Journal of Chemical Information and Modeling 最新文献

{"title":"Pathways to reduce global plastic waste mismanagement and greenhouse gas emissions by 2050","authors":"A. Samuel Pottinger, Roland Geyer, Nivedita Biyani, Ciera C Martinez, Neil Nathan, Molly R Morse, Chao Liu, Shanying Hu, Magali de Bruyn, Carl Boettiger, Elijah Baker, Douglas J McCauley","doi":"10.1126/science.adr3837","DOIUrl":"https://doi.org/10.1126/science.adr3837","url":null,"abstract":"Plastic production and plastic pollution negatively affect our environment, environmental justice, and climate change. Using detailed global and regional plastics datasets coupled with socio-economic data, we employ machine learning to predict that, without intervention, annual mismanaged plastic waste will nearly double to 121 Mt (100 - 139 Mt 95% CI) by 2050. Annual greenhouse gas emissions from the plastic system are projected to grow by 37% to 3.35 Gt CO <jats:sub>2</jats:sub> equivalent (3.09 - 3.54 CO <jats:sub>2</jats:sub> e) over the same period. The United Nations plastic pollution treaty presents a unique opportunity to reshape these outcomes. We simulate eight candidate treaty policies and find that just four could together reduce mismanaged plastic waste by 91% (86% - 98%) and gross plastic-related greenhouse gas emissions by one third.","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":"18 1","pages":""},"PeriodicalIF":56.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Putting wellbeing at the core of diabetes care","authors":"","doi":"10.1016/s2213-8587(24)00345-0","DOIUrl":"https://doi.org/10.1016/s2213-8587(24)00345-0","url":null,"abstract":"No Abstract","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":"216 1","pages":""},"PeriodicalIF":44.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142609767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UNIQUE: A Framework for Uncertainty Quantification Benchmarking.","authors":"Jessica Lanini, Minh Tam Davide Huynh, Gaetano Scebba, Nadine Schneider, Raquel Rodríguez-Pérez","doi":"10.1021/acs.jcim.4c01578","DOIUrl":"10.1021/acs.jcim.4c01578","url":null,"abstract":"<p><p>Machine learning (ML) models have become key in decision-making for many disciplines, including drug discovery and medicinal chemistry. ML models are generally evaluated prior to their usage in high-stakes decisions, such as compound synthesis or experimental testing. However, no ML model is robust or predictive in all real-world scenarios. Therefore, uncertainty quantification (UQ) in ML predictions has gained importance in recent years. Many investigations have focused on developing methodologies that provide accurate uncertainty estimates for ML-based predictions. Unfortunately, there is no UQ strategy that consistently provides robust estimates about model's applicability on new samples. Depending on the dataset, prediction task, and algorithm, accurate uncertainty estimations might be unfeasible to obtain. Moreover, the optimum UQ metric also varies across applications, and previous investigations have shown a lack of consistency across benchmarks. Herein, the UNIQUE (UNcertaInty QUantification bEnchmarking) framework is introduced to facilitate a comparison of UQ strategies in ML-based predictions. This Python library unifies the benchmarking of multiple UQ metrics, including the calculation of nonstandard UQ metrics (combining information from the dataset and model), and provides a comprehensive evaluation. In this framework, UQ metrics are evaluated for different application scenarios, e.g., eliminating the predictions with the lowest confidence or obtaining a reliable uncertainty estimate for an acquisition function. Taken together, this library will help to standardize UQ investigations and evaluate new methodologies.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Probabilistic Approach in the Search Space of the Molecular Distance Geometry Problem.","authors":"Rômulo S Marques, Michael Souza, Fernando Batista, Miguel Gonçalves, Carlile Lavor","doi":"10.1021/acs.jcim.4c00427","DOIUrl":"https://doi.org/10.1021/acs.jcim.4c00427","url":null,"abstract":"<p><p>The discovery of the three-dimensional shape of protein molecules using interatomic distance information from nuclear magnetic resonance (NMR) can be modeled as a discretizable molecular distance geometry problem (DMDGP). Due to its combinatorial characteristics, the problem is conventionally solved in the literature as a depth-first search in a binary tree. In this work, we introduce a new search strategy, which we call frequency-based search (FBS), that for the first time utilizes geometric information contained in the protein data bank (PDB). We encode the geometric configurations of 14,382 molecules derived from NMR experiments present in the PDB into binary strings. The obtained results show that the sample space of the binary strings extracted from the PDB does not follow a uniform distribution. Furthermore, we compare the runtime of the symmetry-based build-Up (SBBU) algorithm (the most efficient method in the literature to solve the DMDGP) combined with FBS and the depth-first search (DFS) in finding a solution, ascertaining that FBS performs better in about 70% of the cases.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Setmelanotide in patients aged 2–5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial","authors":"Jesús Argente, Charles F Verge, Uzoma Okorie, Ilene Fennoy, Megan M Kelsey, Casey Cokkinias, Cecilia Scimia, Hak-Myung Lee, I Sadaf Farooqi","doi":"10.1016/s2213-8587(24)00273-0","DOIUrl":"https://doi.org/10.1016/s2213-8587(24)00273-0","url":null,"abstract":"&lt;h3&gt;Background&lt;/h3&gt;Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, has been shown to reduce hunger and weight in patients aged 6 years and older with proopiomelanocortin (POMC) deficiency (including biallelic variants in proprotein convertase subtilisin/kexin type 1 [&lt;em&gt;PCSK1&lt;/em&gt;]), leptin receptor (LEPR) deficiency, or Bardet-Biedl syndrome (BBS). No approved therapies for patients younger than 6 years old currently exist. The phase 3, open-label VENTURE trial aimed to evaluate the efficacy and safety of setmelanotide in patients aged 2–5 years with POMC or LEPR deficiency or BBS.&lt;h3&gt;Methods&lt;/h3&gt;This phase 3, open-label, multicentre trial, conducted across six sites in the USA, the UK, Spain, and Australia, enrolled eligible patients aged 2–5 years who had hyperphagia and obesity due to biallelic &lt;em&gt;POMC&lt;/em&gt; (including &lt;em&gt;PCSK1&lt;/em&gt;) or &lt;em&gt;LEPR&lt;/em&gt; variants or genetically confirmed BBS. Open-label subcutaneous setmelanotide was administered once daily for 52 weeks, starting at 0·5 mg with doses increasing every 2 weeks in 0·5 mg increments until reaching the maximum dose based on weight. The co-primary endpoints at week 52 were the percentage of patients reaching a 0·2-point decrease or greater in BMI Z score (a statistical measure used to assess BMI in paediatric patients considering a patient's BMI and comparing it to reference values for the same age and sex) and mean percent change in BMI. Additional endpoints measured safety, hunger, weight-related outcomes, and caregiver burden. The study is registered at &lt;span&gt;&lt;span&gt;ClinicalTrials.gov&lt;/span&gt;&lt;svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"&gt;&lt;path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"&gt;&lt;/path&gt;&lt;/svg&gt;&lt;/span&gt; (&lt;span&gt;&lt;span&gt;NCT04966741&lt;/span&gt;&lt;svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"&gt;&lt;path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"&gt;&lt;/path&gt;&lt;/svg&gt;&lt;/span&gt;) and is complete.&lt;h3&gt;Findings&lt;/h3&gt;Between March 8, 2022, and Sept 18, 2023, 13 patients were screened at the six sites, and 12 patients were enrolled in the study (seven with POMC or LEPR and five with BBS); one patient with BBS was excluded as their BMI was not at the 97th percentile or above. Of the 12 patients enrolled, most were male (seven [58%] &lt;em&gt;vs&lt;/em&gt; five [42%] for female) and the mean age was 3·6 years (SD 0·9). 11 patients completed the trial. Ten (83%) of the 12 overall participants reached a 0·2-point reduction or more in BMI Z score per WHO methodology at week 52 (95% CI 58·7–99·8). The mean percent change in BMI from baseline at week 52 was −18% (SD 13) in the overall safety population. Mean percent change in BMI at week 52 was −26% (SD 11) in patients with POMC or LEPR deficiency and −10% (9) in patients with BBS. Mean reductions in secondary endpoints of BMI Z score (3·4 [2·5]) and percent of the BMI 95th percentile (32·5 [22·9]) we","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":"39 1","pages":""},"PeriodicalIF":44.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142609769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Setmelanotide for the treatment of severe early-childhood genetic obesity","authors":"Christian L Roth","doi":"10.1016/s2213-8587(24)00312-7","DOIUrl":"https://doi.org/10.1016/s2213-8587(24)00312-7","url":null,"abstract":"No Abstract","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":"5 1","pages":""},"PeriodicalIF":44.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142609768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI Promoted Virtual Screening, Structure-Based Hit Optimization, and Synthesis of Novel COVID-19 S-RBD Domain Inhibitors.","authors":"Ioannis Gkekas, Sotirios Katsamakas, Stelios Mylonas, Theano Fotopoulou, George Ε Magoulas, Alia Cristina Tenchiu, Marios Dimitriou, Apostolos Axenopoulos, Nafsika Rossopoulou, Simona Kostova, Erich E Wanker, Theodora Katsila, Demetris Papahatjis, Vassilis G Gorgoulis, Maria Koufaki, Ioannis Karakasiliotis, Theodora Calogeropoulou, Petros Daras, Spyros Petrakis","doi":"10.1021/acs.jcim.4c01110","DOIUrl":"https://doi.org/10.1021/acs.jcim.4c01110","url":null,"abstract":"<p><p>Coronavirus disease 2019 (COVID-19) is caused by a new, highly pathogenic severe-acute-respiratory syndrome coronavirus 2 (SARS-CoV-2) that infects human cells through its transmembrane spike (S) glycoprotein. The receptor-binding domain (RBD) of the S protein interacts with the angiotensin-converting enzyme II (ACE2) receptor of the host cells. Therefore, pharmacological targeting of this interaction might prevent infection or spread of the virus. Here, we performed a virtual screening to identify small molecules that block S-ACE2 interaction. Large compound libraries were filtered for drug-like properties, promiscuity and protein-protein interaction-targeting ability based on their ADME-Tox descriptors and also to exclude pan-assay interfering compounds. A properly designed AI-based virtual screening pipeline was applied to the remaining compounds, comprising approximately 10% of the starting data sets, searching for molecules that could bind to the RBD of the S protein. All molecules were sorted according to their screening score, grouped based on their structure and postfiltered for possible interaction patterns with the ACE2 receptor, yielding 31 hits. These hit molecules were further tested for their inhibitory effect on Spike RBD/ACE2 (19-615) interaction. Six compounds inhibited the S-ACE2 interaction in a dose-dependent manner while two of them also prevented infection of human cells from a pseudotyped virus whose entry is mediated by the S protein of SARS-CoV-2. Of the two compounds, the benzimidazole derivative <b>CKP-22</b> protected Vero E6 cells from infection with SARS-CoV-2, as well. Subsequent, hit-to-lead optimization of <b>CKP-22</b> was effected through the synthesis of 29 new derivatives of which compound <b>CKP-25</b> suppressed the Spike RBD/ACE2 (19-615) interaction, reduced the cytopathic effect of SARS-CoV-2 in Vero E6 cells (IC₅₀ = 3.5 μM) and reduced the viral load in cell culture supernatants. Early in vitro ADME-Tox studies showed that <b>CKP-25</b> does not possess biodegradation or liver metabolism issues, while isozyme-specific CYP450 experiments revealed that <b>CKP-25</b> was a weak inhibitor of the CYP450 system. Moreover, <b>CKP-25</b> does not elicit mutagenic effect on <i>Escherichia coli</i> WP2 uvrA strain. Thus, <b>CKP-25</b> is considered a lead compound against COVID-19 infection.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping Protein Conformational Landscapes from Crystallographic Drug Fragment Screens.","authors":"Ammaar A Saeed, Margaret A Klureza, Doeke R Hekstra","doi":"10.1021/acs.jcim.4c01380","DOIUrl":"10.1021/acs.jcim.4c01380","url":null,"abstract":"<p><p>Proteins are dynamic macromolecules. Knowledge of a protein's thermally accessible conformations is critical to determining important transitions and designing therapeutics. Accessible conformations are highly constrained by a protein's structure such that concerted structural changes due to external perturbations likely track intrinsic conformational transitions. These transitions can be thought of as paths through a conformational landscape. Crystallographic drug fragment screens are high-throughput perturbation experiments, in which thousands of crystals of a drug target are soaked with small-molecule drug precursors (fragments) and examined for fragment binding, mapping potential drug binding sites on the target protein. Here, we describe an open-source Python package, COnformational LAndscape Visualization (COLAV), to infer conformational landscapes from such large-scale crystallographic perturbation studies. We apply COLAV to drug fragment screens of two medically important systems: protein tyrosine phosphatase 1B (PTP1B), which regulates insulin signaling, and the SARS CoV-2 Main Protease (MPro). With enough fragment-bound structures, we find that such drug screens enable detailed mapping of proteins' conformational landscapes.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypothalamic obesity: from basic mechanisms to clinical perspectives","authors":"Jesús Argente, I Sadaf Farooqi, Julie A Chowen, Peter Kühnen, Miguel López, Eugenia Morselli, Hoong-Wei Gan, Helen A Spoudeas, Martin Wabitsch, Manuel Tena-Sempere","doi":"10.1016/s2213-8587(24)00283-3","DOIUrl":"https://doi.org/10.1016/s2213-8587(24)00283-3","url":null,"abstract":"Despite the diverse nature of obesity, there is compelling genetic, clinical, and experimental evidence that endorses the important contribution of brain circuits to this condition. The hypothalamus contains major regulatory circuits for bodyweight homoeostasis, the deregulation of which can lead to obesity. Although functional perturbation of hypothalamic pathways could lie at the basis of common forms of obesity, the term hypothalamic obesity has been created to define those rare forms of severe obesity where a clear hypothalamic substrate can be identified, either of genetic or acquired origin. An in-depth understanding of the pathogenesis, clinical presentation, and therapeutic targets of hypothalamic obesity relies on the comprehension of the physiological basis of hypothalamic pathways governing bodyweight control, the mechanisms (either genetic or acquired) whereby they are perturbed, and the consequences of such perturbation. In this Review, we provide a synoptic overview of hypothalamic obesity, from basic mechanisms to clinical perspectives, with a major focus on current developments and new avenues for the diagnosis and precise treatment of these rare forms of obesity.","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":"19 1","pages":""},"PeriodicalIF":44.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating Antibiotic Permeation through the <i>Escherichia coli</i> Outer Membrane: Insights from Molecular Dynamics.","authors":"Javad Deylami, Shu Sin Chng, Ee Hou Yong","doi":"10.1021/acs.jcim.4c01249","DOIUrl":"10.1021/acs.jcim.4c01249","url":null,"abstract":"<p><p>Antibiotic resistance represents a critical public health threat, with an increasing number of Gram-negative pathogens demonstrating resistance to a broad range of clinical drugs. A primary challenge in enhancing antibiotic efficacy is overcoming the robust barrier presented by the bacterial outer membrane. Our research addresses a longstanding question: What is the rate of antibiotic permeation across the outer membrane (OM) of Gram-negative bacteria? Utilizing molecular dynamics (MD) simulations, we assess the passive permeability profiles of four commercially available antibiotics─gentamicin, novobiocin, rifampicin, and tetracycline across an asymmetric atomistic model of the <i>Escherichia coli</i> (<i>E. coli</i>) OM, employing the inhomogeneous solubility-diffusion model. Our examination of the interactions between these drugs and their environmental context during OM permeation reveals that extended hydrogen bond formation and drug-cation interactions significantly hinder the energetics of passive permeation, notably affecting novobiocin. Our MD simulations corroborate well with experimental data and reveal new implications of solvation on drug permeability, overall advancing the possible use of computational prediction of membrane permeability in future antibiotic discovery.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":" ","pages":"8310-8321"},"PeriodicalIF":5.6,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}