Microsoft Word - G-Baicalein+Supplementary+files Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 1 Supporting Information Supplementary Tables Table S-I. PubChem ID and canonical SMILES of Baicalein and reference compounds Ligands Name of Ligands Synonyms PubChem ID Canonical SMILES A Baicalein Noroxylin 5281605 C1=CC=C(C=C1)C2=CC(=O)C3=C(O 2)C=C(C(=C3O)O)O B 1,5-Naphthyridine 1,5- Pyridopyridine 136070 C1=CC2=C(C=CC=N2)N=C1 C 4-(4-(benzo[d][1,3]dioxol-5- yl)-5-(1yridine-2-yl)-1H- imidazol-2-yl)benzamide SB431542 4521392 C1OC2=C(O1)C=C(C=C2)C3=C(NC( =N3)C4=CC=C(C=C4)C(=O)N)C5=C C=CC=N5 D 5-[(3S)-5,5-dimethyloxolan-3- yl]-6-methoxy-3-(2- methoxypyridin-4- yl)pyrazolo[1,5-a]pyrimidine CHEMBL47924 64 156022737 CC1(C[C@H](CO1)C2=NC3=C(C=N N3C=C2OC)C4=CC(=NC=C4)OC)C Table S-II. Ramachandran plot statistical analysis S.N. Target model Region Most favoured Additional allowed Generously allowed Disallowed 1. 1VJY 90.7% 9.3% 0.0% 0.0% 2. 3TZM 92.5% 7.5% 0.0% 0.0% 3. 7DV6 95.3% 4.7% 0.0% 0.0% Table S-III. Swiss ADME and drug-likeness prediction summary S. N. ADME Parameters Baicalein Physicochemical Properties 1. Formula C15H10O5 Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 2 2. Molecular weight (g/mol) 270.24 3. Num. heavy atoms 20 4. Num. arom. heavy atoms 16 5. Fraction Csp3 0.00 6. Num. rotatable bonds 1 7. Num. H-bond acceptors 5 8. Num. H-bond donors 3 9. Molar Refractivity (MR) 73.99 10. TPSA (Ų) 90.90 Lipophilicity 11. Log Po/w (iLOGP) 2.43 12. Log Po/w (XLOGP3) 3.16 13. Log Po/w (WLOGP) 2.58 Water solubility 14. Log S (ESOL) -4.0 15. Qualitative solubility Moderately soluble Pharmacokinetics 16. GI absorption High 17. Intestinal absorption (human)* 90.14% 18. BBB permeant No 19. P-gp substrate No 20. CYP1A2 inhibitor Yes 21. CYP2C19 inhibitor No 22. CYP2C9 inhibitor No 23. CYP2D6 inhibitor Yes 24. CYP3A4 inhibitor Yes 25. Log Kp (skin permeation) (cm/s) -5.70 26. Skin Permeability (Log Kp)* -3.433 27. Total Clearance (log ml/min/kg)* 0.273 28. Renal OCT2# substrate* No Drug-likeness 29. Lipinski (RO5) Yes; 0 violation 30. Ghose Yes 31. Veber Yes 32. Bioavailability score 0.55 33. Lead-likeness Yes 34. SA 3.02 Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 3 Fraction Csp3 : Fraction of carbon atoms that are sp3 hybridised; TPSA : Topological polar surface area; Log Po/w : partition coefficient between n-octanol and water; Log S : decimal logarithm of the molar solubility in water; Lipinski (RO5) : Range are MW ≤ 500, MLOGP ≤ 4.15, N or O ≤ 10, NH or OH ≤ 5; Ghose : Range 160 ≤ MW ≤ 480, -0.4 ≤ WLOGP ≤ 5.6, 40 ≤ MR ≤ 130, 20 ≤ atoms ≤ 70; Veber’s rule : Range are Rotatable bonds ≤ 10, TPSA ≤ 140; SA : Synthetic accessibility score ranges from 1 (very easy) to 10 (very difficult). *According to pkCSM - Biosig Lab prediction tool. #OCT2: Organic cation transporter 2 Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 4 Table S-IV. List of the various targets, Baicalein may bind with probable score ranges from 1.0000 to 0.3299 Target Common name Uniprot ID ChEMBL ID Target Class Probability* Known actives (3D/2D) Lysine-specific demethylase 4D-like KDM4E B2RXH2 CHEMBL1293226 Eraser 1 2 / 2 Xanthine dehydrogenase XDH P47989 CHEMBL1929 Oxidoreductase 1 10 / 21 Arachidonate 15-lipoxygenase ALOX15 P16050 CHEMBL2903 Enzyme 1 7 / 9 Cyclin-dependent kinase 1 CDK1 P06493 CHEMBL308 Kinase 1 3 / 10 Arachidonate 12-lipoxygenase ALOX12 P18054 CHEMBL3687 Enzyme 1 10 / 12 G protein-coupled receptor kinase 6 GRK6 P43250 CHEMBL6144 Kinase 1 3 / 4 Cytochrome P450 19A1 CYP19A1 P11511 CHEMBL1978 Cytochrome P450 0.436430316 6 / 19 Carbonic anhydrase VII CA7 P43166 CHEMBL2326 Lyase 0.346270483 8 / 11 Carbonic anhydrase XII CA12 O43570 CHEMBL3242 Lyase 0.346270483 13 / 16 Carbonic anhydrase IV CA4 P22748 CHEMBL3729 Lyase 0.346270483 9 / 11 P-glycoprotein 1 ABCB1 P08183 CHEMBL4302 Primary active transporter 0.346270483 12 / 45 Cytochrome P450 1B1 CYP1B1 Q16678 CHEMBL4878 Cytochrome P450 0.346270483 12 / 47 Estradiol 17-beta-dehydrogenase 1 HSD17B1 P14061 CHEMBL3181 Enzyme 0.33811031 8 / 4 Aldose reductase AKR1B1 P15121 CHEMBL1900 Enzyme 0.329868485 22 / 69 Cyclin-dependent kinase 5/CDK5 activator 1 CDK5R1 CDK5 Q15078 Q00535 CHEMBL1907600 Kinase 0.329868485 6 / 18 *Probability for the query molecule - assumed as bioactive - to have the protein as target. Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 5 Table S-V. Oral toxicity model report of Baicalein Classification Target Shorthand Predictio n Probability Organ toxicity Hepatotoxicity dili Inactive 0.69 Organ toxicity Neurotoxicity neuro Inactive 0.89 Organ toxicity Nephrotoxicity nephro Active 0.62 Organ toxicity Respiratory toxicity respi Active 0.83 Organ toxicity Cardiotoxicity cardio Inactive 0.99 Toxicity end points Carcinogenicity carcino Active 0.68 Toxicity end points Immunotoxicity immuno Inactive 0.99 Toxicity end points Mutagenicity mutagen Active 0.51 Toxicity end points Cytotoxicity cyto Inactive 0.99 Toxicity end points BBB-barrier bbb Active 0.53 Toxicity end points Ecotoxicity eco Inactive 0.53 Toxicity end points Clinical toxicity clinical Inactive 0.53 Toxicity end points Nutritional toxicity nutri Active 0.63 Tox21-Nuclear receptor signalling pathways Aryl hydrocarbon Receptor (AhR) nr_ahr Active 0.91 Tox21-Nuclear receptor signalling pathways Androgen Receptor (AR) nr_ar Inactive 0.99 Tox21-Nuclear receptor signalling pathways Androgen Receptor Ligand Binding Domain (AR-LBD) nr_ar_lbd Inactive 0.97 Tox21-Nuclear receptor signalling pathways Aromatase nr_aromatas e Inactive 0.91 Tox21-Nuclear receptor signalling pathways Estrogen Receptor Alpha (ER) nr_er Active 0.87 Tox21-Nuclear receptor signalling pathways Estrogen Receptor Ligand Binding Domain (ER-LBD) nr_er_lbd Active 0.95 Tox21-Nuclear receptor signalling pathways Peroxisome Proliferator Activated Receptor Gamma (PPAR- Gamma) nr_ppar_ga mma Inactive 0.98 Tox21-Stress response pathways Nuclear factor (erythroid-derived 2)-like 2/antioxidant responsive element (nrf2/ARE) sr_are Inactive 0.99 Tox21-Stress response pathways Heat shock factor response element (HSE) sr_hse Inactive 0.99 Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 6 Tox21-Stress response pathways Mitochondrial Membrane Potential (MMP) sr_mmp Active 1 Tox21-Stress response pathways Phosphoprotein (Tumor Supressor) p53 sr_p53 Inactive 0.97 Tox21-Stress response pathways ATPase family AAA domain- containing protein 5 (ATAD5) sr_atad5 Inactive 0.99 Molecular Initiating Events Thyroid hormone receptor alpha (THRα) mie_thr_alp ha Inactive 0.90 Molecular Initiating Events Thyroid hormone receptor beta (THRβ) mie_thr_bet a Inactive 0.78 Molecular Initiating Events Transtyretrin (TTR) mie_ttr Inactive 0.97 Molecular Initiating Events Ryanodine receptor (RYR) mie_ryr Inactive 0.98 Molecular Initiating Events GABA receptor (GABAR) mie_gabar Inactive 0.96 Molecular Initiating Events Glutamate N-methyl-D-aspartate receptor (NMDAR) mie_nmdar Inactive 0.92 Molecular Initiating Events alpha-amino-3-hydroxy-5-methyl- 4-isoxazolepropionate receptor (AMPAR) mie_ampar Inactive 0.97 Molecular Initiating Events Kainate receptor (KAR) mie_kar Inactive 0.99 Molecular Initiating Events Achetylcholinesterase (AChE) mie_ache Inactive 0.69 Molecular Initiating Events Constitutive androstane receptor (CAR) mie_car Inactive 0.98 Molecular Initiating Events Pregnane X receptor (PXR) mie_pxr Inactive 0.92 Molecular Initiating Events NADH-quinone oxidoreductase (NADHOX) mie_nadhox Inactive 0.97 Molecular Initiating Events Voltage gated sodium channel (VGSC) mie_vgsc Inactive 0.95 Molecular Initiating Events Na+/I- symporter (NIS) mie_nis Inactive 0.98 Metabolism Cytochrome CYP1A2 CYP1A2 Active 1 Metabolism Cytochrome CYP2C19 CYP2C19 Active 0.77 Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 7 Metabolism Cytochrome CYP2C9 CYP2C9 Active 0.99 Metabolism Cytochrome CYP2D6 CYP2D6 Inactive 0.85 Metabolism Cytochrome CYP3A4 CYP3A4 Inactive 0.79 Metabolism Cytochrome CYP2E1 CYP2E1 Inactive 1 Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 8 Table S-VI. Osiris and molinspiration calculation of apigenin, fisetin acid, cosmosiin and baicalein. Compound name 2D/3D Molecular structure Drug Score (DS) Apigenin miLogP 2.46 TPSA 90.89 natoms 20 MW 270.24 nON 5 nOHNH 3 nviolations 0 nrotb 1 volume 224.05 Fisetin acid miLogP 1.97 TPSA 111.12 natoms 21 MW 286.24 nON 6 nOHNH 4 nviolations 0 nrotb 1 volume 232.07 Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 9 Cosmosiin miLogP 0.39 TPSA 190.28 natoms 32 MW 448.38 nON 11 nOHNH 7 nviolations 2 nrotb 4 volume 364.19 Baicalein miLogP 2.68 TPSA 90.89 natoms 20 MW 270.24 nON 5 nOHNH 3 nviolations 0 nrotb 1 volume 224.05 Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 10 Supplementary Figures Fig. S1. Organigram of POM Theory, serving as a guide to identify various pharmacophore sites of bioactive molecules (46,47). Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 11 A B C D Fig. S2. Chemical structures of Baicalein (A), 1,5-Naphthyridine (B), 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin- 2-yl-1H-imidazol-2-yl)benzamide (C) and 5-[(3S)-5,5-dimethyloxolan-3-yl]-6-methoxy-3-(2- methoxypyridin-4-yl)pyrazolo[1,5-a]pyrimidine (D). Fig. S3. Ramachandran plots generated via PROCHECK for 1VJY, 3TZM (B), and 7DV6 demonstrate that the target protein’s geometry matches the most likely shape based on the torsional angles (ϕ and Ψ) of its amino acid residues. PROCHECK displays the residues in most favoured (red), additionally allowed (light brown), generously allowed (yellow) and disallowed regions (pale yellow). Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 12 Fig. S4. Analysis of hydropathy demonstrating the presence of hydrophilic and hydrophobic regions in the chain of amino acids, (a): 1VJY, (b): 3TZM, and (c): 7DV6. Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 13 Fig. S5. Bioavailability radar plots of Baicalein. The colour zone is the suitable physicochemical space for oral bioavailability. LIPO = lipophilicity (−0.7 < XLOGP3 < +5.0 and +3.0), SIZE: 150 < MV < 500 g/mol, POLAR = polarity (20 Å2 < TPSA < 130 Å2), INSOLU = Insolubility (not higher than -6 < Log S (ESOL) < 0), INSATU = Instauration (0.25 < Fraction Csp3 < 1), FLEX = Flexibility (0 < no of rotatable bonds < 9). Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 14 Fig. S6. Boiled-egg plot between lipophilicity (WLOGP) and polarity (TPSA) showing Baicalein is not able to permeate blood–brain barrier (BBB) but passive absorption by the gastrointestinal tract is possible. Fig. S7. Top 15 targets predicted for Baicalein. Baicalein Drug Target Insights 2025 | DOI: 10.33393/dti.2025.3574 | Mishra et al 15 Fig. S8. Oral toxicity model report of Baicalein. Apigenin Cosmosin Fisetin acid Baicalein Fig. S9. Atomic charge of the compounds.