Opportunities For Drug Development Research Articles

Rare tumor list provide vast opportunities for novel drug development in China

Rare tumor list provide vast opportunities for novel drug development in China

Using Genetics to Assess the Role of Acetate in Ischemic Heart Disease, Diabetes, and Sex-Hormone-Related Cancers: A Mendelian Randomization Study.

Acetate, a short-chain fatty acid, has gained attention for its contrasting roles, with evidence suggesting it may offer cardiovascular protection but also promote cancer, particularly those involving sex hormones. However, these influences have been scarcely assessed in epidemiological research. To investigate the relationship between acetate and ischemic heart disease (IHD), diabetes, and cancers related to sex hormones. Mendelian randomization (MR) was used to assess potential causal effects, selecting genetic variants without linkage disequilibrium (r2 < 0.001) and with genome-wide significance for acetate (p < 5 × 10-8). These variants were applied to large genome-wide association studies (GWAS) for ischemic heart disease (IHD; up to 154,373 cases), diabetes (109,731 cases), and five sex-hormone-related cancers (breast, colorectal, prostate, ovarian, and endometrial cancers, ranging from 8679 to 122,977 cases). We employed various methods for analysis, including penalized inverse variance weighting (pIVW), inverse variance weighting, weighted mode, and weighted median. This study indicates that acetate may be associated with a lower risk of ischemic heart disease (IHD), with an odds ratio (OR) of 0.62 per standard deviation (SD) increase in acetate and a 95% confidence interval (CI) of 0.39 to 0.98. Additionally, acetate was linked to a higher breast cancer risk, with an OR of 1.26 and a 95% CI ranging from 1.08 to 1.46. This association remained robust across multiple sensitivity analyses. Acetate, along with factors that influence its activity, may serve as possible targets for breast cancer treatment and possibly IHD, offering opportunities for new drug development.

A patient-derived HCC spheroid system to model the tumor microenvironment and treatment response

Background & AimsHepatocellular carcinoma (HCC) is the third leading and fastest rising cause of cancer-related death worldwide. The discovery and preclinical development of compounds targeting HCC is hampered by the absence of authentic tractable systems recapitulating the heterogeneity of patient HCC tumors and the tumor microenvironment (TME). MethodsWe established a novel and simple patient-derived multicellular tumorspheroid model based on clinical HCC tumor tissues, processed using enzymatic and mechanical dissociation. After quality controls, 22 HCC tissues and 17 HCC serum were selected for tumorspheroid generation and perturbation studies. Cells were grown in 3D in optimized medium in presence of patient serum. Characterization of the tumorspheroid cell populations was performed by flow cytometry, immunohistochemistry and functional assays. As a proof of concept, we treated patient-derived spheroids with FDA approved anti-HCC compounds. ResultsThe model was successfully established independently from cancer etiology and grade from 22 HCC tissues. We show that the use of HCC patient serum was essential for tumorspheroid generation, the TME function and to maintain cell viability. The tumorspheroids comprised the main cell compartments including epithelial cancer cells as well as all major cell populations of the TME (cancer-associated fibroblasts, macrophages and T cells, endothelial cells). Tumorspheroids reflect HCC heterogeneity, including variability in cell type proportions and TME, and mimic the original tumor features. Moreover, we observed differential responses to FDA HCC approved drugs between donors as observed in patients. ConclusionThis patient HCC serum-tumorspheroid model provides novel opportunities for drug discovery and development as well as mechanism of action studies including compounds targeting the TME. This model will likely contribute to improve the dismal outcome of patients with HCC. Impact and implicationsHepatocellular carcinoma (HCC) is a leading and fast rising cause of cancer-related death worldwide. Despite approval of novel therapies, the outcome of advanced HCC remains unsatisfactory. By developing a novel patient-derived tumorspheroid model recapitulating tumor heterogeneity and microenvironment, we provide new opportunities for HCC drug development and analysis of mechanism of action in authentic patient tissues. The application of the patient-derived tumorspheroids combined with other HCC models will likely contribute to drug development and to improve the dismal outcome of patients with HCC.

The efficacy and mechanism of action of the Umei decoction in insomnia: A randomized active-controlled clinical trial

Insomnia, affecting the quality of life of millions globally, necessitates urgent and effective treatment strategies. This study conducted a randomized controlled trial to compare traditional and novel treatment methods in a cohort of 60 insomnia patients. Sleep quality and symptoms were assessed using the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS). Additionally, transcranial Doppler (TCD) technology was employed to measure cerebral hemodynamic parameters. We divided the patients into two groups for insomnia treatment: (1) Control group: oral administration of zopiclone tablets; (2) Treatment group: oral administration of WuMei Decoction. The findings revealed that novel treatment approaches significantly improved sleep quality, disturbances, daytime functionality, and cerebral hemodynamic indicators. Furthermore, identifying 220 potential target genes through systems biology approaches offers new insights into the molecular mechanisms of insomnia and opportunities for drug development.

Public health case for microbiome-sparing antibiotics and new opportunities for drug development.

Although antibiotics remain a cornerstone of modern medicine, the issues of widespread antibiotic resistance and collateral damage to the microbiome from antibiotic use are driving a need for drug developers to consider more tailored, patient-directed products to avoid antibiotic-induced perturbations of the structure and function of the indigenous microbiota. This perspective summarizes a cascade of microbiome health effects that is initiated by antibiotic-mediated microbiome disruption at an individual level and ultimately leads to infection and transmission of multidrug-resistant pathogens across patient populations. The scientific evidence behind each of the key steps of this cascade is presented. The interruption of this cascade through the use of highly targeted, microbiome-sparing antibiotics aiming to improve health outcomes is discussed. Further, this perspective reflects on some key clinical trial design and reimbursement considerations to be addressed as part of the drug development path.

Electrosynthesis for the Development of Selective Organic Reactions

The development of efficient and selective reactions play a vital role in chemical synthesis and drug discovery, serving as crucial drivers for advancements in these fields. Electrosynthesis has emerged as a versatile and powerful tool within organic chemistry, enabling the exploration and development of new organic reactions. This state-of-the-art technique harnesses the power of electricity to propel chemical transformations, paving the way for synthetic chemists to create intricate organic molecules. In this presentation, we will showcase notable discoveries from the Malapit Lab, highlighting the innovative application of electrochemistry in the exploration of novel and transformative reactions. Among these groundbreaking findings are a site-selective C–H functionalization reaction and the utilization of organoboron reagents to generate diverse carbon-heteroatom products through radical intermediates. These reactions hold promise for the late-stage functionalization of numerous biologically active compounds, presenting exciting opportunities for drug development and synthesis.

Molecular nociceptive mechanisms in migraine: The migraine cascade.

This review will explore the categorization of migraine-provoking molecules, their cellular actions, site of action and potential drug targets based on the migraine cascade model. Personal experience and literature. Migraine impacts over 1 billion people worldwide but is underfunded in research. Recent progress, particularly through the human and animal provocation model, has deepened our understanding of its mechanisms. This model have identified endogenous neuropeptides such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) that induces controlled migraine-like attacks leading to significant discoveries of their role in migraine. This knowledge led to the development of CGRP-inhibiting drugs; a groundbreaking migraine treatment now accessible globally. Also a PACAP-inhibiting drug was effective in a recent phase II trial. Notably, rodent studies have shed light on pain pathways and the mechanisms of various migraine-inducing substances identifying novel drug targets. This is primarily done by using selective inhibitors that target specific signaling pathways of the known migraine triggers leading to the hypothesized cellular cascade model of migraine. The model of migraine presents numerous opportunities for innovative drug development. The future of new migraine treatments is limited only by the investment from pharmaceutical companies.

The Dual Roles of S-Nitrosylation of Proteins in Cancer: Molecular Mechanisms and Recent Advancements

&lt;p class="MsoNormal" style="text-align: justify;"&gt;&lt;span lang="EN-US" style="font-family: Nunito; color: #212529; background: white;"&gt;Protein S-nitrosylation (SNO), emerging as an important posttranslational modification, involves covalent addition of nitric oxide (NO) to the sulfur atom of cysteine in proteins. Accumulated evidence suggests that protein SNO plays crucial roles in pathophysiological mechanisms in cancer, which is attracting great attention. However, there are still controversies about whether S-nitrosylated proteins act as oncogenic proteins or tumor suppressors in cancer. In this review, we provide an overview of the early and latest evidence regarding the underlying mechanism and dual roles of SNO in cancer, in an effort to clarify its contribution in tumor progression. It has been well established that S-nitrosylated proteins restrain tumor progression in several types of cancer, while they have exhibited activities in promoting cell proliferation and inhibiting apoptosis in some other kinds of cancer. Interestingly, emerging evidence also has highlighted both its anti-cancer and pro-tumorigenic roles in several other cancer diseases. Finally, current limitations and future research prospects are presented. The overview of targeting SNO in cancer will provide new opportunities for drug development through in-depth exploration of SNO-mediated signaling pathways.&lt;/span&gt;&lt;/p&gt;

Advancements in diabetic kidney disease management: integrating innovative therapies and targeted drug development.

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease and affects approximately 40% of individuals with diabetes . Cases of DKD continue to rise globally as the prevalence of diabetes mellitus increases, with an estimated 415 million people living with diabetes in 2015 and a projected 642 million by 2040. DKD is associated with significant morbidity and mortality, representing 34% and 36% of all chronic kidney disease deaths in men and women, respectively. Common comorbidities including hypertension and ageing-related nephron loss further complicate disease diagnosis and progression. The progression of DKD involves several mechanisms including glomerular endothelial cell dysfunction, inflammation, and fibrosis. Targeting these mechanisms has formed the basis of several therapeutic agents. Renin-angiotensin-aldosterone system (RAAS) blockers, specifically angiotensin receptor blockers (ARBs), demonstrate significant reductions in macroalbuminuria. Sodium-glucose transporter type 2 (SGLT-2) inhibitors demonstrate kidney protection independent of diabetes control while also decreasing the incidence of cardiovascular events. Emerging agents including glucagon-like peptide 1 (GLP-1) agonists, anti-inflammatory agents like bardoxolone, and mineralocorticoid receptor antagonists show promise in mitigating DKD progression. Many novel therapies including monoclonal antibodies CSL346, lixudebart, and tozorakimab; mesenchymal stem/stromal cell infusion; and cannabinoid-1 receptor inverse agonism via INV-202 are currently in clinical trials and present opportunities for further drug development.

Identification of active main metabolites of anti-infective inhibitors of the macrophage infectivity potentiator protein by liquid chromatography using mass detection.

Due to increasing antibiotic resistance, the development of anti-infectives with new mechanisms of action is crucial. Virulence factors such as the "macrophage infectivity potentiator" (Mip) protein, which catalyzes the folding of proline-containing proteins by means of their cis-trans isomerase (PPIase) activity, have come into focus as a potential new target. Since the inhibition of Mip by small molecules has been shown to lead to reduced virulence and survival in vitro, especially of Gram-negative bacteria such as Burkholderia pseudomallei (Bp), Neisseria meningitidis (Nm), and Neisseria gonorrhoeae (Ng), or Coxiella burnetii (Cb), among many others, a library of Mip inhibitors was developed. As drug metabolism has a significant impact on the overall therapeutic outcome, this report describes the biotransformation of the most potent Mip inhibitors. Therefore, the anti-infectives were treated using human liver microsomes in vitro. Liquid chromatography with tandem mass spectrometry (LC/MS-MS) methods were applied to identify the metabolites and quantify the metabolic degradation of the hit compounds. Active metabolites, N-oxides, were found, leading to new opportunities for further drug development.

Discovery and development of macrocyclic peptide modulators of the cannabinoid 2 receptor

The cannabinoid type 2 receptor (CB2R), a G protein-coupled receptor, is an important regulator of immune cell function and a promising target to treat chronic inflammation and fibrosis. While CB2R is typically targeted by small molecules, including endo-, phyto-, and synthetic cannabinoids, peptides-owing to their size-may offer a different interaction space to facilitate differential interactions with the receptor. Here, we explore plant-derived cyclic cystine-knot peptides as ligands of the CB2R. Cyclotides are known for their exceptional biochemical stability. Recently, they gained attention as G protein-coupled receptor modulators and as templates for designing peptide ligands with improved pharmacokinetic properties over linear peptides. Cyclotide-based ligands for CB2R were profiled based on a peptide-enriched extract library comprising nine plants. Employing pharmacology-guided fractionation and peptidomics, we identified the cyclotide vodo-C1 from sweet violet (Viola odorata) as a full agonist of CB2R with an affinity (Ki) of 1μM and a potency (EC50) of 8μM. Leveraging deep learning networks, we verified the structural topology of vodo-C1 and modeled its molecular volume in comparison to the CB2R ligand binding pocket. In a fragment-based approach, we designed and characterized vodo-C1-based bicyclic peptides (vBCL1-4), aiming to reduce size and improve potency. Opposite to vodo-C1, the vBCL peptides lacked the ability to activate the receptor but acted as negative allosteric modulators or neutral antagonists of CB2R. This study introduces a macrocyclic peptide phytocannabinoid, which served as a template for the development of synthetic CB2R peptide modulators. These findings offer opportunities for future peptide-based probe and drug development at cannabinoid receptors.

Tailoring epilepsy treatment: personalized micro physiological systems illuminate individual drug responses

Introduction: Approximately 50 million people worldwide have epilepsy, with many not achieving seizure freedom. Organ-on-chip technology, which mimics organ-level physiology, could revolutionize drug development for epilepsy by replacing animal models in preclinical studies. Our goal is to determine if customized micro-physiological systems can lead to tailored drug treatments for epileptic patients. Materials and methods: A comprehensive literature search was conducted utilizing various databases, including PubMed, Ebscohost, Medline, and the National Library of Medicine, using a predetermined search strategy. We focused on articles that addressed the role of personalized micro-physiological systems in individual drug responses and articles that discussed different types of epilepsy, diagnosis, and current treatment options. Additionally, articles that explored the components and design considerations of micro-physiological systems were reviewed to identify challenges and opportunities in drug development for challenging epilepsy cases. Results: The micro-physiological system offers a more accurate and cost-effective alternative to traditional models for assessing drug effects, toxicities, and disease mechanisms. Nevertheless, designing patient-specific models presents critical considerations, including the integration of analytical biosensors and patient-derived cells, while addressing regulatory, material, and biological complexities. Material selection, standardization, integration of vascular systems, cost efficiency, real-time monitoring, and ethical considerations are also crucial to the successful use of this technology in drug development. Conclusion: The future of organ-on-chip technology holds great promise, with the potential to integrate artificial intelligence and machine learning for personalized treatment for epileptic patients.

Alpha-amylase and Alpha-glucosidase Inhibitory Activities of Philippine Indigenous Medicinal Plants

In the Philippines, medicinal plants still provide the first line of therapeutic remedies and their reported efficacy in traditional treatments provides an opportunity for drug discovery and development. The study aimed to evaluate in vitro commonly used Philippine medicinal plants for their alpha-amylase and alpha-glucosidase inhibitory activities as potential sources of antidiabetic agents. The study emphasised the inhibitory activities of 54 medicinal plants against α-amylase and α-glucosidase enzymes. The findings revealed 7 medicinal plants with the highest alpha-glucosidase inhibitory activity of ≥ 50% and 3 with alpha-amylase inhibitory activity of ≥ 20%. Ethyl acetate extract of Cycas sp. exhibited the highest α-glucosidase inhibitory activity with 83.87% ± 1.52 followed by the aqueous extract of cf. Calyptranthera sp. With 82.07% ± 0.14 with Acarbose as the reference standard (99.71% ± 0.63) at 10µg/mL (w/v) concentration. For the alpha-amylase inhibitory assay, the highest bioactivity was observed in ethyl acetate extract of Curcuma longa L. (39.44% ± 1.56) with Acarbose as the reference standard (51.59% ± 0.98) at 10µg/mL (w/v) concentration. These findings suggest the potential of the above-mentioned plants as sources of alpha-amylase and alpha-glucosidase inhibitors that may be used as antidiabetic agents.

Abstract 6765: A patient-derived hepatocellular carcinoma multicellular spheroid platform harnessing autologous patient serum to model the tumor microenvironment and treatment response

Abstract Hepatocellular carcinoma (HCC) is the third leading and fastest rising cause of cancer-related death worldwide. The discovery and preclinical development of compounds targeting HCC is hampered by the absence of authentic tractable systems recapitulating the heterogeneity of patient HCC tumors and the tumor microenvironment (TME). Here, we established a novel, simple and robust patient-derived multicellular tumorspheroid model based on clinical HCC tumor tissues combined with the autologous patient serum. The model was robust and reproducible independently from cancer etiology and grade recapitulating key functional features of original tissue. We show that the use of autologous patient serum was essential for the TME function. The tumorspheroids comprised the main cell compartments including epithelial cancer cells as well as all major cell populations of the TME (cancer-associated fibroblasts, macrophages and T cells). Cell type proportions were variable between tumorspheroids reflecting HCC heterogeneity. Moreover, we observed differential responses to FDA HCC approved drugs (including tyrosine kinase and checkpoint inhibitors as well as VEGF-targeting agents) between donors as in patients. This patient HCC serum-tumorspheroid model provides novel opportunities for drug discovery and development as well mechanism of action studies including compounds targeting the TME. In conclusion, this HCC serum-tumorspheroid platform will contribute to improve the dismal outcome of patients with HCC. Citation Format: Emilie Crouchet, Nuno Almeida, Sarah C. Durand, Marie Parnot, Marine A. Oudot, Fabio Giannone, Cloé Gadenne, Sara Cherradi, Natascha Roehlen, Antonio Saviano, Emanuele Emanuele Felli, Patrick Pessaux, Kazuaki Chayama, Hong Tuan F. Duong, Thomas F. Baumert, Catherine Schuster. A patient-derived hepatocellular carcinoma multicellular spheroid platform harnessing autologous patient serum to model the tumor microenvironment and treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6765.

Abstract 4483: New drug development opportunities for PARP1

Abstract Personalized therapies allow, not only the increase of its therapeutic efficiency, but also the reduction of the secondary effects associated to the treatment of cancer. Data obtained in our group suggest that PARP1 could play a key role in the cell cycle regulation through its interaction with E2F1 transcription factor. Considering that most oncogenic processes is associated with cell cycle deregulation, the disruption of this interaction would provide a new therapeutic target of great interest and wide spectrum of indications. Therefore, our goal was to find molecules that interfere its role in cell-cycle regulation without affecting its function on DNA repair. The identification of novel compounds disrupting the PARP1/E2F1 interaction was carried out by combining in silico and in vitro screening, using a rational drug design. The virtual screen was performed using a molecular library of several million compounds at the selected target site, using AtomNet® (Atomwise), the first deep learning neural network for structure-based drug design and discovery. Since there is no complete structural information of the PARP-1/E2F1 protein-protein interaction, a homologous structure of BRCT domain of BRCA1 complex with the phospho-peptide (PDBID: 1T2V) was utilized to identify the potential binding interface of BRCT domain of PARP-1 (PDBID: 2COK) and the E2F1 protein. Top scoring compounds were clustered and filtered to arrive at a final subset of 83 compounds, library that were incorporated to our in vitro screening, which included both transcriptional (E2F1 activity) and survival studies. Twelve compounds were finally selected, based upon their higher capacity of inhibiting E2F1 activity.This work was supported by Agencia Estatal de Investigación (AEl/10.13039/501100011033), Xunta de Galicia (GPC GI-1862, ED431B 2020/26; ED431G 2019/02) and European Regional Development Fund-ERDF. AIMS Awards Program - Project A19-513, Atomwise Inc. Citation Format: Pablo Iglesias, David Moreiras, Laura Porres-Ventin, Lara Gonzalez-Rendo, Jose A. Zumalave, Victor M. Arce, Jose A. Costoya. New drug development opportunities for PARP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4483.

Clinical Pharmacology Perspective on Development of Adeno-Associated Virus Vector-Based Retina Gene Therapy.

Adeno-associated virus (AAV) vector-based gene therapy is an innovative modality being increasingly investigated to treat diseases by modifying or replacing defective genes or expressing therapeutic entities. With its unique anatomic and physiological characteristics, the eye constitutes a very attractive target for gene therapy. Specifically, the ocular space is easily accessible and is generally considered "immune-privileged" with a low risk of systemic side effects following local drug administration. As retina cells have limited cellular turnover, a one-time gene delivery has the potential to provide long-term transgene expression. Despite the initial success with voretigene neparvovec (Luxturna), the first approved retina gene therapy, there are still challenges to be overcome for successful clinical development of these products and scientific questions to be answered. The current review paper aims to integrate published experience learned thus far for AAV-based retina gene therapy related to preclinical to clinical translation; first-in-human dose selection; relevant bioanalytical assays and strategies; clinical development considerations including trial design, biodistribution and vector shedding, immunogenicity, transgene expression, and pediatric populations; opportunities for model-informed drug development; and regulatory perspectives. The information presented herein is intended to serve as a guide to inform the clinical development strategy for retina gene therapy with a focus on clinical pharmacology.

Challenges and opportunities in oncology drug development and clinical research in China

As one of the world's most populous countries, China bears a heavy burden and a broad spectrum of cancers, including unique types, providing a unique environment for drug research and development. In recent years, China has leapt forward in oncology drug development and clinical trials, presenting new opportunities and challenges.

Antibiofilm and Antibacterial Properties of Herbal Extracts as Alternatives to Current Treatment Approaches: A Narrative Review

Bacterial biofilm formation poses significant challenges in the healthcare sector due to increased antibiotic resistance and persistent infections. This literature review explores the potential of some herbs and their extracts as alternative approaches to combat biofilm formation and multidrug-resistant bacteria. A detailed literature search was conducted across databases for published studies till 2023, to identify studies on medicinal plants' anti-biofilm and antibacterial properties. Key compounds within plant extracts showing anti-biofilm activity and their mechanisms of action were highlighted. A combination of keywords, MeSH terms, and Boolean operators were used to formulate the search strategy. Numerous studies demonstrated the efficacy of medicinal plants in inhibiting biofilm formation and combating multidrug-resistant bacteria. Active compounds such as benzyl (6Z,9Z,12Z)-6,9,12-octadecatrienoate, 3-benzyloxy-1-nitro-butan-2-ol, Pyridine, 3-(1-methyl-2-pyrrolidinyl)-(S), and others exhibited anti-biofilm and antibacterial potential. Extracts from Berginia ciliata, Clematis grata, and Clematis viticella showed over 80% inhibition of biofilm formation, while mango leaf extracts interfered with quorum sensing mechanisms in Pseudomonas aeruginosa PAO1. Salvadora persica extracts displayed significant biofilm inhibition against cariogenic Streptococcus mutans isolates. Medicinal plants and their extracts hold promise as alternative strategies to combat bacterial biofilms and multidrug-resistant bacteria. The identification of active compounds provides opportunities for further research and drug development. Molecular docking studies are crucial for understanding the molecular interactions between these compounds and bacterial targets, guiding the design of effective antibacterial agents based on natural compounds. Further research, including preclinical and clinical trials, is essential to validate the safety and efficacy of these extracts and their compounds for practical application in healthcare.

Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development.

Cholesterol homeostasis is impaired in Alzheimer's disease; however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of Alzheimer's disease. Indeed, neuronal cholesterol was linked to the formation of amyloid-β and neurofibrillary tangles through molecular pathways that were recently delineated in mechanistic studies. Furthermore, remarkable advances in translational molecular imaging have now made it possible to probe cholesterol metabolism in the living human brain with PET, which is an important prerequisite for future clinical trials that target the brain cholesterol machinery in Alzheimer's disease patients-with the ultimate aim being to develop disease-modifying treatments. This work summarizes current concepts of how the biosynthesis, transport and clearance of brain cholesterol are affected in Alzheimer's disease. Further, current strategies to reverse these alterations by pharmacotherapy are critically discussed in the wake of emerging translational research tools that support the assessment of brain cholesterol biology not only in animal models but also in patients with Alzheimer's disease.

Lysine-Specific Demethylase 1 Inhibitors: A Comprehensive Review Utilizing Computer-Aided Drug Design Technologies.

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and other diseases (blood diseases, cardiovascular diseases, etc.), owing to its observed overexpression, thereby presenting significant opportunities in drug development. Since its discovery in 2004, extensive research has been conducted on LSD1 inhibitors, with notable contributions from computational approaches. This review systematically summarizes LSD1 inhibitors investigated through computer-aided drug design (CADD) technologies since 2010, showcasing a diverse range of chemical scaffolds, including phenelzine derivatives, tranylcypromine (abbreviated as TCP or 2-PCPA) derivatives, nitrogen-containing heterocyclic (pyridine, pyrimidine, azole, thieno[3,2-b]pyrrole, indole, quinoline and benzoxazole) derivatives, natural products (including sanguinarine, phenolic compounds and resveratrol derivatives, flavonoids and other natural products) and others (including thiourea compounds, Fenoldopam and Raloxifene, (4-cyanophenyl)glycine derivatives, propargylamine and benzohydrazide derivatives and inhibitors discovered through AI techniques). Computational techniques, such as virtual screening, molecular docking and 3D-QSAR models, have played a pivotal role in elucidating the interactions between these inhibitors and LSD1. Moreover, the integration of cutting-edge technologies such as artificial intelligence holds promise in facilitating the discovery of novel LSD1 inhibitors. The comprehensive insights presented in this review aim to provide valuable information for advancing further research on LSD1 inhibitors.