Data-driven targetome discovery and database requirements: insights from the therapeutic target database

Abstract

Target discovery is pivotal in cutting-edge drug development and impacts translational outcomes and efficacy, the current state of research depends heavily on empirical approaches that can be costly, while there is no publicly available database of drug-target for polypharmacological correlates incorporating relevant clinical data. In the present perspective, 3 Therapeutic Target Database (TTD) exports are utilized: (1) counts of unique target classes having at least one approved drug, (2) approved-drug counts per target class, and (3) the top 20 de-duplicated drug-driven target co-occurrence pairs. These data enabled development of a data-driven map of the targetome. Through comparison of class richness versus translational yield, rating of frequency of drug driven co-occurrence target pairs, we identified emerging, high-yield and biologically plausible but understudied target families, and guide rational combination therapies. The next generation of research should update drug-target databases with more clinical information, quantitative polypharmacology, and provenance metadata to advance combination therapy.

Keywords

Target discovery / Targetome / Therapeutic Target Database / Drug-target database modernization / Combination therapy / Precision medicine

Ethical statements

Not applicable.

Author contributions

The authors confirm contributions to the paper as follows: study conception and design: Shan W, Xu J, Assaraf YG; draft manuscript preparation: Shan W, Xu J, Assaraf YG; manuscript revision: Xu J, Assaraf YG. All authors reviewed the results and approved the final version of the manuscript.

Data availability

All datasets in this perspective can be downloaded from https://zenodo.org/records/17453242.

Acknowledgments

Not applicable.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary information accompanies this paper online at (https://doi.org/10.48130/targetome-0026-0001)

References

[1] Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, et al. 2024. TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Research 52:D1465-D1477

[2] Manglik A, Kobilka B. 2014. The role of protein dynamics in GPCR function: insights from the β2AR and rhodopsin. Current Opinion in Cell Biology 27:136-143

[3] Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. 2017. Trends in GPCR drug discovery: new agents, targets and indica-tions. Nature Reviews Drug Discovery 16:829-842

[4] Wu B, Chien EYT, Mol CD, Fenalti G, Liu W, et al. 2010. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330:1066-1071

[5] Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SGF, Thian FS, et al. 2007. GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science 318:1266-1273

[6] Cohen P. 2002. Protein kinases — the major drug targets of the twenty-first century? Nature Reviews Drug Discovery 1:309-315

[7] Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, et al. 2008. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proceedings of the National Academy of Sciences 105:2070-2075

[8] Noble MEM, Endicott JA, Johnson LN. 2004. Protein kinase inhibitors: insights into drug design from structure. Science 303:1800-1805

[9] Klaeger S, Heinzlmeir S, Wilhelm M, Polzer H, Vick B, et al. 2017. The target landscape of clinical kinase drugs. Science 358:eaan4368

[10] Attwood MM, Fabbro D, Sokolov AV, Knapp S, Schiöth HB. 2021. Trends in kinase drug discovery: targets, indications and inhibitor design. Nature Reviews Drug Discovery 20:839-861

[11] Rawlings ND, Barrett AJ, Thomas PD, Huang X, Bateman A, et al. 2018. The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database. Nucleic Acids Research 46:D624-D632

[12] Rawlings ND, Barrett AJ. 1993. Evolutionary families of peptidases. Biochemical Journal 290:205-218

[13] Raj VS, Mou H, Smits SL, Dekkers DHW, Müller MA, et al. 2013. Dipep-tidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 495:251-254

[14] Nauck MA, Meier JJ, Cavender MA, Abd El Aziz M, Drucker DJ. 2017. Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Circulation 136:849-870

[15] Zhou CK, Liu ZZ, Peng ZR, Luo XY, Zhang XM, et al. 2025. M28 family peptidase derived from Peribacillus frigoritolerans initiates trained immunity to prevent MRSA via the complosome-phosphatidyl-choline axis. Gut Microbes 17:2484386

[16] Hörlein AJ, Näär AM, Heinzel T, Torchia J, Gloss B, et al. 1995. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377:397-404

[17] Chen JD, Evans RM. 1995. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377:454-457

[18] Zhang M, Xie X, Chen E, Guo Y, Wang H, et al. 2025. The ribonucleo-protein hnRNP K promotes hepatic steatosis by suppressing the nuclear hormone receptor PPARα. Journal of Biological Chemistry 301:110500

[19] Jefferson WN, Wang T, Padilla-Banks E, Williams CJ. 2024. Unexpected nuclear hormone receptor and chromatin dynamics regulate estrous cycle dependent gene expression. Nucleic Acids Research 52:10897-10917

[20] Vlamis-Gardikas A, Aslund F, Spyrou G, Bergman T, Holmgren A. 1997. Cloning, overexpression, and characterization of glutaredoxin 2, an atypical glutaredoxin from Escherichia coli. Journal of Biological Chem-istry 272:11236-11243

[21] Abdelwaly A, Helal MA, Fathy MM, Alaaeldeen H, Klein ML, et al. 2025. Design and synthesis of novel small molecules targeting the Kv1.3 voltage-gated potassium ion channel. Scientific Reports 15:32756

[22] Kariev AM, Green ME. 2025. H+ and confined water in gating in many voltage-gated potassium channels: ion/water/counterion/protein networks and protons added to gate the channel. International Jour-nal of Molecular Sciences 26:7325

[23] Catterall WA, Cestèle S, Yarov-Yarovoy V, Yu FH, Konoki K, et al. 2007. Voltage-gated ion channels and gating modifier toxins. Toxicon 49:124-141

[24] Isom LL, De Jongh KS, Catterall WA. 1994. Auxiliary subunits of volt-age-gated ion channels. Neuron 12:1183-1194

[25] Lai HC, Jan LY. 2006. The distribution and targeting of neuronal volt-age-gated ion channels. Nature Reviews Neuroscience 7:548-562

[26] Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, et al. 2005. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immu-nity 23:479-490

[27] Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, et al. 2009. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regu-lating NLRP3 expression. The Journal of Immunology 183:787-791

[28] Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, et al. 2003. IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex. Nature Immunology 4:69-77

[29] Kunze R, Navratil F, Beichert J, Geyer F, Floss DM, et al. 2025. iBody-mediated tuning of synthetic cytokine receptor activation via rational nanobody interface engineering. mAbs 17:2563009

[30] Naz F, Arish M, Singh S, Naqvi N, Alam A. 2025. Mycobacterium tuber-culosis PE5 stimulates anti-inflammatory cytokine production via innate immune toll-like receptor 4 signaling. Microbial Pathogenesis 208:107966

[31] Ercan M, Fırat Oğuz E, Özcan M, Alp HH. 2026. Within- and Between-Subject biological variation estimates of serum free light immuno-globulin chains in healthy individuals in Turkey. Clinica Chimica Acta 578:120545

[32] Wang Y, Liu N, Zou Y, Jie J, Liu Z, et al. 2026. A robust label-free work-flow for the immunoglobulin G subclass site-specific N-glycopeptides and the glycosylation of IgG 2 correlated with colorectal cancer. Talanta 296:128326

[33] Ishida Y, Agata Y, Shibahara K, Honjo T. 1992. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. The EMBO Journal 11:3887-3895

[34] Langerak AW, Brüggemann M, Evans PAS, Hummel M, et al. 2003. Design and standardization of PCR primers and proto-cols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations:report of the BIOMED-2 concerted action BMH4-CT98-3936. Leukemia 17:2257-2317

[35] Rief M, Gautel M, Oesterhelt F, Fernandez JM, Gaub HE. 1997. Reversible unfolding of individual titin immunoglobulin domains by AFM. Science 276:1109-1112

[36] Guo H, Ingolia NT, Weissman JS, Bartel DP. 2010. Mammalian microR-NAs predominantly act to decrease target mRNA levels. Nature 466:835-40

[37] Cheng Q, Wei T, Farbiak L, Johnson LT, Dilliard SA, et al. 2020. Selec-tive organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing. Nature Nanotechnology 15:313-320

[38] Llave C, Xie Z, Kasschau KD, Carrington JC. 2002. Cleavage of scare-crow-like mRNA targets directed by a class of Arabidopsis miRNA. Science 297:2053-2056

[39] Yoon JH, Abdelmohsen K, Srikantan S, Yang X, Martindale Jennifer L, et al. 2012. LincRNA-p 21 suppresses target mRNA translation. Molecu-lar Cell 47:648-655

[40] Luo PK, Chang WA, Peng SY, Chu LA, Chuang YH, et al. 2026. Endoge-nous macrophages as "Trojan horses" for targeted oral delivery of mRNA-encoded cytokines in tumor microenvironment immunother-apy. Biomaterials 325:123620

[41] Xiong XC, Zhang NN, Wu M, Cao TS, Deng K, et al. 2025. Development and characterization of a bivalent mRNA vaccine targeting the Delta and Omicron variants of SARS-CoV-2. Human Vaccines & Immunother-apeutics 21:2562730

[42] Hou X, Zaks T, Langer R, Dong Y. 2021. Lipid nanoparticles for mRNA delivery. Nature Reviews Materials 6:1078-1094

[43] Tenchov R, Bird R, Curtze AE, Zhou Q. 2021. Lipid nanoparticles─from liposomes to mRNA vaccine delivery, a landscape of research diver-sity and advancement. ACS Nano 15:16982-17015

[44] Ouranidis A, Vavilis T, Mandala E, Davidopoulou C, Stamoula E, et al. 2022. mRNA Therapeutic Modalities Design, Formulation and Manu-facturing under Pharma 4.0 Principles. Biomedicines 10:50

[45] Lu RM, Hsu HE, Perez SJLP, Kumari M, Chen GH, et al. 2024. Current landscape of mRNA technologies and delivery systems for new modality therapeutics. Journal of Biomedical Science 31:89

[46] Zhang M, Hussain A, Yang H, Zhang J, Liang XJ, et al. 2023. mRNA-based modalities for infectious disease management. Nano Research 16:672-691

[47] Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, et al. 2019. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575:688-692

[48] Mazel D, Pochet S, Marlière P. 1994. Genetic characterization of polypeptide deformylase, a distinctive enzyme of eubacterial transla-tion. The EMBO Journal 13:914-923

[49] Jadhav R, Shekar A, Westenhaver Z, Skandhan A. 2025. Abstract 4370073: a delayed diagnosis of anti-HMG-CoA reductase immune-mediated necrotizing myopathy. Circulation 152:A4370073

[50] Leitans J, Kazaks A, Balode A, Ivanova J, Zalubovskis R, et al. 2015. Effi-cient Expression and Crystallization System of Cancer-Associated Carbonic Anhydrase Isoform IX. Journal of Medicinal Chemistry 58:9004-09

[51] Ruusuvuori E, Hong L, Huttu K, Palva JM, Smirnov S, et al. 2004. Carbonic anhydrase isoform VII acts as a molecular switch in the development of synchronous gamma-frequency firing of hippocam-pal CA1 pyramidal cells. The Journal of Neuroscience 24:2699-2707

[52] Temperini C, Scozzafava A, Vullo D, Supuran CT. 2006. Carbonic anhy-drase activators. Activation of isozymes I, II, IV, VA, VII, and XIV with l-and d-histidine and crystallographic analysis of their adducts with isoform II: engineering proton-transfer processes within the active site of an enzyme. Chemistry 12:7057-66

[53] Kamel EM, Ahmed NA, Maodaa S, Abuamarah BA, Othman SI, et al. 2025. Entrance-channel plugging by natural sulfonamide antibiotics yields isoform-selective carbonic anhydrase IX inhibitors: an inte-grated in silico/ in vitro discovery of the lead SB-203207. BMC Chem-istry 19:263

[54] Torres SW, Lan C, Harthorn A, Schmitz Z, Blanchard PL, et al. 2025. Molecular determinants of affinity and isoform selectivity in protein─small molecule hybrid inhibitors of carbonic anhydrase. Bioconjugate Chemistry 36:549-562

[55] Ives NJ, Stowe RL, Marro J, Counsell C, Macleod A, et al. 2004. Monoamine oxidase type B inhibitors in early Parkinson's disease: meta-analysis of 17 randomised trials involving 3525 patients. BMJ 329:593

[56] Scozzafava A, Supuran CT. 2000. Carbonic anhydrase and matrix metalloproteinase inhibitors: sulfonylated amino acid hydroxamates with MMP inhibitory properties act as efficient inhibitors of CA isozymes I, II, and IV, and N-hydroxysulfonamides inhibit both these zinc enzymes. Journal of Medicinal Chemistry 43:3677-3687

[57] Mori M, Li G, Abe I, Nakayama J, Guo Z, et al. 2006. Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat. The Journal of Clinical Investigation 116:395-404

[58] Mullins EA, Francois JA, Kappock TJ. 2008. A specialized citric acid cycle requiring succinyl-coenzyme A (CoA): acetate CoA-transferase (AarC) confers acetic acid resistance on the acidophile Acetobacter aceti. Journal of Bacteriology 190:4933-4940

[59] Kusano H, Li H, Minami H, Kato Y, Tabata H, et al. 2019. Evolutionary developments in plant specialized metabolism, exemplified by two transferase families. Frontiers in Plant Science 10:794

[60] Hediger MA, Romero MF, Peng JB, Rolfs A, Takanaga H, et al. 2004. The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins. Pflügers Archiv 447:465-468

[61] César-Razquin A, Snijder B, Frappier-Brinton T, Isserlin R, Gyimesi G, et al. 2015. A call for systematic research on solute carriers. Cell 162:478-487

[62] Palmiter RD, Huang L. 2004. Efflux and compartmentalization of zinc by members of the SLC 30 family of solute carriers. Pflügers Archiv 447:744-751

[63] Kirii M, Yoshida Y, Takashima S, Uchio-Yamada K, Oh-hashi K. 2025. Transcriptional regulation of solute carrier family 6 member 9 gene. Molecular Biology Reports 52:540

[64] Ren X, Li W. 2025. Iron-handling solute carrier SLC22A17 as a blood-brain barrier target after stroke. Neural Regeneration Research 20:3207-3208

[65] Markadieu N, Delpire E. 2014. Physiology and pathophysiology of SLC12A1/ 2 transporters. Pflügers Archiv - European Journal of Physiol-ogy 466: 91-105

[66] Yokomori T, Tozaki T, Ohnuma A, Ishimaru M, Sato F, et al. 2024. Non-synonymous substitutions in Cadherin 13, solute carrier family 6 member 4, and monoamine oxidase A genes are associated with personality traits in thoroughbred horses. Behavior Genetics 54:333-341

[67] Brown KK, Hann MM, Lakdawala AS, Santos R, Thomas PJ, et al. 2018. Approaches to target tractability assessment - a practical perspective. Medchemcomm 9:606-613

[68] Ou B, Hampsch-Woodill M, Prior RL. 2001. Development and valida-tion of an improved oxygen radical absorbance capacity assay using fluorescein as the fluorescent probe. Journal of Agricultural and Food Chemistry 49:4619-4626

[69] Gulati P, Taneja S, Ramasamy SK. 2026. Recent progress and develop-ments on phenothiazine-based fluorescence probe for hypochlorous acid sensing. Journal of Molecular Structure 1349:143837

[70] Matuskey D, Gallezot JD, Nabulsi N, Henry S, Torres K, et al. 2023. Neurotransmitter transporter occupancy following administration of centanafadine sustained-release tablets: a phase 1 study in healthy male adults. Journal of Psychopharmacology 37:164-71

[71] Simon A, Nghiem KS, Gampe N, Garádi Z, Boldizsár I, et al. 2022. Stability study of Alpinia galanga constituents and investigation of their membrane permeability by ChemGPS-NP and the parallel artifi-cial membrane permeability assay. Pharmaceutics 14:1967

[72] Madras BK, Xie Z, Lin Z, Jassen A, Panas H, et al. 2006. Modafinil occu-pies dopamine and norepinephrine transporters in vivo and modu-lates the transporters and trace amine activity in vitro. The Journal of Pharmacology and Experimental Therapeutics 319:561-569

[73] Verrico CD, Miller GM, Madras BK. 2007. MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. Psychopharmacol-ogy 189:489-503

[74] Bottalico B, Larsson I, Brodszki J, Hernandez-Andrade E, Casslén B, et al. 2004. Norepinephrine Transporter (NET), Serotonin Transporter (SERT), Vesicular Monoamine Transporter (VMAT2) and Organic Cation Transporters (OCT1, 2 and EMT) in human placenta from pre-eclamptic and normotensive pregnancies. Placenta 25:518-529

[75] Meltzer PC, Butler D, Deschamps JR, Madras BK. 2006. 1-(4-Methyl-phenyl)-2-pyrrolidin-1-yl-pentan-1-one (pyrovalerone) analogues: a promising class of monoamine uptake inhibitors. Journal of Medicinal Chemistry 49:1420-1432

[76] Green H, Persson M, Wikström M, Monti MC. 2025. In vitro mono-amine reuptake inhibition and forensic case series in Sweden of the synthetic cathinones 2-, 3-, and 4-Me-alpha-PiHP. Forensic Science International 377:112657

[77] Persson M, Vikingsson S, Kronstrand R, Green H. 2024. Characteriza-tion of neurotransmitter inhibition for seven cathinones by a propri-etary fluorescent dye method. Drug Testing and Analysis 16:339-347

[78] Sora I, Hall FS, Andrews AM, Itokawa M, Li XF, et al. 2001. Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proceed-ings of the National Academy of Sciences of the United States of America 98:5300-05

[79] Shen HW, Hagino Y, Kobayashi H, Shinohara-Tanaka K, Ikeda K, et al. 2004. Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters. Neuropsychopharmacology 29:1790-1799

[80] Capuron L, Miller AH. 2011. Immune system to brain signaling: Neuropsychopharmacological implications. Pharmacology & Thera-peutics 130:226-238

[81] Nakatsuka N, Yang KA, Abendroth JM, Cheung KM, Xu X, et al. 2018. Aptamer-field-effect transistors overcome Debye length limitations for small-molecule sensing. Science 362:319-324

[82] Marder SR, Davis JM, Chouinard G. 1997. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. The Journal of Clinical Psychiatry 58:538-546

[83] Daw ND, Kakade S, Dayan P. 2002. Opponent interactions between serotonin and dopamine. Neural Networks 15:603-616

[84] Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, et al. 2003. Arip-iprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 28:1400-1411

[85] Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O'Laughlin IA, et al. 2001. 5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsy-chotic-induced cortical dopamine release. Journal of Neurochemistry 76:1521-1531

[86] Brunello N, Masotto C, Steardo L, Markstein R, Racagni G. 1995. New Insights into the Biology of Schizophrenia through the Mechanism of Action of Clozapine. Neuropsychopharmacology 13:177-213

[87] Łupina M, Wąsik A, Baranowska-Bosiacka I, Tarnowski M, Słowik T, et al. 2024. Acute and chronic exposure to linagliptin, a selective inhibitor of dipeptidyl peptidase-4 (DPP-4), has an effect on dopamine, serotonin and noradrenaline level in the striatum and hippocampus of rats. International Journal of Molecular Sciences 25:3008

[88] Collin F, Karkare S, Maxwell A. 2011. Exploiting bacterial DNA gyrase as a drug target: current state and perspectives. Applied Microbiology and Biotechnology 92:479-497

[89] Gradišar H, Pristovšek P, Plaper A, Jerala R. 2007. Green tea catechins inhibit bacterial DNA gyrase by interaction with its ATP binding site. Journal of Medicinal Chemistry 50:264-271

[90] Khalid M, Haider A, Shahzadi I, Ul-Hamid A, Imran M, et al. 2025. Dual functional samarium-chitosan doped CdTe nanoparticles: Dye degra-dation and bacterial inhibition targeting DHFR and DNA gyrase. Surfaces and Interfaces 72:107046

[91] Ferrero L, Cameron B, Manse B, Lagneaux D, Crouzet J, et al. 1994. Cloning and primary structure of Staphylococcus aureus DNA topoiso-merase IV: a primary target of fluoroquinolones. Molecular Micro-biology 13:641-653

[92] Drlica K, Zhao X. 1997. DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiology and Molecular Biology Reviews 61:377-392

[93] Aldred KJ, Kerns RJ, Osheroff N. 2014. Mechanism of Quinolone Action and Resistance. Biochemistry 53:1565-74

[94] Pham TDM, Ziora ZM, Blaskovich MAT. 2019. Quinolone antibiotics. Medchemcomm 10:1719-1739

[95] Patil GS, Gaikwad KN, Suryawanshi SS, Bhandurge P. 2025. A compre-hensive review on discovery, development, the chemistry of quinolones, and their antimicrobial resistance. Current Topics in Medic-inal Chemistry 00:1-16

[96] Khanna A, Narang A, Thakur V, Singh K, Kumar N, et al. 2025. Design, synthesis, antibacterial evaluation, and molecular modelling studies of 1,2,3-triazole-linked coumarin-vanillin hybrids as potential DNA gyrase and topoisomerase IV inhibitors. Bioorganic Chemistry 164:108815

[97] Zhu M, Tse MW, Weller J, Chen J, Blainey PC. 2021. The future of antibiotics begins with discovering new combinations. Annals of the New York Academy of Sciences 1496:82-96

[98] Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, et al. 2000. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflam-matory drugs for osteoarthritis and rheumatoid arthritis: The CLASS Study: a randomized controlled trial. JAMA 284:1247-1255

[99] Vane JR, Bakhle YS, Botting RM. 1998. Cyclooxygenases 1 and 2. Annual Review of Pharmacology and Toxicology 38:97-120

[100] Smith WL, DeWitt DL, Garavito RM. 2000. Cyclooxygenases: structural, cellular, and molecular biology. Annual Review of Biochemistry 69:145-182

[101] Abdul-Malik MA, El-Dean AMK, Hussein AHM, Abdelmonsef AH, Tolba MS. 2026. Synthesis, in silico and in vivo evaluation of new pyrazole-based thiosemicarbazones containing thiazole and thiazolone moieties as potential anti-inflammatory agents. Journal of Molecular Structure 1350:143990

[102] Isa A, Banevičiūtė E, Piskin E, Cetinkaya A, Atici EB, et al. 2026. Design of an electrochemical sensor based on molecularly imprinted poly-mers for sensitive and selective detection of the JAK inhibitor barici-tinib. Journal of Pharmaceutical and Biomedical Analysis 267:117154

[103] Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, et al. 2016. Mutations Associated with Acquired Resistance to PD-1 Block-ade in Melanoma. The New England Journal of Medicine 375:819-829

[104] Heinrich PC, Behrmann I, Müller-Newen G, Schaper F, Graeve L. 1998. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. The Biochemical Journal 334:297-314

[105] Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, et al. 2010. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. The New England Journal of Medicine 363:1117-1127

[106] McNally R, Eck MJ. 2014. JAK-cytokine receptor recognition, unboxed. Nature Structural & Molecular Biology 21:431-33

[107] Tong X, Qiao S, Dong Z, Zhao X, Du X, et al. 2024. Targeting CSF1R in myeloid-derived suppressor cells: insights into its immunomodula-tory functions in colorectal cancer and therapeutic implications. Jour-nal of Nanobiotechnology 22:409

[108] Yu H, Pardoll D, Jove R. 2009. STATs in cancer inflammation and immunity: a leading role for STAT3. Nature Reviews Cancer 9:798-809

[109] Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, et al. 2003. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. The Biochemical Journal 374:1-20

[110] Wang Z, Wang M, Sun Y. 2025. Vitiligo exacerbation during upadaci-tinib treatment for atopic dermatitis and improvement following a switch to abrocitinib: a case report. Journal of Dermatological Treat-ment 36:2528344

[111] Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, et al. 2008. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. Jour-nal of the National Cancer Institute 100:672-9

[112] Aggarwal BB, Shishodia S. 2006. Molecular targets of dietary agents for prevention and therapy of cancer. Biochemical Pharmacology 71:1397-1421

[113] Mekheimer RA, Al-Sheikh MA, Medrasi HY, Jaragh-Alhadad L, Moustafa MS, et al. 2026. Design, synthesis, and antiproliferative activ-ity of antipyrine linked 2-amino-quinoline-3-carbonitrile derivatives as potential dual EGFR/HER-2 inhibitors. Journal of Molecular Structure 1349:143789

[114] Munir M, Forentin AM, Febrian MB, Fakih TM, Utomo RY, et al. 2025. Radiosynthesis of [131I]I-hesperidin: optimization, physicochemical profiling, and computational insights for targeted radiopharmaceuti-cals. Applied Radiation and Isotopes 225:111977

[115] Salemi A, Zenjanab MK, Adili Aghdam MA, Sahragardan N, Esfahlan RJ. 2025. Niosome-loaded silibinin and methotrexate for synergistic breast cancer combination chemotherapy: in silico and in vitro study. Cancer Cell International 25:336

[116] Moura SPSP, Cascante M, Rufino I, Guedes RC, Marin S, et al. 2025. Synthesis and biological evaluation of novel carnosic acid derivatives with anticancer activity. RSC Advances 15:36861-36878

[117] Hu H, Wang Y, Wang M, Zhang Z, Gu X, et al. 2025. Translational Research on the Oral Delivery of the Cytotoxic PROTAC Molecule via Tumor-Targeting Prodrug Strategy for Triple-Negative Breast Cancer Treatment. Journal of Medicinal Chemistry 68:20464-86

[118] Vani S, Balasubramanyam D, Karthickeyan SMK, Tirumurugan KG, Gopinathan A, et al. 2025. Genome-wide selective sweeps providing classic evidence of emotional and behavioural control in Bos indicus cattle breeds. Journal of Livestock Science 16:392-401

[119] Shang Y, Wang Q, Feng S, Du Z, Liang S, et al. 2024. Antioxidant mech-anism of black garlic based on network pharmacology and molecular docking. Journal of Biobased Materials and Bioenergy 18:215-224

[120] McCoach CE, Le AT, Gowan K, Jones K, Schubert L, et al. 2018. Resis-tance mechanisms to targeted therapies in ROS1+ and ALK+ non-small cell lung cancer. Clinical Cancer Research 24:3334-3347

[121] Suehara Y, Alex D, Bowman A, Middha S, Zehir A, et al. 2019. Clinical genomic sequencing of pediatric and adult osteosarcoma reveals distinct molecular subsets with potentially targetable alterations. Clin-ical Cancer Research 25:6346-6356

[122] Gorin NC. 2022. Développements thérapeutiques en hématologie au XXIe siècle. Bulletin de l'Académie Nationale de Médecine 206:952-60

[123] Pyne S, Pyne NJ. 2000. Sphingosine 1-phosphate signalling in mammalian cells. The Biochemical Journal 349:385-402

[124] Hunter T. 2012. Why nature chose phosphate to modify proteins. Philosophical Transactions of the Royal Society of London Series b, Biological Sciences 367:2513-2516

[125] Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, et al. 2008. A quantitative analysis of kinase inhibitor selectivity. Nature Biotechnology 26:127-132

[126] Lipson D, Capelletti M, Yelensky R, Otto G, Parker A, et al. 2012. Identi-fication of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nature Medicine 18:382-384

[127] Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, et al. 2011. SCFFBW 7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471:104-109

[128] Louandre C, Ezzoukhry Z, Godin C, Barbare JC, Mazière JC, et al. 2013. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. International Journal of Cancer 133:1732-1742

[129] Gao S, Wang X, Zhao X, Xiao Z. 2026. Rational design of next-genera-tion FLT 3 inhibitors in acute myeloid leukemia: from laboratory to clinics. European Journal of Medicinal Chemistry 301:118214

[130] Yuan Y, Wang MR, Ding Y, Lin Y, Xu TT, et al. 2025. Lenvatinib promotes hepatocellular carcinoma pyroptosis by regulating GSDME palmitoylation. Cancer Biology & Therapy 26:2532217

[131] Guo J, Liu H, Zheng J. 2016. SynLethDB: synthetic lethality database toward discovery of selective and sensitive anticancer drug targets. Nucleic Acids Research 44:D1011-D1017

[132] Wang J, Wu M, Huang X, Wang L, Zhang S, et al. 2022. SynLethDB 2.0: a web-based knowledge graph database on synthetic lethality for novel anticancer drug discovery. Database 2022:baac030

[133] Ying S, Hamdy FC, Helleday T. 2012. Mre11-dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1. Cancer Research 72:2814-2821

[134] Liu H, Zhang W, Zou B, Wang J, Deng Y, Deng L. 2020. DrugCombDB: a comprehensive database of drug combinations toward the discovery of combinatorial therapy. Nucleic Acids Research 48:D871-D881

[135] Neri D, Supuran CT. 2011. Interfering with pH regulation in tumours as a therapeutic strategy. Nature Reviews Drug Discovery 10:767-777

[136] Supuran CT. 2016. Structure and function of carbonic anhydrases. The Biochemical Journal 473:2023-2032

[137] Pala N, Ladu F, Szlasa W, Cadoni R, Lomelino C, et al. 2025. Design, anticancer activity, and mechanistic evaluation of a novel class of selective human carbonic anhydrase IX inhibitors featuring a trifluo-rodihydroxypropanone pharmacophore. European Journal of Medici-nal Chemistry 298:118043

[138] Jung S, Strotmann R, Schultz G, Plant TD. 2002. TRPC6 is a candidate channel involved in receptor-stimulated cation currents in A7r5 smooth muscle cells. American Journal of Physiology Cell Physiology 282:C347-C359

[139] Soboloff J, Spassova M, Xu W, He LP, Cuesta N, Gill DL. 2005. Role of endogenous TRPC6 channels in Ca2+ signal generation in A7r5 smooth muscle cells. The Journal of Biological Chemistry 280:39786-39794

[140] Kola PK, Oraegbuna CS, Lei S. 2024. Ionic mechanisms involved in arginine vasopressin-mediated excitation of auditory cortical and thalamic neurons. Molecular and Cellular Neuroscience 130:103951

[141] Colović MB, Krstić DZ, Lazarević-Pašti TD, Bondžić AM, Vasić VM. 2013. Acetylcholinesterase inhibitors: pharmacology and toxicology. Current Neuropharmacology 11:315-335

[142] Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL. 2007. Evolving the lock to fit the key to create a family of G protein-coupled recep-tors potently activated by an inert ligand. Proceedings of the National Academy of Sciences of the United States of America 104:5163-5168

[143] Oğlak SC, Aşır F, Korak T, Aşır A, Yılmaz EZ, et al. 2025. Reduced M3 muscarinic acetylcholine receptor expression in gestational diabetes mellitus: implications for placental dysfunction and vascular regula-tion. The Journal of Maternal-Fetal & Neonatal Medicine 38:2521799

[144] Marsh SA, Heslep N, Paronis CA, Bergman J, Negus SS, et al. 2025. Xanomeline treatment attenuates cocaine self-administration in rats and nonhuman primates. Neuropharmacology 281:110686

[145] Liu W, Putnam AL, Zhou XY, Szot GL, Lee MR, et al. 2006. CD 127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. The Journal of Experimental Medicine 203:1701-11

[146] Bendall SC, Simonds EF, Qiu P, Amir el AD, Krutzik PO, et al. 2011. Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science 332:687-96

[147] Chistiakov DA, Killingsworth MC, Myasoedova VA, Orekhov AN, Bobry-shev YV. 2017. CD68/macrosialin: not just a histochemical marker. Laboratory Investigation 97:4-13

[148] Li S, Li J, Al Faruque H, Shami P, Knoechel B, et al. 2025. Self-assem-bling multi-antigen T cell hybridizers for precision immunotherapy of multiple myeloma. Advanced Healthcare Materials 14:e02156

[149] Furka Á. 2022. Forty years of combinatorial technology. Drug Discov-ery Today 27:103308

[150] Hajduk PJ, Greer J. 2007. A decade of fragment-based drug design: strategic advances and lessons learned. Nature Reviews Drug Discov-ery 6:211-219

[151] Shi B, Zhou Y, Li X. 2022. Recent advances in DNA-encoded dynamic libraries. RSC Chemical Biology 3:407-419

[152] Clark MA, Acharya RA, Arico-Muendel CC, Belyanskaya SL, Benjamin DR, et al. 2009. Design, synthesis and selection of DNA-encoded small-molecule libraries. Nature Chemical Biology 5:647-54

[153] Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, et al. 2020. Struc-ture, function, and antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 181:281-292.e6

[154] Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, et al. 2020. Cryo-EM structure of the 2019-nCoV spike in the prefusion conforma-tion. Science 367:1260-63

[155] Altman JD, Moss PAH, Goulder PJR, Barouch DH, McHeyzer-Williams MG, et al. 1996. Phenotypic analysis of antigen-specific T lympho-cytes. Science 274:94-96

[156] Jiang B, Koo SH, Ang DSW, Ang TL, Lee HZ, et al. 2026. Development of a real-time polymerase chain reaction (RT-PCR) assay for simultane-ous detection of Helicobacter pylori infection and genetic mutations associated with clarithromycin resistance: A single-center, cross-sectional study from Singapore. Diagnostic Microbiology and Infec-tious Disease 114:117131

[157] Schedin F, Geim AK, Morozov SV, Hill EW, Blake P, et al. 2007. Detec-tion of individual gas molecules adsorbed on graphene. Nature Mate-rials 6:652-5

[158] Josefsen LB, Boyle RW. 2012. Unique diagnostic and therapeutic roles of porphyrins and phthalocyanines in photodynamic therapy, imag-ing and theranostics. Theranostics 2:916-66

[159] Lee KY, Mooney DJ. 2012. Alginate: properties and biomedical appli-cations. Progress in Polymer Science 37:106-126

[160] Stuart MAC, Huck WTS, Genzer J, Müller M, Ober C, et al. 2010. Emerg-ing applications of stimuli-responsive polymer materials. Nature Mate-rials 9:101-113

[161] Cho JH, Collins JJ, Wong WW. 2018. Universal Chimeric antigen recep-tors for multiplexed and logical control of T cell responses. Cell 173:1426-1438.e11

[162] Röthlisberger P, Hollenstein M. 2018. Aptamer chemistry. Advanced Drug Delivery Reviews 134:3-21

[163] Giraudet R, Laroche A, Chalopin B, Dubois S, Correia E, et al. 2025. Immunogenicity of single-chain antibodies: germlining of a VHH lowers T-cell activation from epitopes in FR2 and CDR regions. mAbs 17:2571406

[164] Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, et al. 2020. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. The New England Journal of Medicine 383:2603-15

[165] Millán-Martín S, Guapo F, Carillo S, Mistarz UH, Cook K, et al. 2026. Characterisation of small RNA-based therapeutics and their process impurities by fast and sensitive liquid chromatography high resolu-tion mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis 268:117097

[166] Cheng L, Wang T, Pi R, Zhao P, Chen J. 2025. A novel derivative of rhein overcomes temozolomide resistance in glioblastoma by regu-lating SOX9 through m6A methylation. Brain Research 1866:149889

[167] Illuminati D, Foschi R, Marchetti P, Zanirato V, Fantinati A, et al. 2025. Multi-step synthesis of chimeric nutlin-DCA compounds targeting dual pathways for treatment of cancer. Molecules 30:3908

[168] Xie SS, Lan JS, Wang X, Wang ZM, Jiang N, et al. 2016. Design, synthe-sis and biological evaluation of novel donepezil-coumarin hybrids as multi-target agents for the treatment of Alzheimer's disease. Bio-organic & Medicinal Chemistry 24:1528-1539

[169] Zheng W, Zhao Y, Luo Q, Zhang Y, Wu K, Wang F. 2017. Multi-targeted anticancer agents. Current Topics in Medicinal Chemistry 17:3084-3098

[170] Assaraf YG, Brozovic A, Gonçalves AC, Jurkovicova D, Linē A, et al. 2019. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resistance Updates 46:100645

[171] Cohen L, Livney YD, Assaraf YG. 2021. Targeted nanomedicine modal-ities for prostate cancer treatment. Drug Resistance Updates 56:100762

[172] Perona MTG, Waters S, Hall FS, Sora I, Lesch KP, et al. 2008. Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine trans-porter deletions. Behavioural Pharmacology 19:566-574

[173] Fathullahzadeh S, Mirzaei H, Honardoost MA, Sahebkar A, Salehi M. 2016. Circulating microRNA-192 as a diagnostic biomarker in human chronic lymphocytic leukemia. Cancer Gene Therapy 23:327-332

[174] Honardoost MA, Kiani-Esfahani A, Ghaedi K, Etemadifar M, Salehi M. 2014. miR-326 and miR-26a, two potential markers for diagnosis of relapse and remission phases in patient with relapsing-remitting multiple sclerosis. Gene 544:128-133

[175] Wang Y, Zhang S, Li F, Zhou Y, Zhang Y, et al. 2020. Therapeutic target database 2020:enriched resource for facilitating research and early development of targeted therapeutics. Nucleic Acids Research 48:D1031-D1041

[176] Avillach P, Mougin F, Joubert M, Thiessard F, Pariente A, et al. 2009. A semantic approach for the homogeneous identification of events in eight patient databases: a contribution to the European eu-ADR project. Studies in Health Technology and Informatics 150:190-194

[177] Avillach P, Joubert M, Thiessard F, Trifirò G, Dufour JC, et al. 2010. Design and evaluation of a semantic approach for the homogeneous identification of events in eight patient databases: a contribution to the European EU-ADR project. Studies in Health Technology and Infor-matics 160:1085-1089

[178] Simon J, Dos Santos M, Fielding J, Smith B. 2006. Formal ontology for natural language processing and the integration of biomedical databases. International Journal of Medical Informatics 75:224-231

[179] Bodenreider O. 2004. The Unified Medical Language System (UMLS): integrating biomedical terminology. Nucleic Acids Research 32:D267-D270

[180] Schnell R, Bachteler T, Reiher J. 2009. Privacy-preserving record link-age using Bloom filters. BMC Medical Informatics and Decision Making 9:41

[181] Schnell R, Borgs C.Building a National Perinatal Data Base without the Use of Unique Personal Identifiers. 2015 IEEE International Conference on Data Mining Workshop (ICDMW), 2015, Atlantic City, NJ, USA. USA: IEEE. pp. 232-239 doi: 10.1109/ICDMW.2015.19

[182] Brown EG. 2003. Methods and pitfalls in searching drug safety databases utilising the Medical Dictionary for Regulatory Activities (MedDRA). Drug Safety 26:145-158

[183] Djennaoui M, Ficheur G, Beuscart R, Chazard E. 2015. Improvement of the quality of medical databases: data-mining-based prediction of diagnostic codes from previous patient codes. Studies in Health Tech-nology and Informatics 210:419-423

[184] Voss EA, Makadia R, Matcho A, Ma Q, Knoll C, et al. 2015. Feasibility and utility of applications of the common data model to multiple, disparate observational health databases. Journal of the American Medical Informatics Association 22:553-64

[185] Stadler CB, Lindvall M, Lundström C, Bodén A, Lindman K, et al. 2021. Proactive construction of an annotated imaging database for artificial intelligence training. Journal of Digital Imaging 34:105-115