Pharmacophore Modeling of Janus Kinase Inhibitors: Tools for Drug Discovery and Exposition Prediction

Abstract

Pesticides are essential in agriculture for protecting crops and boosting productivity, but their widespread use may pose significant health risks. Farmworkers face direct exposure through skin contact and inhalation, which may lead to hormonal imbalances, neurological disorders, and elevated cancer risks. Moreover, pesticide residues in food and water may affect surrounding communities. One of the lesser investigated issues is immunotoxicity, mostly because the chronic effects of compound exposure are very complex to study. As a case study, this work utilized pharmacophore modeling and virtual screening to identify pesticides that may inhibit Janus kinases (JAK1, JAK2, JAK3) and tyrosine kinase 2 (TYK2), which are pivotal in immune response regulation, and are associated with cancer development and increased infection susceptibility. We identified 64 potential pesticide candidates, 22 of which have previously been detected in the human body, as confirmed by the Human Metabolome Database. These results underscore the critical need for further research into potential immunotoxic and chronic impacts of the respective pesticides on human health.

Keywords: JAK1; JAK2; JAK3; TYK2; immunosuppression; pesticides; pharmacophore modeling.

Figure 1

2D structures of the pharmacophore modeling training compounds for JAK1 (1 [25], 2 [26], 3 [27], 4 [28]) JAK2 (5 [29], 6 [30], 7 [31], 8 [32], 9 [33], 10 [34]), JAK3 (11 [35], 12 [36], 13 [30]), and TYK2 (14 [37], 15 [38], 16 [39]) used to develop the shown pharmacophore models, along with their corresponding IC₅₀ values.

Figure 2

Two exemplary pharmacophore models for JAK1, illustrating key interactions and structural features. (a) JAK1_SB1 developed from the X-ray structure PDB: 5HX8 [25] in complex with its co-crystallized ligand compound 1 [25]. The model consists of one HBD with Glu957 and one HBA with Leu959, as well as two HCs. Furthermore, the model includes 66 Xvols. (b) Shows LB pharmacophore model JAK1_LB1 in complex with compound 2 [26]. This model was generated through alignment and merging of features from compound 2 [26], compound 3 [27], and compound 4 [28] JAK1_LB1 includes three HBAs, two AIs, and forty-seven Xvols. Chemical features are color-coded: HBDs—green, HBAs red, HCs—yellow, AIs—blue.

Figure 3

Two exemplary pharmacophore models for JAK2, illustrating key interactions and structural features. (a) JAK2_SB1, developed from the X-ray structure PDB: 6VNB [29] in complex with its co-crystallized ligand compound 5 [29]. This model consisted of one HBD with Leu932, one HBA with Glu930, two HCs, and nine Xvols. (b) Shows the LB pharmacophore model JAK2_LB1 in complex with compound 6 [30]. This model was generated through alignment and merging of features from compound 7 [31], compound 8 [32], compound 9 [33], and compound 10 [37]. JAK2_LB1 includes one HBD, two HBAs, two AIs, and nine Xvols. Chemical features are color-coded: HBDs—green, HBAs red, HCs—yellow, AIs—blue.

Figure 4

Two pharmacophore models for JAK3, illustrating key interactions and structural features. (a) JAK3_SB1, developed from the X-ray structure PDB: 4Z16 [35] in complex with its co-crystallized ligand compound 11 [35]. This model includes one HBD with Leu905, one HBA, three HCs, and twenty Xvols. (b) Shows LB pharmacophore model JAK3_LB1 in complex with compound 12. This model was generated through alignment and merging of features from compound 12 [36] and compound 13 [40]. JAK3_LB1 includes one HBA, two AIs, two HCs, and twenty-nine Xvols. Chemical features are color-coded: HBDs—green, HBAs red, HCs—yellow, AIs—blue.

Figure 5

Two pharmacophore models for TYK2, illustrating key interactions and structural features. (a) TYK2_SB1, based on the X-ray structure PDB: 6VNS [37] in complex with the co-crystallized ligand compound 14 [37]. This model consists of one HBD with Val981, one HBA and two HBAs directed to Ser985, two HCs, and twenty-six Xvols. (b) Shows LB pharmacophore model TYK2_LB1 in complex with compound 15 [38]. This model was generated through alignment and merging of features from compound 15 [38] and compound 16 [39] TYK2_LB1 includes one HBD, two HBAs, one HC, one AI, and thirty-five Xvols. Chemical features are color-coded: HBDs—green, HBAs red, HCs—yellow, AIs—blue.

Figure 6

ROC curves of the overall models, including the AUC. Panel (a) shows JAK1, panel (b) shows JAK2, panel (c) shows JAK3, and panel (d) shows TYK2.

Figure 7

Identified pesticides from the virtual screening that are listed as qualitatively detected in the Human Metabolome Database. The hit list included fungicides (Section (A)), such as boscalid (17), bupirimate (18), isavuconazole (19), mepanipyrim (20), ravuconazole, (21), thiophanate-methyl (22). (Section (B)) comprises herbicides, including metsulfuron-methyl (23), tribenuron (24), tribenuron-methyl (25), cyanazine (26), penoxsulam (27), phenmedipham (28), diflufenican (29), florasulam (30), flufenoxuron (31), and isoxaben (32). (Section (C)) represents metabolites, such as 3,5,6-trichloro-2-pyridinol (33), deisopropylatrazine (34), and desethylterbutylazine (35). (Section (D)) includes insecticides, such as fenazaquin (36), pymetrozine (37), and terbutryn (38).

Figure 8

Exemplary virtual hits for JAK1. (a) Identified insecticide 36 (pymetrozine) in complex with model JAK1_SB1. (b) Identified herbicide 30 (florasulam) in model JAK1_LB1. Chemical features are color-coded: HBDs—green, HBAs red, HCs—yellow, AIs—blue.

Figure 9

Exemplary virtual hits for JAK2. (a) Identified insecticide 27 (cynacine) in complex with model JAK2_SB1. (b) The fungicide 17 (boscalid) mapping model JAK2_LB1. Chemical features are color-coded: HBDs—green, HBAs red, HCs—yellow, AIs—blue.

Figure 10

Exemplary virtual hits for JAK3. (a) The identified herbicide 26 (cyanazine) in complex with model JAK3_SB1. (b) The fungicide 20 (mepanipyrim) in model JAK3_LB1. Chemical features are color-coded: HBDs—green, HBAs red, HCs—yellow, AIs—blue.

Figure 11

Exemplary virtual hits for TYK2. (a) The identified fungicide 18 (bupirimate) fitting into model TYK2_SB1. (b) The herbicide 28 (diflufenican) mapping to model TYK2_LB1. Chemical features are color-coded: HBDs—green, HBAs red, HCs—yellow, AIs—blue.