{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T10:45:12Z","timestamp":1764240312809,"version":"3.46.0"},"reference-count":63,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Merck Sharp & Dohme LLC"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Proinsulin, the precursor to insulin, has limited activity on the insulin receptor. Proinsulin levels increase with increasing insulin resistance in type 2 diabetes due to incomplete processing by the \u03b2-cell. To assess whether the development of peptides that could convert circulating proinsulin to insulin in the blood would provide therapeutic value, we used a quantitative systems pharmacology (QSP) model of glucose homeostasis. In silico hypothesis testing such as this is an example of how modeling can inform decisions in drug discovery. Methods: In silico hypothesis testing involved (1) the addition and qualification of proinsulin biology into a preexisting QSP model, (2) the creation and validation of virtual patients (VPs) for subpopulations of type 2 diabetics based on phenotypic traits, and (3) the simulation of clinical trials evaluating the therapeutic value of the conversion of circulating proinsulin to insulin in the VPs created. Results: Proinsulin conversion led to a ~0.2% reduction in HbA1c in VPs at varying stages of diabetes, a decrease that does not hold meaningful therapeutic value. The lack of significant impact on HbA1c was likely a result of the surprisingly small effect on plasma insulin levels from proinsulin, which has a significantly slower secretion and clearance rate. Although patients with higher proinsulin\/insulin ratios showed the largest reductions, clinically significant \u2265 0.5% reduction in HbA1c required ratios of proinsulin\/insulin above the reported physiological range. Conclusions: This effort demonstrates how in silico hypothesis testing using QSP modeling can provide insights on the probability of success of novel interventions with minimal time and resources. These efficiencies are a means of overcoming the pressures on the pharmaceutical industry to do more with less in providing therapies that improve the lives of patients.<\/jats:p>","DOI":"10.3390\/pharmaceutics17121522","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T10:25:16Z","timestamp":1764239116000},"page":"1522","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Silico Hypothesis Testing in Drug Discovery: Using Quantitative Systems Pharmacology Modeling to Evaluate the Therapeutic Value of Proinsulin Conversion to Insulin Therapy for Type 2 Diabetes Mellitus"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-5532","authenticated-orcid":false,"given":"Maria E.","family":"Trujillo","sequence":"first","affiliation":[{"name":"Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7372-6724","authenticated-orcid":false,"given":"Yue","family":"Han","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3966-6320","authenticated-orcid":false,"given":"Rebecca A.","family":"Baillie","sequence":"additional","affiliation":[{"name":"Rosa and Co., LLC, San Carlos, CA 94070, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael C.","family":"Weis","sequence":"additional","affiliation":[{"name":"Rosa and Co., LLC, San Carlos, CA 94070, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4243-234X","authenticated-orcid":false,"given":"Douglas","family":"Chung","sequence":"additional","affiliation":[{"name":"Rosa and Co., LLC, San Carlos, CA 94070, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean","family":"Hayes","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul E.","family":"Carrington","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Reed","sequence":"additional","affiliation":[{"name":"Rosa and Co., LLC, San Carlos, CA 94070, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"682","DOI":"10.2337\/diacare.27.3.682","article-title":"Fasting intact proinsulin is a highly specific predictor of insulin resistance in type 2 diabetes","volume":"27","author":"Pfutzner","year":"2004","journal-title":"Diabetes Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/BF00400421","article-title":"Fasting proinsulin and 2-h post-load glucose levels predict the conversion to NIDDM in subjects with impaired glucose tolerance: The Hoorn Study","volume":"39","author":"Nijpels","year":"1996","journal-title":"Diabetologia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1177\/193229681100500333","article-title":"Elevated intact proinsulin levels are indicative of Beta-cell dysfunction, insulin resistance, and cardiovascular risk: Impact of the antidiabetic agent pioglitazone","volume":"5","author":"Pfutzner","year":"2011","journal-title":"J. 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