Medicine in Drug Discovery最新文献

{"title":"Flavonoids and anxiety: decoding their role in brain function and pathophysiology","authors":"Riya Singla ,&nbsp;Sonia Kamboj ,&nbsp;Brijesh Kumar Duvey ,&nbsp;Anurag Bhargava ,&nbsp;Jasmine Chaudhary","doi":"10.1016/j.medidd.2025.100214","DOIUrl":"10.1016/j.medidd.2025.100214","url":null,"abstract":"<div><div>Anxiety disorder ranks among the most common mental health issues globally, thereby emphasizing the pressing necessity for the development of safer and more effective treatment alternatives. A noteworthy class of compounds in this context is flavonoids, which are naturally polyphenolic substances found in abundance within fruits, vegetables, and various medicinal plants. These compounds have garnered attention as candidates for the modulation of behaviours associated with anxiety. Examining the neurological mechanisms that underlie the anxiolytic effects of flavonoids reveals significant interaction with essential neurotransmitter systems. Specifically, engagement with serotonergic and dopaminergic pathways has been observed, indicating the multifaceted nature of flavonoids’ influence on anxiety responses. The biological activities, including antioxidant, anti-inflammatory properties, contribute to an additional layer to the potential therapeutic effect. Therefore, this review mainly focuses on the pathological facets of anxiety and explores the possible mechanism of flavonoids with the preclinical and clinical aspects for curing anxiety. Moreover, a growing body of experimental and clinical evidence indicates that certain flavonoids, including apigenin, quercetin, and luteolin, possess a considerable capacity to mitigate symptoms of anxiety, frequently resulting in a reduced incidence of adverse effects relative to traditional pharmacological therapies. This body of work reinforces the proposition that flavonoids may serve as viable natural alternatives to supplementary treatments in the management of anxiety disorders. Nevertheless, it remains imperative that additional research is conducted to clarify the mechanisms underlying the pharmacological effects of these flavonoids. Furthermore, investigations aimed at optimizing their bioavailability and validating clinical efficacy through extensive human trials are essential to fully ascertain their therapeutic potential in anxiety management.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"27 ","pages":"Article 100214"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel indole-based synthetic molecules in cancer treatment: Synthetic strategies and structure-activity relationship","authors":"Biplab Debnath ,&nbsp;Bikram Nandi ,&nbsp;Samiran Paul ,&nbsp;Swarup Manna ,&nbsp;Arindam Maity ,&nbsp;Krishnalekha Bandyopadhyay ,&nbsp;Shambo Panda ,&nbsp;Shah Alam Khan ,&nbsp;Rajarshi Nath ,&nbsp;Md Jawaid Akhtar","doi":"10.1016/j.medidd.2025.100208","DOIUrl":"10.1016/j.medidd.2025.100208","url":null,"abstract":"<div><div>Indole is one of the naturally occurring nitrogen-containing bicyclic heterocyclic ring systems where benzene and pyrrole rings are fused. It has been demonstrated to exhibit versatile biological activities. The indole scaffold regulates many proteins and genes which play a significant role in cancer development. US Food and Drug Administration (FDA) approved anti-cancer drugs having indole rings in their structure including alectinib, sunitinib, osimertinib, anlotinib, and panobinostat. Several research studies have focused on developing new indole derivatives for the treatment of cancer. Various studies have shown that indole C-3 atom; π-bond in between C-3 and C-2; and nitrogen atom can be substituted with varieties of other structural fragments to overcome the problem of drug resistance and toxicity. The anti-cancer potential of various indole derivatives, their synthetic strategies, and structure–activity relationships (SAR) for the further development and advancement of anticancer therapy. The article also summarizes how different proteins like TRK, VEGFR, EGFR, CDKs, ERK, BRD4, genes like Bcl2, intracellular pathways such as PI3K/AKT/mTOR, enzymes like tubulin and topoisomerase II are inhibited by indole derivatives. Synthetic strategies and SAR will help medicinal chemists to design and develop effective indole derivatives as anticancer agents.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"27 ","pages":"Article 100208"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current demands for standardization of Indian medicinal plants: A critical review","authors":"Rishabh Kaundal ,&nbsp;Dinesh Kumar","doi":"10.1016/j.medidd.2025.100211","DOIUrl":"10.1016/j.medidd.2025.100211","url":null,"abstract":"<div><div>The resurgence of interest in natural products and traditional medicines offers promising avenues for drug discovery. Medicinal plants’ novel chemical and molecular entities dominate current pharmaceutical research. India has mega biodiversity, including medicinal plants that contribute to drug development and health care via traditional practices. Due to the huge demand, a false practice, and quality issues have been observed in the market. Therefore, comprehensive information about standardization methods and processes are the need of hours to maintain quality of raw materials and final products. Thus, the current review insights the significant role of traditional medicines in India, where over 80<!--> <!-->% of the population relies on traditional and folklore practices for healthcare needs. This review also summarizes several standardization parameters, including stepwise pharmacognostic studies, WHO guidelines and official pharmacopeia standards. Published literature suggests that research on medicinal plants needs to be encouraged by governments through good policies, regulations, and trade standards of global market. The reviewed information will provide a foundation to develop monographs and quality parameters for Indian traditional drugs and herbal pharmacopoeia.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"27 ","pages":"Article 100211"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of CYP3A5 rs776746 and CYP3A7 rs2257401 polymorphism on steroid metabolism and dose optimization in pediatric nephrotic syndrome","authors":"Praveenkumar Kochuthakidiyel Suresh ,&nbsp;Yogalakshmi Venkatachalapathy ,&nbsp;Nandita Ganesh ,&nbsp;George Priya Doss C ,&nbsp;Sangeetha Geminiganesan ,&nbsp;Sudha Ekambaram ,&nbsp;Mohana Priya C.D","doi":"10.1016/j.medidd.2025.100216","DOIUrl":"10.1016/j.medidd.2025.100216","url":null,"abstract":"<div><div>A multicentric genetic study was conducted on 200 paediatric patients with nephrotic-range proteinuria, including 100 cases each of steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS). The study analysed two genetic variants: <em>CYP3A5</em> (rs776746) and <em>CYP3A7</em> (rs2257401). For <em>CYP3A5</em> Variant rs776746 A &gt; G is also known as 6986A &gt; G <em>CYP3A5*3</em> allele. Individuals with the A allele (6986A) carry the <em>CYP3A5*1</em> (functional) allele. Individuals with the G allele (6986G) carry the <em>CYP3A5*3</em> (non-functional) allele. overall genotype frequencies were 20.5 % AA, 30 % GG, and 49.5 % AG. In the SSNS group, the distribution was 13 % AA, 36 % GG, and 51 % AG (A allele: 0.38, G allele: 0.62), while the SRNS group showed 28 % AA, 24 % GG, and 48 % AG (A allele: 0.52, G allele: 0.48). For <em>CYP3A7</em> rs2257401, genotype frequencies were 15 % GG, 21 % CC, and 64 % GC. In SSNS, 14 % were GG, 24 % CC, and 62 % GC; in SRNS, 16 % GG, 18 % CC, and 66 % GC. G and C allele frequencies were equal (0.5) in both groups for <em>CYP3A7</em>. The findings suggest that <em>CYP3A5</em> rs776746, particularly the GG genotype, may be associated with reduced steroid response, potentially requiring alternative treatment approaches in SRNS patients. The rs776746 polymorphism involves an A &gt; G substitution, where the AA genotype (<em>CYP3A5 3/3</em>) indicates non-functional enzyme expression. Genotypic comparison showed higher AA frequency in SRNS patients. The AA genotype was associated with lower steroid metabolism, necessitating dose reduction. In contrast, <em>CYP3A7</em> rs2257401 showed no significant correlation. This suggests that <em>CYP3A5</em> genotyping could aid dose optimization in steroid-resistant cases.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"27 ","pages":"Article 100216"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Neutralization of systemic toxicity of Daboia russelii venom and reprotoxin fraction by IgY antibodies” [Med. Drug Discov. 27 (2025) 100217]","authors":"Punithkumar Naraganahalli Krishnaraj ,&nbsp;Kiran Kumar Mudnakudu-Nagaraju ,&nbsp;Nagalambika Prasad ,&nbsp;Chandavi Venkatesh ,&nbsp;Deekshith Ramesh ,&nbsp;Druthi Venktesh ,&nbsp;Anusha Chikkamandagere Kumar ,&nbsp;Kumar Jajur Ramanna","doi":"10.1016/j.medidd.2025.100219","DOIUrl":"10.1016/j.medidd.2025.100219","url":null,"abstract":"","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"27 ","pages":"Article 100219"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144860586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repositioning of rhodanine-thiazole hybrids as aldose reductase inhibitors","authors":"Shankar Gharge,&nbsp;Shankar G. Alegaon,&nbsp;Shriram D. Ranade,&nbsp;Rohini S. Kavalapure","doi":"10.1016/j.medidd.2025.100215","DOIUrl":"10.1016/j.medidd.2025.100215","url":null,"abstract":"<div><div>This study investigates the aldose reductase (AR) inhibitory potential of a series of synthesized rhodanine-thiazole hybrids (7a–7 l) through a combination of biological assays and computational modeling. The derivatives were divided into two categories: rhodanine (7a–7f) and rhodanine acetic acid derivatives (7g–7l). Biological evaluation revealed that rhodanine acetic acid derivatives demonstrated superior AR inhibition, with IC₅₀ values ranging from 6.87 to 9.07 µM, compared to rhodanine derivatives (11.79–15.90 µM). Among them, compound 7i (4-fluoro rhodanine acetic acid) exhibited the highest potency (IC₅₀ = 6.87 ± 1.22 µM), outperforming the standard Quercetin. Kinetic studies confirmed 7i as a reversible, non-competitive inhibitor (Ki = 6.87 µM), indicating interaction at an allosteric site of AR. Molecular docking using Schrödinger’s Glide XP mode against AKR1B1 (PDB ID: 4JIR) revealed that 7i had the most favorable docking score (−10.02) and binding energy (−67.51 kcal/mol), surpassing the standard inhibitor Epalrestat. Molecular dynamics simulations (200 ns) for 7 h and 7i indicated stable binding within the active site, with TRP111 identified as a key interacting residue. Interaction profiling revealed consistent hydrogen bonding and hydrophobic interactions, especially for 7i. Further, Principal Component Analysis (PCA) and Free Energy Landscape (FEL) analysis confirmed the stability of the 7i-bound complex, showing a dominant low-energy conformation. Dynamic Cross-Correlation Matrix (DCCM) analysis suggested that 7i enhances protein stability by modulating internal dynamics. Overall, 7i emerges as a promising AR inhibitor with potential therapeutic relevance for diabetic complications.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"27 ","pages":"Article 100215"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144580925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retrospective analysis of glomerular filtration rate estimated using different equations with and without adjustment to individual body surface area","authors":"Sara Armani ,&nbsp;Julia Stingl ,&nbsp;Thomas Forst ,&nbsp;Josef Höfler ,&nbsp;Hannah Wecker ,&nbsp;Astrid Trion","doi":"10.1016/j.medidd.2025.100212","DOIUrl":"10.1016/j.medidd.2025.100212","url":null,"abstract":"<div><div>The assessment of the influence of renal function on the pharmacokinetics of a new drug is pivotal in many clinical development programs. In clinical trials, renal function is commonly assessed by estimating the glomerular filtration rate (GFR).</div><div>Our retrospective analysis compared the assignment of 60 Caucasian volunteers to renal function groups based on their estimated GFR (eGFR). For each volunteer, GFR as measure of renal function was calculated using six commonly used equations (MDRD₂₀₀₆, CKD-EPI_creat2009, CKD-EPI_creat2021, CKD-EPI_cyst2012, CKD-EPI_{creat/cyst2012}, and CKD-EPI_{creat/cyst2021}) with and without adjustment to individual body surface area (BSA).</div><div>The resulting distribution of individuals to renal function groups varied across equations. The CKD-EPI_{creat/cyst2012} and CKD-EPI_{creat/cyst2021}, using both creatinine and cystatin C, showed the highest consistency in the renal function group assignment (agreement rate). The agreement rate improved by adjusting with individual BSA (aGFR).</div><div>The results support that BSA-adjustment of eGFR may improve the comparability and reproducibility of results of clinical trials where renal function categories are part of the trial design.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"27 ","pages":"Article 100212"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144524215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum albumin nanoparticles: Ligand functionalization for enhanced targeted therapeutics in precision medicine","authors":"Sakshi Shahapurmath,&nbsp;Bhuvaneshwari R. Sharannavar,&nbsp;Rahul Koli","doi":"10.1016/j.medidd.2025.100218","DOIUrl":"10.1016/j.medidd.2025.100218","url":null,"abstract":"<div><div>Serum albumin-based nanoparticles, derived from bovine (BSA) and human (HSA) sources, have emerged as versatile carriers in drug delivery systems due to their intrinsic biocompatibility, biodegradability, and amenability to surface modification. This review provides a comprehensive analysis of recent advancements in the functionalization of albumin nanoparticles with diverse ligands to enhance targeting specificity and therapeutic efficacy. Functional moieties such as folic acid, peptides, aptamers, antibodies and their fragments, polymers, chitosan, hyaluronic acid, biotin, transferrin, cholesterol, surfactants, and apolipoproteins have been extensively explored for their role in modulating cellular uptake, drug release kinetics, and site-specific accumulation. A systematic discussion of ligand selection, conjugation strategies, and encapsulated therapeutics is presented, along with a comprehensive evaluation of <em>in vitro</em> and <em>in vivo</em> studies assessing the pharmacokinetics, biodistribution, and therapeutic potential of ligand modified albumin nanoparticles. Particular empHSAis is placed on the applications of functionalized albumin nanoparticles in oncology, inflammatory and neurological disorders, and infectious diseases. Emerging trends highlight the development of multifunctional nanocarriers integrating imaging agents for theranostic applications and the application of cutting-edge functionalization techniques to facilitate personalized medicine. This review serves as a critical resource for researchers, fostering advancements in the rational design and optimization of albumin-based nanocarriers for precision drug delivery.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"27 ","pages":"Article 100218"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144720905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutralization of systemic toxicity of Daboia russelii venom and reprotoxin fraction by IgY antibodies","authors":"Punithkumar Naraganahalli Krishnaraj ,&nbsp;Kiran Kumar Mudnakudu-Nagaraju ,&nbsp;Nagalambika Prasad ,&nbsp;Chandavi Venkatesh ,&nbsp;Deekshith Ramesh ,&nbsp;Druthi Venktesh ,&nbsp;Anusha Chikkamandagere Kumar ,&nbsp;Kumar Jajur Ramanna","doi":"10.1016/j.medidd.2025.100217","DOIUrl":"10.1016/j.medidd.2025.100217","url":null,"abstract":"<div><div><em>Daboia russelii</em>, a highly venomous snake prevalent in South Asia, causes significant morbidity and mortality due to its complex venom, which includes neurotoxins, hemotoxins, and reprotoxins. Current equine-derived antivenoms, while effective, are associated with adverse effects like serum sickness. This study explores the potential of chicken-derived IgY antibodies as a safer, cost-effective alternative. Venom was fractionated using gel filtration chromatography, yielding six protein peaks, with Peak-I (large molecular weight fraction, LMF) and Peak-II (reprotoxin) used for immunization and neutralization studies. IgY antibodies raised against LMF in hens effectively neutralized twice the LD₅₀ dose of reprotoxin (1:4 ratio) and whole venom (1:8 ratio), mitigating neurotoxicity, edema, hemolysis, anticoagulation, proteolysis, and cytotoxicity. Compared to equine antivenoms, IgY showed comparable neutralization efficacy with potentially fewer side effects, highlighting its therapeutic promise. These findings suggest IgY antibodies merit further investigation as a novel antivenom for <em>D. russelii</em> envenomation.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"27 ","pages":"Article 100217"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generative AI for drug discovery and protein design: the next frontier in AI-driven molecular science","authors":"Uddalak Das","doi":"10.1016/j.medidd.2025.100213","DOIUrl":"10.1016/j.medidd.2025.100213","url":null,"abstract":"<div><div>Generative artificial intelligence (AI) has emerged as a disruptive paradigm in molecular science, enabling algorithmic navigation and construction of chemical and proteomic spaces through data-driven modeling. This review systematically delineates the theoretical underpinnings, algorithmic architectures, and translational applications of deep generative models—including variational autoencoders (VAEs), generative adversarial networks (GANs), autoregressive transformers, and score-based denoising diffusion probabilistic models (DDPMs)—in the rational design of bioactive small molecules and functional proteins. We examine the role of latent space learning, probabilistic manifold exploration, and reinforcement learning in inverse molecular design, focusing on optimization of pharmacologically relevant objectives such as ADMET profiles, synthetic accessibility, and target affinity. Furthermore, we survey advancements in graph-based molecular generative frameworks, LLM-guided protein sequence modeling, and diffusion-based structural prediction pipelines (e.g., RFdiffusion, FrameDiff), which have demonstrated state-of-the-art performance in de novo protein engineering and conformational sampling. Generative AI is also catalyzing a paradigm shift in structure-based drug discovery via AI-augmented molecular docking (e.g., DiffDock), end-to-end binding affinity prediction, and quantum chemistry-informed neural potentials. We explore the convergence of generative models with Bayesian retrosynthesis planners, self-supervised pretraining on ultra-large chemical corpora, and multimodal integration of omics-derived features for precision therapeutics. Finally, we discuss translational milestones wherein AI-designed ligands and proteins have progressed to preclinical and clinical validation, and speculate on the synthesis of generative AI, closed-loop automation, and quantum computing in future autonomous molecular design ecosystems.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"27 ","pages":"Article 100213"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144570577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}