Advances in pharmacology最新文献_第4页

Harnessing machine learning for rational drug design.

Advances in pharmacology Pub Date : 2025-01-01 Epub Date: 2025-03-03 DOI: 10.1016/bs.apha.2025.02.001

Sandhya Chaudhary, Kalpana Rahate, Shuchita Mishra

{"title":"Harnessing machine learning for rational drug design.","authors":"Sandhya Chaudhary, Kalpana Rahate, Shuchita Mishra","doi":"10.1016/bs.apha.2025.02.001","DOIUrl":"10.1016/bs.apha.2025.02.001","url":null,"abstract":"A crucial part of biomedical research is drug discovery, which aims to find and create innovative medical treatments for a range of illnesses. However, there are intrinsic obstacles to the traditional approach of discovering novel medications, including high prices, lengthy turnaround times, and poor clinical trial success rates. In recent times, the use of designing algorithms for machine learning has become a groundbreaking way to improve and optimise many stages of medication development. An outline of the quickly developing area of machine learning algorithms for drug discovery is given in this review, emphasising how revolutionary treatment development might be. To effectively get a novel medication into the market, modern medicinal development often involves many interconnected stages. The use of computational tools has become more and more crucial in reducing the time and cost involved in the investigation and creation of new medications. Our latest efforts to combine molecular modelling as well as machine learning to create the computational resources for designing modulators utilising a sensible design influenced by the pocket process that targets protein-protein interactions via AlphaSpace are reviewed in this Perspective. A significant shift in pharmaceutical research has occurred with the introduction of AI in drug discovery, which combines cutting-edge computer techniques with conventional scientific investigation to address enduring problems. By highlighting significant advancements and methodologies, this review paper elucidates the many applications of AI throughout several stages of drug discovery.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"103 ","pages":"209-230"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770842","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}

引用次数: 0

Identifying novel drug targets with computational precision.

Advances in pharmacology Pub Date : 2025-01-01 Epub Date: 2025-02-06 DOI: 10.1016/bs.apha.2025.01.003

Riya Dave, Pierpaolo Giordano, Sakshi Roy, Hiba Imran

{"title":"Identifying novel drug targets with computational precision.","authors":"Riya Dave, Pierpaolo Giordano, Sakshi Roy, Hiba Imran","doi":"10.1016/bs.apha.2025.01.003","DOIUrl":"10.1016/bs.apha.2025.01.003","url":null,"abstract":"Computational precision in drug discovery integrates algorithms and high-performance computing to analyze complex biological data with unprecedented accuracy, revolutionizing the identification of therapeutic targets. This process encompasses diverse computational and experimental approaches that enhance drug discovery's speed and precision. Advanced techniques like next-generation sequencing enable rapid genetic characterization, while proteomics explores protein expression and interactions driving disease progression. In-silico methods, including molecular docking, virtual screening, and pharmacophore modeling, predict interactions between small molecules and biological targets, accelerating early drug candidate identification. Structure-based drug design and molecular dynamics simulations refine drug designs by elucidating target structures and molecular behaviors. Ligand-based methods utilize known chemical properties to anticipate new compound activities. AI and machine learning optimizes data analysis, offering novel insights and improving predictive accuracy. Systems biology and network pharmacology provide a holistic view of biological networks, identifying critical nodes as potential drug targets, which traditional methods might overlook. Computational tools synergize with experimental techniques, enhancing the treatment of complex diseases with personalized medicine by tailoring therapies to individual patients. Ethical and regulatory compliance ensures clinical applicability, bridging computational predictions to effective therapies. This multi-dimensional approach marks a paradigm shift in modern medicine, delivering safer, more effective treatments with precision. By integrating bioinformatics, genomics, and proteomics, computational drug discovery has transformed how therapeutic interventions are developed, ensuring an era of personalized, efficient healthcare.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"103 ","pages":"231-263"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770874","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}

引用次数: 0

Stimulant prodrugs: A pharmacological and clinical assessment of their role in treating ADHD and binge-eating disorder. 兴奋剂原药：对其在治疗多动症和暴食症方面作用的药理学和临床评估。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2023-10-25 DOI: 10.1016/bs.apha.2023.10.002

David J Heal, Jane Gosden, Sharon L Smith

{"title":"Stimulant prodrugs: A pharmacological and clinical assessment of their role in treating ADHD and binge-eating disorder.","authors":"David J Heal, Jane Gosden, Sharon L Smith","doi":"10.1016/bs.apha.2023.10.002","DOIUrl":"10.1016/bs.apha.2023.10.002","url":null,"abstract":"In this review, we critically evaluate the contribution of prodrugs to treating two related psychiatric disorders, attention-deficit hyperactivity disorder (ADHD) and binge-eating disorder (BED). ADHD is characterized by inattentiveness, distractibility, impulsiveness, and hyperactivity. BED is also an impulse-control disorder which leads to frequent, compulsive episodes of excessive eating (binges). Lisdexamfetamine (LDX; prodrug of d-amphetamine) is approved to treat both ADHD and BED. Serdexmethylphenidate (SDX; prodrug of d-threo-methylphenidate) is not clinically approved as monotherapy but, in a fixed-dose combination with immediate release d-threo-methylphenidate (Azstarys™), SDX is approved for managing ADHD in children/adolescents. The pharmacological actions of a stimulant mediate both its efficacy and side-effects. Therefore, daily management of ADHD or BED to maintain optimum efficacy and tolerability places highly restrictive requirements on the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of stimulant medications, especially prodrugs. Prodrugs must have good bioavailability and rapid metabolism to provide therapeutic efficacy soon after morning dosing combined with providing stimulant coverage throughout the day/evening. A wide selection of dosages and linear PK for the prodrug and its active metabolite are essential requirements for treatment of these conditions. The proposed neurobiological causes of ADHD and BED are described. The chemical, pharmacological and PK/PD properties responsible for the therapeutic actions of the prodrugs, LDX and SDX, are compared and contrasted. Finally, we critically assess their contribution as ADHD and BED medications, including advantages over their respective active metabolites, d-amphetamine and d-threo-methylphenidate, and also their potential for misuse and abuse.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"99 ","pages":"251-286"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140100827","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}

引用次数: 0

Structural and functional perspectives on interactions between synthetic cathinones and monoamine transporters. 从结构和功能角度看合成卡西酮与单胺转运体之间的相互作用。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2023-10-20 DOI: 10.1016/bs.apha.2023.09.001

Vy T Nguyen, Alan C Harris, Jose M Eltit

{"title":"Structural and functional perspectives on interactions between synthetic cathinones and monoamine transporters.","authors":"Vy T Nguyen, Alan C Harris, Jose M Eltit","doi":"10.1016/bs.apha.2023.09.001","DOIUrl":"10.1016/bs.apha.2023.09.001","url":null,"abstract":"Synthetic cathinone derivatives comprise a family of psychoactive compounds structurally related to amphetamine. Over the last decade, clandestine chemists have synthesized a consistent stream of innovative cathinone derivatives to outpace governmental regulatory restrictions. Many of these unregulated substances are produced and distributed as designer drugs. Two of the principal chemical scaffolds exploited to expand the synthetic cathinone family are methcathinone and α-pyrrolidinopentiophenone (or α-pyrrolidinovalerophenone, α-PVP). These compounds' main physiological targets are monoamine transporters, where they promote addiction by potentiating dopaminergic neurotransmission. This chapter describes techniques used to study the pharmacodynamic properties of cathinones at monoamine transporters in vitro. Biochemical techniques described include uptake inhibition and release assays in rat brain synaptosomes and in mammalian expression systems. Electrophysiological techniques include current measurements using the voltage clamp technique. We describe a Ca2+ mobilization assay wherein voltage-gated Ca2+ channels function as reporters to study the action of synthetic cathinones at monoamine transporters. We discuss results from systematic structure-activity relationship studies on simple and complex cathinones at monoamine transporters with an emphasis on identifying structural moieties that modulate potency and selectivity at these transporters. Moreover, different profiles of selectivity at monoamine transporters directly predict compounds associated with behavioral and subjective effects within animals and humans. In conclusion, clarification of the structural aspects of compounds which modulate potency and selectivity at monoamine transporters is critical to identify and predict potential addictive drugs. This knowledge may allow prompt allocation of resources toward drugs that represent the greatest threats after drugs are identified by forensic laboratories.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"99 ","pages":"83-124"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140100828","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}

引用次数: 0

Discovery of novel anti-infective agents. 发现新型抗感染药物。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-06-25 DOI: 10.1016/bs.apha.2024.05.001

Arnab K Chatterjee

引用次数: 0

IVT-mRNA reprogramming of myeloid cells for cancer immunotherapy. IVT-mRNA 重编程髓系细胞，用于癌症免疫疗法。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-05-18 DOI: 10.1016/bs.apha.2024.04.004

Kevon J Jolly, Fan Zhang

{"title":"IVT-mRNA reprogramming of myeloid cells for cancer immunotherapy.","authors":"Kevon J Jolly, Fan Zhang","doi":"10.1016/bs.apha.2024.04.004","DOIUrl":"https://doi.org/10.1016/bs.apha.2024.04.004","url":null,"abstract":"In the past decade, in vitro transcribed messenger RNAs (IVT-mRNAs) have emerged as promising therapeutic molecules. The clinical success of COVID-19 mRNA vaccines developed by Pfizer-BioNTech and Moderna, have demonstrated that IVT-mRNAs can be safely and successfully used in a clinical setting, and efforts are underway to develop IVT-mRNAs for therapeutic applications. Current applications of mRNA-based therapy have been focused on (1) mRNA vaccines for infectious diseases and cancer treatment; (2) protein replacement therapy; (3) gene editing therapy; and (4) cell-reprogramming therapies. Due to the recent clinical progress of cell-based immunotherapies, the last direction-the use of IVT-mRNAs as a therapeutic approach to program immune cells for the treatment of cancer has received extensive attention from the cancer immunotherapy field. Myeloid cells are important components of our immune system, and they play critical roles in mediating disease progression and regulating immunity against diseases. In this chapter, we discussed the progress of using IVT-mRNAs as a therapeutic approach to program myeloid cells against cancer and other immune-related diseases. Towards this direction, we first reviewed the pharmacology of IVT-mRNAs and the biology of myeloid cells as well as myeloid cell-targeting therapeutics. We then presented a few cases of current IVT-mRNA-based approaches to target and reprogram myeloid cells for disease treatment and discussed the advantages and limitations of these approaches. Finally, we presented our considerations in designing mRNA-based approaches to target myeloid cells for disease treatment.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"100 ","pages":"247-288"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733281","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}

引用次数: 0

Progress in the development of ERK1/2 inhibitors for treating cancer and other diseases. 用于治疗癌症和其他疾病的 ERK1/2 抑制剂的研发进展。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-04-24 DOI: 10.1016/bs.apha.2024.04.001

Lena Grogan, Paul Shapiro

{"title":"Progress in the development of ERK1/2 inhibitors for treating cancer and other diseases.","authors":"Lena Grogan, Paul Shapiro","doi":"10.1016/bs.apha.2024.04.001","DOIUrl":"10.1016/bs.apha.2024.04.001","url":null,"abstract":"The extracellular signal-regulated kinases-1 and 2 (ERK1/2) are ubiquitous regulators of many cellular functions, including proliferation, differentiation, migration, and cell death. ERK1/2 regulate cell functions by phosphorylating a diverse collection of protein substrates consisting of other kinases, transcription factors, structural proteins, and other regulatory proteins. ERK1/2 regulation of cell functions is tightly regulated through the balance between activating phosphorylation by upstream kinases and inactivating dephosphorylation by phosphatases. Disruption of homeostatic ERK1/2 regulation caused by elevated extracellular signals or mutations in upstream regulatory proteins leads to the constitutive activation of ERK1/2 signaling and uncontrolled cell proliferation observed in many types of cancer. Many inhibitors of upstream kinase regulators of ERK1/2 have been developed and are part of targeted therapeutic options to treat a variety of cancers. However, the efficacy of these drugs in providing sustained patient responses is limited by the development of acquired resistance often involving re-activation of ERK1/2. As such, recent drug discovery efforts have focused on the direct targeting of ERK1/2. Several ATP competitive ERK1/2 inhibitors have been identified and are being tested in cancer clinical trials. One drug, Ulixertinib (BVD-523), has received FDA approval for use in the Expanded Access Program for patients with no other therapeutic options. This review provides an update on ERK1/2 inhibitors in clinical trials, their successes and limitations, and new academic drug discovery efforts to modulate ERK1/2 signaling for treating cancer and other diseases.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"100 ","pages":"181-207"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733284","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}

引用次数: 0

Journey from lab to clinic: Design, preclinical, and clinical development of systemic, targeted dendrimer-N-acetylcysteine (D-NAC) nanomedicines. 从实验室到临床的旅程：系统性、靶向性树枝状聚合物-N-乙酰半胱氨酸（D-NAC）纳米药物的设计、临床前和临床开发。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-06-22 DOI: 10.1016/bs.apha.2024.05.003

Wathsala Liyanage, Narendra Kale, Sujatha Kannan, Rangaramanujam M Kannan

{"title":"Journey from lab to clinic: Design, preclinical, and clinical development of systemic, targeted dendrimer-N-acetylcysteine (D-NAC) nanomedicines.","authors":"Wathsala Liyanage, Narendra Kale, Sujatha Kannan, Rangaramanujam M Kannan","doi":"10.1016/bs.apha.2024.05.003","DOIUrl":"https://doi.org/10.1016/bs.apha.2024.05.003","url":null,"abstract":"Drug discovery is challenging task with numerous obstacles in translating drug candidates into clinical products. Dendrimers are highly adaptable nanostructured polymers with significant potential to improve the chances of clinical success for drugs. Yet, dendrimer-based drug products are still in their infancy. However, Hydroxyl polyamidoamine (PAMAM) dendrimers showed significant promise in drug discovery efforts, owning their remarkable potential to selectively target and deliver drugs specifically to activated microglia and astrocytes at the site of brain injury in several preclinical models. After a decade's worth of academic research and pre-clinical efforts, the hydroxyl PAMAM dendrimer-N-acetyl cysteine conjugate (OP-101) nanomedicine has made a significant advancement in the field of nanomedicine and targeted delivery. The OP-101 conjugate, primarily developed and validated in academic labs, has now entered clinical trials as a potential treatment for hyperinflammation in hospitalized adults with severe COVID-19 through Ashvattha Therapeutics. This chapter, we delve into the journey of the hydroxyl PAMAM dendrimer-N-acetylcysteine (NAC) OP-101 formulation from the laboratory to the clinic. It will specifically focus on the design, synthesis, preclinical, and clinical development of OP-101, highlighting the potential it holds for the future of medicine and the positive Phase 2a results for treating severe COVID-19.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"100 ","pages":"119-155"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733282","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}

引用次数: 0

Therapeutic resurgence of 6-diazo-5-oxo-l-norleucine (DON) through tissue-targeted prodrugs. 通过组织靶向原药使 6-重氮-5-氧代-1-正亮氨酸（DON）重新成为治疗药物。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-05-09 DOI: 10.1016/bs.apha.2024.04.003

Kateřina Novotná, Lukáš Tenora, Barbara S Slusher, Rana Rais

{"title":"Therapeutic resurgence of 6-diazo-5-oxo-l-norleucine (DON) through tissue-targeted prodrugs.","authors":"Kateřina Novotná, Lukáš Tenora, Barbara S Slusher, Rana Rais","doi":"10.1016/bs.apha.2024.04.003","DOIUrl":"https://doi.org/10.1016/bs.apha.2024.04.003","url":null,"abstract":"The recognition that rapidly proliferating cancer cells rely heavily on glutamine for their survival and growth has renewed interest in the development of glutamine antagonists for cancer therapy. Glutamine plays a pivotal role as a carbon source for synthesizing lipids and metabolites through the TCA cycle, as well as a nitrogen source for synthesis of amino acid and nucleotides. Numerous studies have explored the significance of glutamine metabolism in cancer, providing a robust rationale for targeting this metabolic pathway in cancer treatment. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) has been explored as an anticancer therapeutic for nearly six decades. Initial investigations revealed remarkable efficacy in preclinical studies and promising outcomes in early clinical trials. However, further advancement of DON was hindered due to dose-limiting gastrointestinal (GI) toxicities as the GI system is highly dependent on glutamine for regulating growth and repair. In an effort to repurpose DON and mitigate gastrointestinal (GI) toxicity concerns, prodrug strategies were utilized. These strategies aimed to enhance the delivery of DON to specific target tissues, such as tumors and the central nervous system (CNS), while sparing DON delivery to normal tissues, particularly the GI tract. When administered at low daily doses, optimized for metabolic inhibition, these prodrugs exhibit remarkable effectiveness without inducing significant toxicity to normal tissues. This approach holds promise for overcoming past challenges associated with DON, offering an avenue for its successful utilization in cancer treatment.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"100 ","pages":"157-180"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733295","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}

引用次数: 0

AXL: A novel therapeutic target in IBD. AXL：一种新型的 IBD 治疗靶点。

Advances in pharmacology Pub Date : 2024-01-01 Epub Date: 2024-10-22 DOI: 10.1016/bs.apha.2024.10.009

Bejan J Saeedi, Hannah E Carr, Peter D R Higgins, Calen A Steiner

引用次数: 0