{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:55:40Z","timestamp":1792526140528,"version":"4.5.0"},"reference-count":54,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100023015","name":"Advanced Research Projects Agency for Health","doi-asserted-by":"publisher","award":["1AY2AX000124"],"award-info":[{"award-number":["1AY2AX000124"]}],"id":[{"id":"10.13039\/100023015","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The target\u2010engagement predictor, implemented within the InSilicoTrials cloud\u2010based, AI\u2010powered platform for model\u2010informed drug discovery and development, enables early exploration of time\u2010dependent pharmacological responses. Predictions can be generated using inputs ranging from molecular structure to in\u00a0vitro, animal, and clinical data. Scaling and translation across species are supported, accounting for differences in body size and plasma protein binding. This tutorial demonstrates the application of the target\u2010engagement predictor for benchmarking and decision\u2010support in the evaluation of new drug candidates. Pharmacokinetic (PK) and pharmacodynamic (PD) data for carvedilol, ivabradine, and sunitinib were used as illustrative examples. The ANDROMEDA and PLATO software were used to predict human clinical PK and target affinity parameters, respectively, based on molecular SMILES representations of the drugs. These predictions were subsequently incorporated into longitudinal PKPD simulation models. User\u2010friendly input wizards and interactive results dashboards were developed to facilitate clinical trial simulation for broader project teams, without requiring programming expertise. Predictions derived from molecular structure were compared with data generated from in\u00a0vitro, rat, and clinical experimental settings. The target\u2010engagement predictor enables integration of heterogenous data sources to support drug development decisions, including early benefit\u2013risk assessment and dose selection for Phase 1 studies. Direct prediction based on molecular structure alone represents a promising approach for early\u2010stage screening and evaluation of new drug candidates.<\/jats:p>","DOI":"10.1002\/psp4.70353","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:38:52Z","timestamp":1792157932000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Target\u2010Engagement Prediction From Molecular Structure, In\u00a0Vitro and Animal Data: A Tutorial for Early Assessment of Clinical Drug Exposure and Therapeutic\/Adverse Potential Using the\n                    <scp>ANDROMEDA<\/scp>\n                    and\n                    <scp>PLATO<\/scp>\n                    Software on the\n                    <scp>InSilicoTrials<\/scp>\n                    Platform"],"prefix":"10.1002","volume":"15","author":[{"given":"Niccol\u00f2","family":"Totis","sequence":"first","affiliation":[{"name":"InSilicoTrials Technologies S.P.A.  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fianne","family":"Sips","sequence":"additional","affiliation":[{"name":"InSilicoTrials Technologies B.V.  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6132-5712","authenticated-orcid":false,"given":"Simona","family":"Catozzi","sequence":"additional","affiliation":[{"name":"InSilicoTrials Technologies S.P.A.  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc\u2010Antonio","family":"Bisotti","sequence":"additional","affiliation":[{"name":"InSilicoTrials Technologies S.P.A.  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Bambury","sequence":"additional","affiliation":[{"name":"InSilicoTrials Technologies S.P.A.  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Stathopoulos","sequence":"additional","affiliation":[{"name":"InSilicoTrials Technologies S.P.A.  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0800-7138","authenticated-orcid":false,"given":"Vincenzo","family":"Carbone","sequence":"additional","affiliation":[{"name":"InSilicoTrials Technologies S.P.A.  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Emili","sequence":"additional","affiliation":[{"name":"InSilicoTrials Technologies S.P.A.  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3589-8648","authenticated-orcid":false,"given":"Mario","family":"Torchia","sequence":"additional","affiliation":[{"name":"InSilicoTrials Technologies S.P.A.  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Belgiovine","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia\u2014Scienze del Farmaco Universit\u00e0 degli Studi di Bari \u201cAldo Moro\u201d  Bari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0695-6607","authenticated-orcid":false,"given":"Fulvio","family":"Ciriaco","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica Universit\u00e0 degli Studi di Bari \u201cAldo Moro\u201d  Bari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6533-5539","authenticated-orcid":false,"given":"Orazio","family":"Nicolotti","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia\u2014Scienze del Farmaco Universit\u00e0 degli Studi di Bari \u201cAldo Moro\u201d  Bari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6300-359X","authenticated-orcid":false,"given":"Urban","family":"Fagerholm","sequence":"additional","affiliation":[{"name":"Prosilico AB  Huddinge Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7793-3008","authenticated-orcid":false,"given":"Candice N.","family":"Baker","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1425-5939","authenticated-orcid":false,"given":"J. Matthew","family":"Mahoney","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1633-7999","authenticated-orcid":false,"given":"Daniel","family":"R\u00f6shammar","sequence":"additional","affiliation":[{"name":"InSilicoTrials Technologies S.P.A.  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the CARDIOVERSE Project","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.drudis.2021.12.010","article-title":"Achieving End\u2010To\u2010End Success in the Clinic: Pfizer's Learnings on R&D Productivity","volume":"27","author":"Fernando K.","year":"2022","journal-title":"Drug Discovery Today"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.drudis.2020.10.019","article-title":"Reviving an R&D Pipeline: A Step Change in the Phase II Success Rate","volume":"26","author":"Wu S. S.","year":"2021","journal-title":"Drug Discovery Today"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.drudis.2011.12.020","article-title":"Can the Flow of Medicines Be Improved? Fundamental Pharmacokinetic and Pharmacological Principles Toward Improving Phase II Survival","volume":"17","author":"Morgan P.","year":"2012","journal-title":"Drug Discovery Today"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248\u2010008\u20109041\u20108"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.13479"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.16195"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13812"},{"key":"e_1_2_9_9_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.cmpb.2023.107860","article-title":"Combining Pharmacokinetic and Electrophysiological Models for Early Prediction of Drug\u2010Induced Arrhythmogenicity","volume":"242","author":"Llopis\u2010Lorente J.","year":"2023","journal-title":"Computer Methods and Programs in Biomedicine"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476\u20105381.2011.01255.x"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/ftox.2024.1352783"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/10915818251375348"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117575"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c00498"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.8b00698"},{"issue":"9","key":"e_1_2_9_16_1","doi-asserted-by":"crossref","DOI":"10.3390\/ijms23095245","article-title":"PLATO: A Predictive Drug Discovery Web Platform for Efficient Target Fishing and Bioactivity Profiling of Small Molecules","volume":"23","author":"Ciriaco F.","year":"2022","journal-title":"International Journal of Molecular Sciences"},{"key":"e_1_2_9_17_1","doi-asserted-by":"crossref","DOI":"10.3390\/molecules26092572","article-title":"Advances in Predictions of Oral Bioavailability of Candidate Drugs in Man With New Machine Learning Methodology","volume":"26","author":"Fagerholm U.","year":"2021","journal-title":"Molecules"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498254.2021.2011"},{"key":"e_1_2_9_19_1","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1080\/00498254.2021.1964044","article-title":"Comparison Between Lab Variability and In Silico Prediction Errors for the Unbound Fraction of Drugs in Human Plasma","volume":"51","author":"Fagerholm U.","year":"2021","journal-title":"Xenobiot"},{"issue":"1","key":"e_1_2_9_20_1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1177\/02611929221148447","article-title":"In Silico Prediction of Human Clinical Pharmacokinetics With ANDROMEDA by Prosilico: Predictions for an Established Benchmarking Data Set, a Modern Small Drug Data Set, and a Comparison With Laboratory Methods","volume":"51","author":"Fagerholm U.","year":"2023","journal-title":"sAlternatives to Laboratory Animals"},{"key":"e_1_2_9_21_1","doi-asserted-by":"crossref","unstructured":"U.Fagerholm \u201cEvaluation of the Basis and Performance of Simple Allometry for Predictions of Clearance and Oral Clearance in Humans and Improvement Potential With Added In Silico Predictions \u201d (2025) bioRxiv: The Preprint Server for Biology.","DOI":"10.1101\/2025.05.05.652242"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010023\u201009878\u20104"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10439\u2010022\u201003052\u20106"},{"key":"e_1_2_9_24_1","unstructured":"K.Baron \u201cmrgsolve: Simulate From ODE\u2010Based Models \u201d (2025) R package version 1.6.1 https:\/\/mrgsolve.org\/docs\/mrgsolve.org."},{"key":"e_1_2_9_25_1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.xphs.2020.09.055","article-title":"Predicting With Confidence: Using Conformal Prediction in Drug Discovery","volume":"110","author":"Alvarsson J.","year":"2021","journal-title":"Journal of Pharmaceutical Sciences"},{"key":"e_1_2_9_26_1","doi-asserted-by":"crossref","DOI":"10.1186\/s13321-024-00870-9","article-title":"CPSign: Conformal Prediction for Cheminformatics Modeling","volume":"16","author":"Arvidsson McShane S.","year":"2024","journal-title":"Journal of Cheminformatics"},{"key":"e_1_2_9_27_1","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/sj.bjp.0706048","article-title":"The Selectivity of b\u2010Adrenoceptor Antagonists at the Human b1, b2 and b3 Adrenoceptors","volume":"144","author":"Baker J. G.","year":"2005","journal-title":"British Journal of Pharmacology"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1211\/jpp.62.07.0010"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.3346\/jkms.2023.38.e173"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.19933260907"},{"key":"e_1_2_9_31_1","unstructured":"https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2005\/020297s013lbl.pdf."},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm1006758"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.120.000348"},{"key":"e_1_2_9_34_1","unstructured":"M.Skerlep E.Mezzalana M.Chenel N.Gendrot andS.Fouliard \u201cModel\u2010Based Approach for a New Prolonged\u2010Release (PR) Formulation of Ivabradine: PK and PKPD Assessment to Support Bioequivalence \u201d Abstr 11678 (2025) 11678 https:\/\/www.page\u2010meeting.org\/?abstract=11678."},{"key":"e_1_2_9_35_1","unstructured":"\u201cFDA Pharmacology Review for Ivabradine \u201d (2015) https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2015\/206143Orig1s000PharmR.pdf."},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0304782"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401\u2010019\u20100331\u20108"},{"issue":"7","key":"e_1_2_9_38_1","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1158\/1078-0432.CCR-08-1893","article-title":"A Population Pharmacokinetic Meta\u2010Analysis of Sunitinib Malate (SU11248) and Its Primary Metabolite (SU12662) in Healthy Volunteers and Oncology Patients","volume":"15","author":"Houk B. E.","year":"2009","journal-title":"Clinical Cancer Research"},{"issue":"9","key":"e_1_2_9_39_1","first-page":"604","article-title":"Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib\u2010Treated Cancer","volume":"6","author":"Diekstra M. H.","year":"2017","journal-title":"CPT: Pharmacometrics & Systems Pharmacology"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S112242"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.22550"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2024.104238"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2020.03.004"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdd.2359"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.6c00429"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci400084k"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1846"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2022.107171"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010016\u20100404\u20105"},{"key":"e_1_2_9_50_1","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1111\/bph.14103","article-title":"Quantifying the Relationship Between Inhibition of VEGF Receptor 2, Drug\u2010Induced Blood Pressure Elevation and Hypertension","volume":"175","author":"Collins T.","year":"2018","journal-title":"British Journal of Pharmacology"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.119.018101"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(05)67394\u20101"},{"key":"e_1_2_9_53_1","doi-asserted-by":"crossref","first-page":"47","DOI":"10.18773\/austprescr.2004.039","article-title":"Inside the Isomers: The Tale of Chiral Switches","volume":"27","author":"Somogyi A.","year":"2004","journal-title":"Australian Prescriber"},{"key":"e_1_2_9_54_1","first-page":"185","article-title":"Stereospecific Pharmacokinetics and Pharmacodynamics of Beta\u2010Adrenergic Blockers in Humans","volume":"4","author":"Mehvar R.","year":"2001","journal-title":"Journal of Pharmacy & Pharmaceutical Sciences"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.260057060"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70353","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.70353","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70353","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:38:56Z","timestamp":1792157936000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.70353"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,16]]},"references-count":54,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["10.1002\/psp4.70353"],"URL":"https:\/\/doi.org\/10.1002\/psp4.70353","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,16]]},"assertion":[{"value":"2026-06-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70353"}}