Molecular Pharmaceutics最新文献

{"title":"A Pharmaceutical Scientist's Journey: My Path to an Academic Career.","authors":"Tze Ning Hiew","doi":"10.1021/acs.molpharmaceut.4c00860","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00860","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coarse-Grained Simulation of mRNA-Loaded Lipid Nanoparticle Self-Assembly","authors":"Douglas J. Grzetic*,&nbsp;Nicholas B. Hamilton and John C. Shelley*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0021610.1021/acs.molpharmaceut.4c00216","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00216https://doi.org/10.1021/acs.molpharmaceut.4c00216","url":null,"abstract":"<p >Ionizable lipid-containing lipid nanoparticles (LNPs) have enabled the delivery of RNA for a range of therapeutic applications. In order to optimize safe, targeted, and effective LNP-based RNA delivery platforms, an understanding of the role of composition and pH in their structural properties and self-assembly is crucial, yet there have been few computational studies of such phenomena. Here we present a coarse-grained model of ionizable lipid and mRNA-containing LNPs. Our model allows access to the large length- and time-scales necessary for LNP self-assembly and is mapped and parametrized with reference to all-atom structures and simulations of the corresponding components at compositions typical of LNPs used for mRNA delivery. Our simulations reveal insights into the dynamics of self-assembly of such mRNA-encapsulating LNPs, as well as the subsequent pH change-driven LNP morphology and release of mRNA.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the Potential of Vitamin B3-Derived Salts with a Salicylate Anion as Dermal Active Agents for Acne Treatment","authors":"Adriana Olejniczak,&nbsp;Witold Stachowiak,&nbsp;Daniel Ziental,&nbsp;Jolanta Długaszewska,&nbsp;Tomasz Rzemieniecki,&nbsp;Marcin Wysokowski,&nbsp;Teofil Jesionowski and Michał Niemczak*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0054310.1021/acs.molpharmaceut.4c00543","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00543https://doi.org/10.1021/acs.molpharmaceut.4c00543","url":null,"abstract":"<p >This study is focused on the utilization of naturally occurring salicylic acid and nicotinamide (vitamin B₃) in the development of novel sustainable Active Pharmaceutical Ingredients (APIs) with significant potential for treating acne vulgaris. The study highlights how the chemical structure of the cation significantly influences surface activity, lipophilicity, and solubility in aqueous media. Furthermore, the new ionic forms of APIs, the synthesis of which was assessed with <i>Green Chemistry</i> metrics, exhibited very good antibacterial properties against common pathogens that contribute to the development of acne, resulting in remarkable enhancement of biological activity ranging from 200 to as much as 2000 times when compared to salicylic acid alone. The molecular docking studies also revealed the excellent anti-inflammatory activity of <i>N</i>-alkylnicotinamide salicylates comparable to commonly used drugs (indomethacin, ibuprofen, and acetylsalicylic acid) and were even characterized by better IC₅₀ values than common anti-inflammatory drugs in some cases. The derivative, featuring a decyl substituent in the pyridinium ring of nicotinamide, exhibited efficacy against <i>Cutibacterium acnes</i> while displaying favorable water solubility and improved wettability on hydrophobic surfaces, marking it as particularly promising. To investigate the impact of the APIs on the biosphere, the EC₅₀ parameter was determined against a model representative of crustaceans─<i>Artemia franciscana</i>. The majority of compounds (with the exception of the salt containing the dodecyl substituent) could be classified as “Relatively Harmless” or “Practically Nontoxic”, indicating their potential low environmental impact, which is essential in the context of modern drug development.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.molpharmaceut.4c00543","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Feasibility of Laboratory Equipment-Based Simulation Methods to Assess the Impact of Vehicle Transportation on Product Quality of mAb Dosing Solutions","authors":"Kashappa Goud Desai*,&nbsp;Cait Sofa,&nbsp;Ning Wang,&nbsp;Bivash Mandal,&nbsp;Brendan Blockus,&nbsp;Nathan Heacock and James D. Colandene,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0068110.1021/acs.molpharmaceut.4c00681","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00681https://doi.org/10.1021/acs.molpharmaceut.4c00681","url":null,"abstract":"<p >Therapeutic monoclonal antibody (mAb) products for intravenous (IV) administration generally require aseptic compounding with a commercially available diluent. When the administration site is located away from the preparation site, the prepared dosing solution may need to be transported in a vehicle. The impact of vehicle transportation on the product quality of mAbs needs to be evaluated to define safe handling and transportation conditions for dosing solutions. The design and execution of actual vehicle transportation studies require considerable resources and time. In this study, we systematically developed three different laboratory equipment-based methods that simulate vehicle transportation stresses: orbital shaker (OS), reciprocating shaker (RS), and vibration test system (VTS)-based simulation methods. We assessed their feasibility by comparing the impact on product quality caused by each simulated method with that caused by actual vehicle transportation. Without residual polysorbate 80 (PS80) in the mAb dosing solution, transportation via a cargo van led to a considerable increase in the subvisible particle counts and did not meet the compendial specifications for the light obscuration method. However, the presence of as low as 0.0004%w/v (4 ppm) PS80 in the dosing solution stabilized the mAb against vehicle transportation stresses and met the compendial specifications. Vehicle transportation of an IV bag with headspace resulted in negligible micro air bubbles and foaming in both PS80-free and PS80-containing mAb dosing solutions. These phenomena were found to be comparable to the VTS-based simulated method. However, the OS- and RS-based simulated methods formed significantly more micro air bubbles and foaming in an IV bag with headspace than either actual vehicle transportation or the VTS-based simulated method. Despite the higher interfacial stress (micro air bubbles and foaming) in the dosing solution created by the OS- and RS-based simulated methods, 0.0004%w/v (4 ppm) PS80 in the dosing solution was found to be sufficient to stabilize the mAb. The study shows that under appropriate simulated conditions, the OS-, RS-, and VTS-based simulated methods can be used as practical and meaningful models to assess the impact and risk of vehicle transportation on the quality of mAb dosing solutions.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Situ Eutectic Formation in a Polymeric Matrix via Hot-Melt Reactive Extrusion and the Use of Partial Least Squares Regression Modeling for Reaction Yield Determination","authors":"Gavin P. Andrews,&nbsp;Alice Culkin,&nbsp;David S. Jones and Shu Li*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0015210.1021/acs.molpharmaceut.4c00152","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00152https://doi.org/10.1021/acs.molpharmaceut.4c00152","url":null,"abstract":"<p >There has been a significant volume of work investigating the design and synthesis of new crystalline multicomponent systems via examining complementary functional groups that can reliably interact through the formation of noncovalent bonds, such as hydrogen bonds (H-bonds). Crystalline multicomponent molecular adducts formed using this approach, such as cocrystals, salts, and eutectics, have emerged as drug product intermediates that can lead to effective drug property modifications. Recent advancement in the production for these multicomponent molecular adducts has moved from batch techniques that rely upon intensive solvent use to those that are solvent-free, continuous, and industry-ready, such as reactive extrusion. In this study, a novel eutectic system was found when processing albendazole and maleic acid at a 1:2 molar ratio and successfully prepared using mechanochemical methods including liquid-assisted grinding and hot-melt reactive extrusion. The produced eutectic was characterized to exhibit a 100 °C reduction in melting temperature and enhanced dissolution performance (&gt;12-fold increase at 2 h point), when compared to the native drug compound. To remove handling of the eutectic as a formulation intermediate, an end-to-end continuous-manufacturing-ready process enables feeding of the raw parent reagents in their respective natural forms along with a chosen polymeric excipient, Eudragit EPO. The formation of the eutectic was confirmed to have taken place in situ in the presence of the polymer, with the reaction yield determined using a multivariate calibration model constructed by combining spectroscopic analysis with partial least-squares regression modeling. The ternary extrudates exhibited a dissolution profile similar to that of the 1:2 prepared eutectic, suggesting a physical distribution (or suspension) of the in situ synthesized eutectic contents within the polymeric matrix.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.molpharmaceut.4c00152","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin-Induced Gene 1-Enhance Secretion of BMSC Exosome Enriched in miR-132–3p Promoting Wound Healing in Diabetic Mice","authors":"Liming Zheng,&nbsp;Honghong Song,&nbsp;Yang Li,&nbsp;Hengfei Li,&nbsp;Guanlin Lin* and Zhenyu Cai*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0032210.1021/acs.molpharmaceut.4c00322","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00322https://doi.org/10.1021/acs.molpharmaceut.4c00322","url":null,"abstract":"<p >Chronic diabetic wounds represent a significant clinical challenge because of impaired healing processes, which require innovative therapeutic strategies. This study explores the therapeutic efficacy of insulin-induced gene 1-induced bone marrow mesenchymal stem cell exosomes (Insig1-exos) in promoting wound healing in diabetic mice. We demonstrated that Insig1 enhanced the secretion of bone marrow mesenchymal stem cell-derived exosomes, which are enriched with miR-132–3p. Through a series of in vitro and in vivo experiments, these exosomes significantly promoted the proliferation, migration, and angiogenesis of dermal fibroblasts under high-glucose conditions. They also regulated key wound-healing factors, including matrix metalloproteinase-9, platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor-β1, and platelet endothelial cell adhesion molecule-1, thereby accelerating wound closure in diabetic mice. Histological analysis showed that Insig1-exos were more effective in promoting epithelialization, enhancing collagen deposition, and reducing inflammation. Additionally, inhibition of miR-132–3p notably diminished these therapeutic effects, underscoring its pivotal role in the wound-healing mechanism facilitated by Insig1-exos. This study elucidates the molecular mechanisms through which Insig1-exos promotes diabetic wound healing, highlighting miR-132–3p as a key mediator. These findings provide new strategies and theoretical foundations for treating diabetes-related skin injuries.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Excipient-Induced Lattice Disorder in Active Pharmaceutical Ingredient: Implications on Drug Product Continuous Manufacturing.","authors":"Bhushan Munjal, Kevin DeBoyace, Fengjuan Cao, Joseph F Krzyzaniak, Kapildev K Arora, Raj Suryanarayanan","doi":"10.1021/acs.molpharmaceut.4c00529","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00529","url":null,"abstract":"<p><p>Our previous work (Mol Pharm, 20 (2023) 3427) showed that crystalline excipients, specifically anhydrous dibasic calcium phosphate (DCPA), facilitated the dehydration of carbamazepine dihydrate (CBZDH) and the formation of an amorphous product phase during the mixing stage of continuous tablet manufacturing. Understanding the mechanism of this excipient-induced effect was the object of this study. Blending with DCPA for 15 min caused pronounced lattice disorder in CBZDH. This was evident from the 190% increase in the apparent lattice strain determined by the Williamson-Hall plot. The rapid dehydration was attributed to the increased reactivity of CBZDH caused by this lattice disorder. Lattice disorder in CBZDH was induced by a second method, cryomilling it with DCPA. The dehydration was accelerated in the milled sample. Annealing the cryomilled sample reversed the effect, thus confirming the effect of lattice disorder on the dehydration kinetics. The hardness of DCPA appeared to be responsible for the disordering effect. DCPA exhibited a similar effect in other hydrates, thereby revealing that the effect was not unique to CBZDH. However, its magnitude varied on a case-by-case basis. The high shear powder mixing was necessary for rapid and efficient powder mixing during continuous drug product manufacturing. The mechanical stress imposed on the CBZDH, and exacerbated by DCPA, caused this unexpected destabilization.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141969993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic Bioequivalence between Generic and Originator Orally Inhaled Drug Products: Validity of Administration of Doses above the Approved Single Maximum Dose","authors":"Gur Jai Pal Singh, Anthony J Hickey","doi":"10.1021/acs.molpharmaceut.4c00479","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00479","url":null,"abstract":"Pharmacokinetic bioequivalence of orally inhaled drug products is a critical component of the US FDA’s “weight of evidence” approach, and it can serve as the sole indicator of safety and effectiveness of follow-on inhalation products approved in Europe and some other geographic areas. The approved labels of the orally inhaled drug products recommend the maximum number of actuations that can be administered in a single dose on one occasion. This single maximum dose may consist of one or more inhalations depending upon the product. Bioequivalence studies for the inhalation drug product registrations in the US and EU have employed single and multiple actuation doses, in some cases over and above the approved single maximum labeled doses, thus, inconsistent with the approved labeling of the reference products. Pharmacokinetics of inhaled drug products after single and multiple doses may be different, with implications for bioequivalence determined at single and multiple doses. Scientific literature indicates that the relative bioavailability of the Test and Reference products may differ between administrations of doses in one and multiple inhalations. Multiple doses not only alter the pharmacokinetics but also may reduce the sensitivity of the bioassay to actual differences between the Test and Reference product performances. Ability of the pharmacokinetic bioassay to accurately determine the extent of difference between two products may also be substantially reduced at high doses. Therefore, in our opinion, pharmacokinetic bioequivalence to support regulatory approvals of inhalation products at doses above the recommended single maximum dose should be avoided. Furthermore, the bioequivalence of products (if any) established at doses exceeding the approved single maximum doses should be revisited to determine if the products maintain bioequivalence when evaluated at the clinically relevant single maximum doses.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141938454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering a 3D Biomimetic Peptides Functionalized-Polyethylene Glycol Hydrogel Model Cocultured with Endothelial Cells and Astrocytes: Enhancing In Vitro Blood–Brain Barrier Biomimicry","authors":"Nesrine Ahmad,&nbsp;Georges Kiriako,&nbsp;John Saliba,&nbsp;Kawthar Abla,&nbsp;Marwan El-Sabban* and Rami Mhanna*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0059910.1021/acs.molpharmaceut.4c00599","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00599https://doi.org/10.1021/acs.molpharmaceut.4c00599","url":null,"abstract":"<p >The blood–brain barrier (BBB) poses a significant challenge for drug delivery and is linked to various neurovascular disorders. In vitro BBB models provide a tool to investigate drug permeation across the BBB and the barrier’s response to external injury events. Yet, existing models lack fidelity in replicating the BBB’s complexity, hindering a comprehensive understanding of its functions. This study introduces a three-dimensional (3D) model using polyethylene glycol (PEG) hydrogels modified with biomimetic peptides that represent recognition sequences of key proteins in the brain. Hydrogels were functionalized with recognition sequences for laminin (IKVAV) and fibronectin peptides (RGD) and chemically cross-linked with matrix metalloprotease-sensitive peptides (MMPs) to mimic the extracellular matrix of the BBB. Astrocytes and endothelial cells were seeded within and on the surface of the hydrogels, respectively. The barrier integrity was assessed through different tests including transendothelial electrical resistance (TEER), the permeability of sodium fluorescence (Na–F), the permeability of Evan’s blue bound to albumin (EBA), and the expression of zonula occluden-1 (ZO-1) in seeded endothelial cells. Hydrogels with a combination of RGD and IKVAV peptides displayed superior performance, exhibiting significantly higher TEER values (55.33 ± 1.47 Ω·cm²) at day 5 compared to other 2D controls including HAECs-monoculture and HAECs-cocultured with NHAs seeded on well inserts and 3D controls including RGD hydrogel and RGD-IKVAV monoculture with HAECs and RGD hydrogel cocultured with HAECs and NHAs. The designed 3D system resulted in the lowest Evan’s blue permeability at 120 min (0.215 ± 0.055 μg/mL) compared to controls. ZO-1 expression was significantly higher and formed a relatively larger network in the functionalized hydrogel cocultured with astrocytes and endothelial cells compared to the controls. Thus, the designed 3D model effectively recapitulates the main BBB structure and function in vitro and is expected to contribute to a deeper understanding of pathological CNS angiogenesis and the development of effective CNS medications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.molpharmaceut.4c00599","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Mechanistic Multiparameter Optimization and Large-Scale In Vitro to In Vivo Pharmacokinetics Correlations to Small-Molecule Therapeutic Projects","authors":"Fabio Broccatelli*,&nbsp;Vijayabhaskar Veeravalli,&nbsp;Daniel Cashion,&nbsp;Javier L. Baylon,&nbsp;Franco Lombardo and Lei Jia*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0025610.1021/acs.molpharmaceut.4c00256","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00256https://doi.org/10.1021/acs.molpharmaceut.4c00256","url":null,"abstract":"<p >Computational chemistry and machine learning are used in drug discovery to predict the target-specific and pharmacokinetic properties of molecules. Multiparameter optimization (MPO) functions are used to summarize multiple properties into a single score, aiding compound prioritization. However, over-reliance on subjective MPO functions risks reinforcing human bias. Mechanistic modeling approaches based on physiological relevance can be adapted to meet different potential key objectives of the project (<i>e.g</i>., minimizing dose, maximizing safety margins, and/or minimizing drug–drug interaction risk) while retaining the same underlying model structure. The current work incorporates recent approaches to predict <i>in vivo</i> pharmacokinetic (PK) properties and validates <i>in vitro</i> to <i>in vivo</i> correlation analysis to support mechanistic PK MPO. Examples of use and impact in small-molecule drug discovery projects are provided. Overall, the mechanistic MPO identifies 83% of the compounds considered as short-listed for clinical experiments in the top second percentile, and 100% in the top 10th percentile, resulting in an area under the receiver operating characteristic curve (AUCROC) &gt; 0.95. In addition, the MPO score successfully recapitulates the chronological progression of the optimization process across different scaffolds. Finally, the MPO scores for compounds characterized in pharmacokinetics experiments are markedly higher compared with the rest of the compounds being synthesized, highlighting the potential of this tool to reduce the reliance on <i>in vivo</i> testing for compound screening.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}