogenean kinases. B) Classification of protein kinases. C) Pipeline used for the identification of drug targets. D) Pipeline used for the prioritization of monogenean drug targets (MDTs). ePKs, eukaryotic protein kinases; aPKs, atypical protein kinases; AGC, cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family; CAMK, calcium/calmodulin-dependent kinase; CK1, cell kinase 1; CMGC, cyclin-dependent kinases and other close relatives; PKL, protein kinase-like; RGC, receptor guanylate cyclase; STE, MAP kinase cascade kinases; TK, protein tyrosine kinase; TKL, tyrosine kinase-like.

Table 1.

Classification of kinases in various platyhelminths.

GroupAGCCAMKCK1CMGCPKLOtherRGCRGC/CAMKSTETKTKLUnknownAtypicalTotal general
MonogeneaR. viridisi291710305252-13199-1160
S. longicornis322711344292-132613-2193
CestodaE. multilocularis43351144-305-254626--265
E. granulosus41351143-305-244222--253
T. solium56361261-37111284523--310
H. microstoma48331364-306-283318--273
TrematodaS. mansoni3438944-393-2734195-252
S. haematobium39419514403-2731204-269
S. japonicum27338416354-233113-1222
F. gigantica44551366-450-353416--308
F. buski33421047-401-233915--250

[i] Information taken from Andrade et al. (2011), Young et al. (2011), Tsai et al. (2013), Stroehlein et al. (2015), Giuliani et al. (2018), and the present study.

Table 2.

Kinases of Rhabdosynochus viridisi and Scutogyrus longicornis predicted to be monogenean drug targets (MDTs).

SpeciesIDClassification (group/family/subfamily)Priority for molecular docking ***
R. viridisiContig3487.p1(CK1/CK1/CK1-A)-
R. viridisiContig474.p1(AGC)-
R. viridisiContig130.p1(AGC/RSK/RSKp70)1**
R. viridisiTRINITY_DN128_c1_g2_i2.p1(TK/Ack)-
R. viridisiTRINITY_DN430_c0_g1_i4.p1(TK/Fer)-
R. viridisiContig2641.p1(AGC/PKG)-
R. viridisiTRINITY_DN4663_c0_g2_i1.p1a(CAMK/CAMKL/BRSK)-
R. viridisiContig4408.p1(CAMK/MLCK)-
R. viridisiContig5219.p1(CMGC/GSK)-
R. viridisiTRINITY_DN1044_c0_g2_i2.p2(STE/STE11/MEKK1)3*
R. viridisiContig3286.p1(CAMK/CAMKL/MARK)-
S. longicornisContig1825.p1(TK/Ack)-
S. longicornisTRINITY_DN2502_c0_g3_i3__g.25108(TK)-
S. longicornisTRINITY_DN770_c0_g1_i4__g.58217(TK/Fer)-
S. longicornisContig3492.p1(AGC/PKG)-
S. longicornisTRINITY_DN1812_c0_g1_i2__g.5503(AGC/RSK/RSKp70)1*
S. longicornisTRINITY_DN7486_c0_g6_i1__g.37596(CAMK/MLCK)-
S. longicornisTRINITY_DN1065_c0_g1_i1__g.51110(CMGC/GSK)-
S. longicornisTRINITY_DN14095_c0_g1_i1__g.60752(CK1/CK1/CK1-A)-
S. longicornisContig772.p1a(CAMK/CAMKL/BRSK)2**
S. longicornisContig773.p1a(CAMK/CAMKL/BRSK)2**
S. longicornisContig3764.p1(CAMK/CAMKL/MARK)-

* Prioritized by KEGG;

** prioritized by network;

*** same numbers indicate orthologous groups;

a TRINITY_DN4663_c0_g2_i1.p1, had two orthologous paralogues in S. longicornis: Contig772.p1 and Contig773.p1.

Table 3.

The highest binding affinities (≤ −9.0 kcal/mol) obtained from molecular docking using a set of FDA-approved drugs.

DrugSpeciesReceptor idBinding affinity (kcal/mol)
DihydroergotamineaS. longicornisContig773.p1 and Contig772.p1−9.7
LomitapidebR. viridisiTRINITY_DN1044_c0_g2_i2.p2−9.5
DihydroergotamineaR. viridisiTRINITY_DN1044_c0_g2_i2.p2−9.4
ErgotaminecS. longicornisContig773.p1 and Contig772.p1−9.2
BicalutamidedR. viridisiContig130.p1−9.1
PiroxicameR. viridisiTRINITY_DN1044_c0_g2_i2.p2−9.0
SuvorexantfR. viridisiTRINITY_DN1044_c0_g2_i2.p2−9.0

Description according DrugBank (Wishart et al., 2018):

a dihydroergotamine (ZINC ID: ZINC3978005) is an ergot alkaloid used in the acute treatment of migraine and cluster headaches;

b lomitapide (ZINC ID: ZINC27990463) is a microsomal triglyceride transfer protein inhibitor used to lower cholesterol associated with homozygous familial hypercholesterolemia, reducing the risk of cardiovascular events such as myocardial infarction and stroke;

c ergotamine (ZINC ID: ZINC52955754) is an α1-selective adrenergic agonist vasoconstrictor used to treat migraines with or without aura and cluster headaches;

d bicalutamide (Casodex, ZINC ID: ZINC538564) is an androgen receptor inhibitor used to treat stage D2 metastatic carcinoma of the prostate;

e piroxicam (ZINC ID: ZINC51133897) is an NSAID used to treat the symptoms of osteoarthritis and rheumatoid arthritis;

f suvorexant (ZINC ID: ZINC49036447) is an orexin receptor antagonist used to treat insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

DOI: https://doi.org/10.2478/helm-2024-0020 | Journal eISSN: 1336-9083 | Journal ISSN: 0440-6605
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Language: English
Page range: 142 - 150
Submitted on: Sep 12, 2023
Accepted on: May 24, 2024
Published on: Jul 16, 2024
Published by: Slovak Academy of Sciences, Institute of Parasitology
In partnership with: Paradigm Publishing Services
Publication frequency: Volume open
Keywords:
Ergotamine,
aquaculture,
fish parasites,
genomics,
Diplectanidae,
Dactylogyridae
Related subjects:
Life sciences,
Zoology,
Ecology,
Life sciences, other,
Medicine,
Clinical medicine,
Microbiology, virology and infection epidemiology

© 2024 V. H. Caña-Bozada, C. Ovando-Vázquez, L. C. Flores-Méndez, J. M. Martínez-Brown, F. N. Morales-Serna, published by Slovak Academy of Sciences, Institute of Parasitology
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

Volume 61 (2024): Issue 2 (June 2024)
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