Medicinal Chemistry Research最新文献

{"title":"Target discovery and drug design in the era of artificial intelligence","authors":"Payton Fleming,&nbsp;Andrey A. Ivanov","doi":"10.1007/s00044-026-03562-1","DOIUrl":"10.1007/s00044-026-03562-1","url":null,"abstract":"<div><p>The identification of therapeutically actionable targets and the design of effective small-molecule modulators remain central challenges in drug discovery, particularly for complex diseases driven by dynamic, interconnected molecular networks. Recent advances in artificial intelligence (AI) and machine learning are reshaping this landscape by enabling integrative analysis of large-scale biological data, systematic navigation of chemical space, and data-driven optimization of molecular properties. In this review, we outline how AI transforms small-molecule drug discovery by linking target discovery, tractability assessment, and chemical design within integrated, experiment-informed workflows. We highlight AI-enabled strategies for target discovery that integrate network biology, multimodal data fusion, and perturbation-aware modeling. These approaches identify context-specific, functionally actionable targets, including non-enzymatic proteins, protein-protein interactions, and other historically challenging classes. We then focus on advances most relevant to medicinal chemistry, including structure and complex prediction, docking and affinity modeling, ligand-based learning, generative molecular design, ADMET prediction, and synthetic feasibility assessment. Finally, we discuss current limitations related to data quality, generalizability, interpretability, and experimental translation. We emphasize the critical future role of integrated, context-aware AI workflows that connect target discovery with chemical design and experimental feedback. Together, these advances position AI as a robust framework for accelerating the discovery of therapeutically relevant targets and small-molecule modulators.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 10","pages":"1874 - 1904"},"PeriodicalIF":3.5,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring NiCl2, PdCl2 and PtCl2 as a catalyst for [3 + 2] cycloaddition in Kopsane alkaloid synthesis by density functional theory study","authors":"Sanghee Yoon,&nbsp;Pratanphorn Nakliang,&nbsp;Bilal Shaker,&nbsp;Tao Ye,&nbsp;Sun Choi","doi":"10.1007/s00044-026-03556-z","DOIUrl":"10.1007/s00044-026-03556-z","url":null,"abstract":"<div><p>Kopsane alkaloids possess a complex heptacyclic scaffold and exhibit significant biological activities, including cholinergic, anti-inflammatory, and anti-cancer effects. While we previously reported PtCl₂-catalyzed [3 + 2] cycloaddition for their synthesis, the high cost and toxicity of platinum necessitate sustainable alternatives. In this study, we employed density functional theory (DFT) to investigate MCl₂ (M = Ni, Pd, and Pt) catalyzed [3 + 2] cycloaddition in Kopsane alkaloid synthesis. Our results indicate consistent reaction characteristics across all metals, with the second cyclization acting as the diastereoselectivity-determining step. The calculated energy gaps between transition states (TS2s) for NiCl₂, PdCl₂, and PtCl₂ were 5.57, 1.45, and 12.25 kcal/mol, respectively. These energy profiles suggest that NiCl₂ can achieve high diastereoselectivity similar to PtCl₂ due to its significant energy gap (&gt; 4 kcal/mol). The implementation of this computational chemistry technique provides theoretical evidence that could help to improve the efficiency of the catalyst designing process.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"784 - 791"},"PeriodicalIF":3.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03556-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular sonification: a multi-modal approach for enhanced ai in drug discovery","authors":"Charles Jianping Zhou,&nbsp;Emily Rong Zhou","doi":"10.1007/s00044-026-03549-y","DOIUrl":"10.1007/s00044-026-03549-y","url":null,"abstract":"<div><p>Artificial intelligence (AI) has achieved remarkable success in the molecular sciences; however, a critical constraint has emerged: prediction without mechanistic understanding. To bridge this gap, we present a multi-modal molecular AI framework based on our patented molecular sonification technology (USP 9,018,506). This approach unifies three critical applications: (1) mapping chemical structures to sound for intuitive human interpretation, (2) transforming spectroscopic data into audio streams for mechanistic AI training, and (3) encoding reaction dynamics for real-time monitoring. Critically, our method is modality-agnostic, providing a universal encoding scheme applicable to diverse systems including small molecules, protein sequences, and crystalline materials. By mapping molecular data to the human audible range, we enable high-efficiency transfer learning from pre-trained voice AI models (such as Wav2Vec 2.0), achieving greater computational efficiency compared to training from scratch. Validation on standard benchmarks demonstrates that this multi-modal spatial intelligence achieves competitive accuracy with a dramatically reduced computational footprint, offering a new paradigm for both global science education and accelerated discovery across chemistry, biology, and materials informatics.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div><div><p>Overview of the Molecular Spatial Intelligence framework. The full architecture supports four input modalities. The current experimental validation (Tables 1–3) evaluates the audio and descriptor pathways (highlighted); graph and spectroscopy channels are planned for future integration.</p></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"778 - 783"},"PeriodicalIF":3.1,"publicationDate":"2026-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein kinases as therapeutic targets in Alzheimer’s disease: challenges, insights, and new frontiers","authors":"Chanwool Tak,&nbsp;Swapnil P. Bhujbal,&nbsp;Jung-Mi Hah","doi":"10.1007/s00044-026-03557-y","DOIUrl":"10.1007/s00044-026-03557-y","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) remains the leading cause of dementia worldwide, imposing an enormous and growing societal burden with more than 55 million people affected globally. Despite decades of intensive investigation, existing therapeutic options provide only modest symptomatic relief and fail to prevent or slow disease progression, emphasizing the critical need for interventions that target the fundamental molecular mechanisms of neurodegeneration. Pathologically, Alzheimer’s disease is characterized by extracellular accumulation of amyloid-β plaques, intracellular neurofibrillary tangles formed by hyperphosphorylated tau, profound synaptic loss, chronic neuroinflammation, and extensive neuronal degeneration. Although amyloid-focused strategies have long dominated drug development, their limited clinical benefit and safety liabilities highlight the multifactorial nature of AD and the need to move beyond amyloid-centric paradigms. Protein kinases have emerged as key integrators of multiple pathogenic processes in AD, governing tau phosphorylation, amyloid precursor protein processing, synaptic signaling, and neuroimmune responses. Aberrant kinase signaling drives tau pathology and propagation, promotes amyloidogenic pathways, disrupts synaptic function, and perpetuates inflammatory cascades. While extensive work on kinases such as GSK-3β, CDK5, JNKs, and CSF1R has firmly established the relevance of kinase dysregulation in AD, no kinase-directed therapy has yet translated into clinical success. This review highlights emerging kinase targets beyond these classical pathways, including Fyn, Casein Kinase 1 Delta (CK1δ), Tau-Tubulin Kinase 1 (TTBK1), and Dual Leucine Zipper Kinase (DLK), which are supported by mechanistic insights and compelling preclinical evidence. Continued advances in brain-penetrant, isoform-selective, and mechanism-driven kinase inhibitor design may enable the development of next-generation disease-modifying therapies for Alzheimer’s disease.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"726 - 756"},"PeriodicalIF":3.1,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and antihepatoma activity of dimeric 1-O-acetylbritannilactone derivatives","authors":"Guang-Xuan Du,&nbsp;Li-Qin He,&nbsp;Meng-Xiang Qin,&nbsp;Yun-Bao Ma,&nbsp;Xiao-Yan Huang,&nbsp;Yong-Cui Wang,&nbsp;Tian-Ze Li,&nbsp;Ji-Jun Chen","doi":"10.1007/s00044-026-03558-x","DOIUrl":"10.1007/s00044-026-03558-x","url":null,"abstract":"<div><p>1-<i>O</i>-Acetylbritannilactone (ABL), a natural 1,10-seco-eudesmane sesquiterpenoid, exhibited moderate antihepatoma activity on HepG2, Huh7, and SK-Hep-1cells with IC₅₀ values of 50.7, 60.7, and 62.4 μM, respectively. Given that sesquiterpenoid dimers often exhibit stronger antitumor activity than their monomeric counterparts, a strategy of dimerization was employed to improve the activity of ABL. A total of 49 dimeric derivatives of ABL linked <i>via</i> ester bonds or carbamate bonds were synthesized and evaluated for their inhibitory activity against human hepatoma cell lines. As a result, all dimeric derivatives significantly enhanced the antihepatoma activity against the three cell line with IC₅₀ values ranging from 0.5 μM–20.2 μM. Among them, 43 derivatives were more active than sorafenib with IC₅₀ values below 7.0 μM. In particular, eight compounds (<b>17</b>, <b>21</b>, <b>23</b>, <b>24</b>, <b>25</b>, <b>30</b>, <b>38</b> and <b>47</b>) displayed IC₅₀ values at or below approximately 1.0 μM, indicating a 27.2- to 123.2-fold enhancement in potency over the parent ABL. These results highlighted their potential as promising novel antihepatoma candidates worthy of further investigation.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 5","pages":"986 - 1001"},"PeriodicalIF":3.1,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148008717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"4’-Thionucleosides as adenosine A3 receptor ligands: a medicinal chemistry perspective","authors":"Hong-Rae Kim,&nbsp;Lak Shin Jeong","doi":"10.1007/s00044-026-03560-3","DOIUrl":"10.1007/s00044-026-03560-3","url":null,"abstract":"<div><p>The adenosine A₃ receptor (A₃AR) is recognized as a potential therapeutic target across multiple human pathologies; however, the development of selective orthosteric ligands remains challenging due to receptor subtype conservation and species-dependent pharmacology. Among nucleoside-derived chemotypes, 4’-thionucleosides, generated by bioisosteric replacement of the ribose endocyclic oxygen with sulfur, constitute a synthetically accessible scaffold for modulating A₃AR activity. This review summarizes synthetic methodologies that have enabled systematic diversification of the 4’-thio chemotype, including β-selective <i>N</i>-glycosylation and de novo cyclization strategies, and analyzes structure–activity relationships (SAR) associated with modifications at the <i>N</i>⁶, C2, and 5’ positions, as well as ribose truncation. These structural variations have been correlated with changes in binding affinity, subtype selectivity, and intrinsic efficacy, supporting the utility of the 4’-thio scaffold in generating distinct pharmacological profiles. The recent availability of cryo-electron microscopy structures of human A₃AR, including active agonist-bound states and, more recently, an inactive antagonist-bound conformation, provides a structural context for interpretation of established SAR trends and may facilitate future structure-guided and modeling-informed ligand optimization.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 10","pages":"1863 - 1873"},"PeriodicalIF":3.5,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and evaluation of mitochondria-targeted caseinolytic protease (ClpP) agonist chemical probes in in vitro breast cancer models","authors":"Xiaoyu Hao,&nbsp;Gunjan Purohit,&nbsp;Yahani P. Jayasinghe,&nbsp;Donald R. Ronning,&nbsp;Oleh Khalimonchuk,&nbsp;Paul C. Trippier","doi":"10.1007/s00044-026-03551-4","DOIUrl":"10.1007/s00044-026-03551-4","url":null,"abstract":"<div><p>Mitochondria carry out a plethora of functions that are vital for cellular physiology and metabolism. Mitochondrial caseinolytic protease (ClpP) is part of the larger CLPXP machinery that is critical for mitochondrial protein homeostasis and has emerged as a prospective molecular target in several types of cancer. ClpP agonists based around the imipridone scaffold have shown some promise in acute myeloid leukemia, but the polypharmacology of these compounds limits their utility. Effective methods to deliver drugs specifically to mitochondria have emerged, involving covalent linking of either a lipophilic cation, such as an alkyltriphenylphosphonium moiety, or a XJB peptide sequence to a pharmacophore of interest. Taking advantage of the evolutionary conservation of ClpP and combination with mitochondria targeting strategies, we designed, synthesized, and tested a series of mitochondria-targeted probe compounds based on the cyclic acyldepsipeptides (ADEP) scaffold, a natural product antibiotic and potent bacterial ClpP agonist. Herein, we report the synthesis and characterization of several ClpP agonist chemical probes that afford specific, and effective targeting of the mitochondrial protein in triple-negative breast cancer cell lines, with XJB conjugation significantly increasing cytotoxicity of the ADEP pharmacophore to triple-negative breast cancer BT549 cells, providing valuable chemical tools for further study.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"814 - 833"},"PeriodicalIF":3.1,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03551-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond cancer: the case for natural product-derived dual DNMT1/HDAC3 modulators in diabetic epigenetic therapy and the need for DFT-guided computational refinement","authors":"Muhammad Javid Iqbal","doi":"10.1007/s00044-026-03554-1","DOIUrl":"10.1007/s00044-026-03554-1","url":null,"abstract":"","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 5","pages":"871 - 875"},"PeriodicalIF":3.1,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148008587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"1,3-Dioxolane derived nucleos(t)ides: synthetic strategies, current position, and future promise in antiviral and anticancer drug discovery","authors":"Meghana Gudi,&nbsp;Jeremy Estes,&nbsp;Yugandhar Kothapalli,&nbsp;Stefan G. Sarafianos,&nbsp;Uma S. Singh","doi":"10.1007/s00044-026-03555-0","DOIUrl":"10.1007/s00044-026-03555-0","url":null,"abstract":"<div><p>To date, altered nucleos(t)ides offer significant potential in antiviral and anticancer drug discovery. In the past several decades, numerous modified nucleos(t)ides have received Food and Drug Administration (FDA) approval for the treatment of viral infections and several cancers. Modifying the base or sugar of a nucleos(t)ide confers specificity and selectivity for viral RNA/DNA polymerases and highly dividing cancer cells. Ribose- and carbocyclic-based nucleosides are well established in medicinal chemistry, yielding many preclinical leads and clinical candidates with therapeutic potential. The insertion of a 1,3-dioxolane ring in place of the ribose sugar represents a unique strategy in nucleoside design to target viral DNA polymerases and rapidly proliferating cancer cells. To date, only a few 1,3-dioxolane-derived nucleos(t)ides (DDNs) have been progressed for clinical development. The chemical space of DDNs remains insufficiently explored. Substantial efforts are still required to develop novel molecules within this class, which may open new avenues for the discovery of potent antiviral and anticancer agents. This review is focused on the synthesis and development of selective DDNs and their potential in preclinical/clinical development.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 10","pages":"1839 - 1862"},"PeriodicalIF":3.5,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03555-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in the development of N-acylbenzo[d][1,2,3]diazaborinin-1(2H)-ols as antibacterial agents by synthesis, characterization, and antimicrobial assay","authors":"Chloe A. Woods,&nbsp;Betty Gutierrez,&nbsp;Naidine Aguinaldo,&nbsp;Prince Kanukwa,&nbsp;Yutong Li,&nbsp;Bethany Hubbard,&nbsp;Juan Daniel Avila,&nbsp;Anthony Jones,&nbsp;Fatime Sebok,&nbsp;Michael P. Groziak,&nbsp;Phattananawee Nalaoh,&nbsp;David M. Jenkins,&nbsp;Matthew B. Carbajal,&nbsp;Heidi T. Chow,&nbsp;H. Howard Xu","doi":"10.1007/s00044-026-03550-5","DOIUrl":"10.1007/s00044-026-03550-5","url":null,"abstract":"<div><p>The ability of bacteria to quickly adapt to environmental stresses, such as exposure to antimicrobial drugs, has necessitated a continued search for novel antibacterial agents with new mechanisms of attack, forever in competition with the rate of adaptation of these pathogens. Antibiotic resistant strains of a multitude of infectious diseases have appeared, imposing a huge burden from diseases once believed to have been reduced to minor health issues. Building on prior work, twenty-one new <i>N</i>-acyl-1-hydroxy-2,3,1-benzodiazaborinines were synthesized and characterized by high-field NMR, FTIR, ESI-MS, and other methods including X-ray crystallography for one unexpected structure. The syntheses by direct condensation using acylhydrazides gave products found to exist in one of three structural forms connected by (de/re)hydration reactions: open hydrazone (<b>a</b>), boron heterocycle (<b>b</b>), and anhydro dimer (<b>c</b>). Multisolvent ¹H and ¹³C NMR analyses showed that in solution these forms can readily interconvert in a solvent-dependent manner. The unanticipated structure of one target was established to be a rare ammonium borate salt arising from an extremely facile intramolecularly boron-catalyzed primary amide group hydrolysis. The new compounds were screened for activity against <i>Escherichia coli</i> in disk diffusion assays and seven of them demonstrated inhibitory activity, thus advancing the development of boron heterocycles towards the goal of producing next-generation antibacterial agents to combat persistently evolving resistant strains.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"847 - 862"},"PeriodicalIF":3.1,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}