Expert Opinion on Drug Discovery最新文献_第7页

Validation guidelines for drug-target prediction methods. 药物靶点预测方法的验证指南。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-01 Epub Date: 2024-11-21 DOI: 10.1080/17460441.2024.2430955

Ziaurrehman Tanoli, Aron Schulman, Tero Aittokallio

{"title":"Validation guidelines for drug-target prediction methods.","authors":"Ziaurrehman Tanoli, Aron Schulman, Tero Aittokallio","doi":"10.1080/17460441.2024.2430955","DOIUrl":"10.1080/17460441.2024.2430955","url":null,"abstract":"Introduction: Mapping the interactions between pharmaceutical compounds and their molecular targets is a fundamental aspect of drug discovery and repurposing. Drug-target interactions are important for elucidating mechanisms of action and optimizing drug efficacy and safety profiles. Several computational methods have been developed to systematically predict drug-target interactions. However, computational and experimental validation of the drug-target predictions greatly vary across the studies.Areas covered: Through a PubMed query, a corpus comprising 3,286 articles on drug-target interaction prediction published within the past decade was covered. Natural language processing was used for automated abstract classification to study the evolution of computational methods, validation strategies and performance assessment metrics in the 3,286 articles. Additionally, a manual analysis of 259 studies that performed experimental validation of computational predictions revealed prevalent experimental protocols.Expert opinion: Starting from 2014, there has been a noticeable increase in articles focusing on drug-target interaction prediction. Docking and regression stands out as the most commonly used techniques among computational methods, and cross-validation is frequently employed as the computational validation strategy. Testing the predictions using multiple, orthogonal validation strategies is recommended and should be reported for the specific target prediction applications. Experimental validation remains relatively rare and should be performed more routinely to evaluate biological relevance of predictions.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"31-45"},"PeriodicalIF":6.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681195","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}

引用次数: 0

Integrated machine learning and physics-based methods assisted de novo design of Fatty Acyl-CoA synthase inhibitors. 基于机器学习和物理学的综合方法辅助从头设计脂肪酸酰-CoA 合酶抑制剂。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-01 Epub Date: 2024-11-25 DOI: 10.1080/17460441.2024.2432972

Atul Pawar, Hemchandra Deka, Monishka Battula, Hossam M Aljawdah, Preeti Chunarkar Patil, Rupesh Chikhale

{"title":"Integrated machine learning and physics-based methods assisted de novo design of Fatty Acyl-CoA synthase inhibitors.","authors":"Atul Pawar, Hemchandra Deka, Monishka Battula, Hossam M Aljawdah, Preeti Chunarkar Patil, Rupesh Chikhale","doi":"10.1080/17460441.2024.2432972","DOIUrl":"10.1080/17460441.2024.2432972","url":null,"abstract":"Background: Tuberculosis is an infectious disease that has become endemic worldwide. The causative bacteria Mycobacterium tuberculosis (Mtb) is targeted via several exciting drug targets. One newly discovered target is the Fatty Acyl-CoA synthase, which plays a significant role in activating the long-chain fatty acids.Research design & methods: This study aims to generate novel compounds using Machine Learning (ML) algorithms to inhibit this synthase. Experimentally derived bioactive compounds were chosen from ChEMBL and used as inputs for effective molecule generation by Reinvent4. The library of new molecules generated was subjected to a two-tiered molecular docking protocol, and the results were further studied to obtain a binding free energy check.Results: The ML-based de novo drug design (DNDD) approach successfully generated a diverse library of novel molecules targeting Fatty Acyl-CoA synthase. After rigorous molecular docking and binding free energy analysis, four new compounds were identified as potential lead candidates with promising inhibitory effects on Mtb lipid metabolism.Conclusions: The study demonstrated the effectiveness of a machine-learning approach in generating novel drug candidates against Mtb. The identified hit compounds show potential as inhibitors of Fatty Acyl-CoA synthase, offering a new avenue for developing treatments for tuberculosis, particularly in combating drug-resistant strains.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"123-135"},"PeriodicalIF":6.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715894","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}

引用次数: 0

Development of environmentally biodegradable drugs: what are the key challenges? 环境可生物降解药物的发展：主要挑战是什么？

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-01 Epub Date: 2024-12-24 DOI: 10.1080/17460441.2024.2442746

Michael G Bertram, Bob B M Wong, Klaus Kümmerer, Manuela Jörg

引用次数: 0

Novel anticancer drug discovery strategies targeting hypoxia-inducible factors. 针对缺氧诱导因子的新型抗癌药物发现策略。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-01 Epub Date: 2024-12-17 DOI: 10.1080/17460441.2024.2442739

Muhamad Mustafa, Mahmoud Rashed, Jean-Yves Winum

{"title":"Novel anticancer drug discovery strategies targeting hypoxia-inducible factors.","authors":"Muhamad Mustafa, Mahmoud Rashed, Jean-Yves Winum","doi":"10.1080/17460441.2024.2442739","DOIUrl":"10.1080/17460441.2024.2442739","url":null,"abstract":"Introduction: Hypoxia is a key feature of solid tumors, associated with aggressive behaviors such as radiation and chemotherapy resistance, increased metastasis, and poor prognosis. Hypoxia-inducible factors (HIFs) are essential transcription factors that help tumor cells adapt to hypoxic environments by promoting the expression of pro-oncogenic genes. Reducing HIF activity presents a promising strategy for advancing cancer treatment.Area covered: In this paper, the authors present an overview of recent studies on the development of HIF-1/2 inhibitors as potential anticancer drugs. The article offers a comprehensive analysis of the structural characteristics of these inhibitors and explores their relationship with anticancer activity, focusing on research conducted over the past decade, from 2015 to 2024.Expert opinion: Because they play a big role in medicinal chemistry and the discovery of anticancer drugs, HIF inhibitors have always gotten a lot of attention and have been used to make a lot of important molecules with different biological effects, especially in the field of cancer research. Several techniques and chemical scaffolds have successfully targeted HIF-1α. However, additional research is required to sustain HIF-1α inhibition while maintaining anticancer activity. The FDA approval of Belzutifan provided researchers with an opportunity to conduct broader HIF-2 studies.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"103-121"},"PeriodicalIF":6.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817734","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}

引用次数: 0

Preclinical in vitro models of HNSCC and their role in drug discovery - an emphasis on the cancer microenvironment and microbiota. HNSCC的临床前体外模型及其在药物发现中的作用-重点是癌症微环境和微生物群。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-01 Epub Date: 2024-12-15 DOI: 10.1080/17460441.2024.2439456

Anne-Sophie Becker, Sonja Oehmcke-Hecht, Erik Dargel, Philipp Kaps, Thomas Freitag, Bernd Kreikemeyer, Christian Junghanss, Claudia Maletzki

{"title":"Preclinical in vitro models of HNSCC and their role in drug discovery - an emphasis on the cancer microenvironment and microbiota.","authors":"Anne-Sophie Becker, Sonja Oehmcke-Hecht, Erik Dargel, Philipp Kaps, Thomas Freitag, Bernd Kreikemeyer, Christian Junghanss, Claudia Maletzki","doi":"10.1080/17460441.2024.2439456","DOIUrl":"10.1080/17460441.2024.2439456","url":null,"abstract":"Introduction: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide. Treatment options and patient outcomes have not improved significantly over the past decades, increasing the need for better preclinical models. Holistic approaches that include an intact and functional immune compartment along with the patient's individual tumor microbiome will help improve the predictive value of novel drug efficacy.Areas covered: In this review, we describe the challenges of modeling the complex and heterogeneous tumor landscape in HNSCC and the importance of sophisticated patient-specific 3D in vitro models to pave the way for clinical trials with novel immunomodulatory drugs. We also discuss the impact of the tumor microbiome and the potential implications for prospective drug screening and validation trials.Expert opinion: The repertoire of well-characterized preclinical 3D in vitro models continues to grow. With the increasing attention to the complex cellular, immunological, molecular, and spatio-temporal characteristics of tumors, well-designed proof-of-concept studies to test novel drug efficacy are on the verge of providing valuable, practice-changing insights for clinical trials. Bringing together expertise and improving collaboration between clinicians, academics, and regulatory agencies will facilitate the translation of preclinical findings into clinically meaningful outcomes.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"81-101"},"PeriodicalIF":6.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827674","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}

引用次数: 0

Advances in chalcone-based anticancer therapy: mechanisms, preclinical advances, and future perspectives. 基于查尔酮的抗癌治疗进展：机制、临床前进展和未来展望。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-12-01 Epub Date: 2024-12-05 DOI: 10.1080/17460441.2024.2436908

Shefali Chowdhary, Preeti, Shekhar, Nikita Gupta, Rajesh Kumar, Vipan Kumar

{"title":"Advances in chalcone-based anticancer therapy: mechanisms, preclinical advances, and future perspectives.","authors":"Shefali Chowdhary, Preeti, Shekhar, Nikita Gupta, Rajesh Kumar, Vipan Kumar","doi":"10.1080/17460441.2024.2436908","DOIUrl":"10.1080/17460441.2024.2436908","url":null,"abstract":"Introduction: Cancer remains a leading cause of death worldwide with traditional treatments like chemotherapy, and radiotherapy becoming less effective due to multidrug resistance (MDR). This highlights the necessity for novel chemotherapeutics like chalcone-based compounds, which demonstrate broad anti-cancer properties and target multiple pathways. These compounds hold promise for improving cancer treatment outcomes compared to existing therapies.Areas covered: This review provides a comprehensive synopsis of the recent literature (2018-2024) for anti-proliferative/anti-cancer activity of chalcones. It includes the identification of potential targets, their mechanisms of action, and possible modes of binding. Additionally, chalcone derivatives in preclinical trials are also discussed.Expert opinion: Chalcones mark a significant stride in anticancer therapies due to their multifaceted approach in targeting various cellular pathways. Their ability to simultaneously target multiple pathways enables them to overcome drug resistance as compared to traditional therapies. With well-defined mechanisms of action, these compounds can serve as lead molecules for designing new, more promising treatments. Continued progress in synthesis and structural optimization, along with promising results from preclinical trials, offers hope for the development of more potent molecules, heralding a new era in cancer therapeutics.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1417-1437"},"PeriodicalIF":6.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766684","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}

引用次数: 0

Advances in the design and discovery of next-generation janus kinase-2 (JAK2) inhibitors for the treatment of myeloproliferative neoplasms. 用于治疗骨髓增生性肿瘤的新一代破伤风激酶-2 (JAK2)抑制剂的设计和发现进展。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-12-01 Epub Date: 2024-10-16 DOI: 10.1080/17460441.2024.2417368

Safa Daoud, Mutasem Omar Taha

{"title":"Advances in the design and discovery of next-generation janus kinase-2 (JAK2) inhibitors for the treatment of myeloproliferative neoplasms.","authors":"Safa Daoud, Mutasem Omar Taha","doi":"10.1080/17460441.2024.2417368","DOIUrl":"10.1080/17460441.2024.2417368","url":null,"abstract":"Introduction: Myeloproliferative neoplasms (MPNs) are rare hematopoietic disorders driven by mutations in the JAK-STAT signaling pathway genes. While JAK2 inhibitors have transformed MPN treatment, they do not eliminate the malignant clone or prevent disease progression in most patients. This limitation underscores the need for more effective therapies.Area covered: This review examines the evolution of JAK2 inhibitors for treating MPNs. Current JAK2 inhibitors primarily function as type I inhibitors, targeting the active kinase conformation, but their effectiveness is limited by ongoing JAK-STAT signaling. To overcome these limitations, next-generation therapies, such as type II JAK2 inhibitors and pseudokinase domain inhibitors, are being developed to target inactive kinase conformations and alternative signaling pathways. Furthermore, combination therapies with PI3K, mTOR, CDK4/6 inhibitors, and epigenetic modulators are being investigated for their potential synergistic effects, aiming for deeper and more durable responses in MPN patients.Expert opinion: Next-generation JAK2 inhibitors are needed to enhance current MPNs treatments by overcoming resistance, improving selectivity, targeting specific patient groups, and exploring combination therapies. Addressing challenges in drug design, preclinical testing, and clinical trials is crucial. Developing dual or multiple inhibitors targeting JAK2 and other MPN-related pathways is urgent to address complex signaling networks and improve efficacy.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1403-1415"},"PeriodicalIF":6.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461543","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}

引用次数: 0

Fragment-based approaches to discover ligands for tumor-specific E3 ligases. 基于片段的方法发现肿瘤特异性 E3 连接酶的配体。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-12-01 Epub Date: 2024-10-17 DOI: 10.1080/17460441.2024.2415310

Junhyeong Yim, Solbi Kim, Hyung Ho Lee, Jin Soo Chung, Jongmin Park

{"title":"Fragment-based approaches to discover ligands for tumor-specific E3 ligases.","authors":"Junhyeong Yim, Solbi Kim, Hyung Ho Lee, Jin Soo Chung, Jongmin Park","doi":"10.1080/17460441.2024.2415310","DOIUrl":"10.1080/17460441.2024.2415310","url":null,"abstract":"Introduction: Targeted protein degradation (TPD) has emerged as an innovative therapeutic strategy through selective degradation of specific proteins by harnessing the cellular ubiquitin-proteasome system (UPS), which involves over 600 E3 ubiquitin ligases. Recent proteome profiling reported tumor-specific E3 ligases in human. Development of those tumor-specific E3 ligase ligands would provide a solution for tumor-specific TPD for effective cancer treatment.Areas covered: This review provides a comprehensive list of E3 ligases found only in specific types of tumor from public databases and highlights examples of their ligands discovered through fragment-based approaches. It details their discovery process and potential applications for precise TPD and effective cancer treatments.Expert opinion: Current TPD strategies using proteolysis-targeting chimeras (PROTACs) primarily utilize general E3 ligases, such as CRBN and VHL. Since these E3 ligases demonstrate effective protein degradation activity in most human cell types, CRBN and VHL-based PROTACs can exhibit undesired TPD in off-target tissues, which often leads to the side effects. Therefore, developing tumor-specific E3 ligase ligands can be crucial for effective cancer treatments. Fragment-based ligand discovery (FBLD) approaches would accelerate the identification of these tumor-specific E3 ligase ligands and associated PROTACs, thereby advancing the field of targeted cancer therapies.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1471-1484"},"PeriodicalIF":6.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461545","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}

引用次数: 0

High-throughput and computational techniques for aptamer design. 用于适配体设计的高通量和计算技术。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-12-01 Epub Date: 2024-10-10 DOI: 10.1080/17460441.2024.2412632

Rajiv K Kar

{"title":"High-throughput and computational techniques for aptamer design.","authors":"Rajiv K Kar","doi":"10.1080/17460441.2024.2412632","DOIUrl":"10.1080/17460441.2024.2412632","url":null,"abstract":"Introduction: Aptamers refer to short ssDNA/RNA sequences that target small molecules, proteins, or cells. Aptamers have significantly advanced diagnostic applications, including biosensors for detecting specific biomarkers, state-of-the-art imaging, and point-of-care technology. Molecular computation helps identify aptamers with high-binding affinity, enabling high-throughput screening, predicting 3D structures, optimizing aptamers for improved stability, specificity, and complex target interactions.Area covered: Aptamers are versatile in the development of specific and sensitive diagnostics. However, there needs to be more understanding of the precise workflow that integrates sequence, structure, and interaction with the target. In this review, the author discusses how significant progress has been made in aptamer discovery using bioinformatics for sequence analysis, docking to model interactions, and MD simulations to account for dynamicity and predict free-energy. Furthermore, the author discusses how quantum chemical calculations are critical for modelling electronic structures and assignin spectroscopic signals.Expert opinion: Incorporating machine learning into the aptamer discovery brings a transformative advancement. With NGS datasets, SELEX, and experimental structures, the implementation of newer workflows yields aptamers with improved binding affinity. Leveraging transfer learning to models using experimental structures and aptamer sequences expands the aptamer design space significantly. As ML continues to evolve, it is poised to become central in accelerating aptamer discovery for biomedical applications in the next 5 years.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1457-1469"},"PeriodicalIF":6.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399906","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}

引用次数: 0

The latest developments in the design and discovery of non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV. 设计和发现用于治疗艾滋病的非核苷类逆转录酶抑制剂（NNRTIs）的最新进展。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-12-01 Epub Date: 2024-10-13 DOI: 10.1080/17460441.2024.2415309

Junyi Li, Bing Ye, Shenghua Gao, Xinyong Liu, Peng Zhan

引用次数: 0