Drug Development Research Articles

PI3K/AKT signaling and neuroprotection in ischemic stroke: molecular mechanisms and therapeutic perspectives.

It has been reported that the PI3K/AKT signaling pathway plays a key role In the pathogenesis of ischemic stroke. As a result, the development of drugs targeting the PI3K/AKT signaling pathway has attracted increasing attention from researchers. This article reviews the pathological mechanisms and advancements in research related to the signaling pathways in ischemic stroke, with a focus on the PI3K/AKT signaling pathway.The key findings include the following: (1) The complex pathological mechanisms of ischemic stroke can be categorized into five major types: excitatory amino acid toxicity, Ca2+ overload, inflammatory response, oxidative stress, and apoptosis. (2) The PI3K/AKT-mediated signaling pathway is closely associated with the occurrence and progression of ischemic stroke, which primarily involves the NF-kB, NRF2, BCL-2, mTOR, and endothelial NOS signaling pathways. (3) Natural products, including flavonoids, quinones, alkaloids, phenylpropanoids, phenols, terpenoids, and iridoids, show great potential as candidate substances for the development of innovative anti-stroke medications. (4) Recently, novel therapeutic techniques, such as electroacupuncture and mesenchymal stem cell therapy, have demonstrated the potential to improve stroke outcomes by activating the PI3K/AKT signaling pathway, providing new possibilities for the treatment and rehabilitation of patients with ischemic stroke. Future investigations should focus on the direct regulatory mechanisms of drugs targeting the PI3K/AKT signaling pathway and their clinical translation to develop innovative treatment strategies for ischemic stroke.

A Quantum Mechanical Approach to The Mechanism of Asymmetric Synthesis of Chiral Amine by Imine Reductase from Stackebrandtia Nassauensis.

The asymmetric synthesis of tetrahydroisoquinolines (THIQs) has gained importance in recent years due to their significant potential in drug development studies. In this study, the conversion of 1-methyl-3,4-dihydroisoquinoline substrate to a chiral amine, 1-methyl-1,2,3,4-tetrahydroisoquinoline, under the catalysis of the stereoselective imine reductase enzyme from Stackebrandtia nassauensis (SnIR) was investigated in detail to elucidate the mechanism and explain the experimental enantioselectivity. The results were found to be in agreement with the experimental data. To elucidate the reaction mechanism, quantum mechanical calculations were performed by considering a large cluster of the active site of the enzyme. In this regard, possible reaction pathways leading to both R- and S-products with the corresponding intermediates and the transition states for the hydride transfer from the cofactor to the substrate were considered by density functional theory (DFT) calculations, and the factors contributing to the observed stereoselectivity were sought. The calculations supported a stepwise mechanism rather than the concerted protonation and the hydride transfer steps. The stereoselectivity in the hydride transfer was found to be due not only to the stability of the enzyme-subtrate complex but also to the corresponding reaction barriers. The calculations were performed at the wB97XD/6-311+G(2df,2p)//B3LYP/6-31G(d,p) level of theory using the PCM approach.

An IQ Industry Perspective on Informing Dosing Recommendations in Patients With Renal Impairment.

The IQ CPLG Organ Impairment WG conducted a survey to understand how various IQ member companies develop dosing recommendations for patients with renal impairment. Eighteen IQ member companies participated in the survey. The survey results were summarized by the working group in light of the regulatory renal impairment guidance documents as well as recent publications from the pharmaceutical industry and nephrology community. There were two important learnings from the survey: (i) pharmaceutical companies do not use a consistent methodology to assess renal function in their drug development programs. (ii) there has been significant improvement in predicting how kidney function affects drug pharmacokinetics (PK) and thus dose recommendations. Applying model-based methods such as population PK, physiologically-based PK (PBPK), and virtual controls has enabled earlier prediction of how kidney function influences PK, leading to the participation of more patients with impaired kidney function in Phase 2 and 3 trials.

Future Therapeutic Strategies for Alzheimer’s Disease: Focus on Behavioral and Psychological Symptoms

Alzheimer’s disease (AD) is a progressive, degenerative brain disorder that impairs memory and thinking skills, leading to significant economic and humanistic burdens. It is associated with various neuropsychiatric symptoms (NPS) such as anxiety, agitation, depression, aggression, apathy, and psychosis. NPSs are common in patients with AD, affecting up to 97% of individuals diagnosed with AD. The severity of NPS is linked to disease progression and cognitive decline. NPS in Alzheimer’s disease leads to increased morbidity, mortality, caregiver burden, earlier nursing home placement, and higher healthcare costs. Despite their significant impact, clinical research on NPS in AD is limited. In clinical settings, accurately distinguishing and diagnosing NPS related to AD remains a challenge. Additionally, conventional treatments for NPS in AD are often ineffective, highlighting the need for new therapies that target these specific symptoms. Understanding these comorbidities can aid in early diagnosis and better management of AD. In this review, we provide a summary of the various neurological and psychiatric symptoms (NPS) associated with AD and new candidates under development for the treatment of NPS based on their therapeutic targets and mechanisms. On top of the conventional NPS studied so far, this review adds recent advancements in the understanding of social functional impairment in AD. This review also provides information that can contribute to the advancement of studies and translational research in this field by emphasizing therapeutic targets and mechanisms of action focused on AD-related NPS rather than conventional mechanisms targeted in AD drug development. Above all, considering the relative lack of research in this new field despite the importance of clinical, medical, and translational research, it may increase interest in NPS in AD, its pathophysiological mechanisms, and potential therapeutic candidates such as molecules with antioxidant potential.

Recruitment to the Proteasome Is Necessary but Not Sufficient for Chemically Induced, Ubiquitin-Independent Degradation of Native Proteins.

Targeted protein degradation (TPD) is a promising strategy for drug development. Most degraders function by forcing the association of the target protein (TP) with an E3 Ubiquitin (Ub) ligase, which, in favorable cases, results in the polyubiquitylation of the TP and its subsequent degradation by the 26S proteasome. An alternative strategy would be to create chemical dimerizers that bypass the requirement for polyubiquitylation by recruiting the target protein directly to the proteasome. Direct-to-proteasome degraders (DPDs) may exhibit different characteristics than ubiquitin-dependent degraders, but few studies of this type of TPD have been published, largely due to the dearth of suitable proteasome ligands. To facilitate studies of DPDs, we report here a mammalian cell line in which the HaloTag protein is fused to the proteasome via Rpn13, one of the ubiquitin receptors. In these cells, a chloroalkane serves as a covalent proteasome ligand surrogate. We show that chimeric molecules comprised of a chloroalkane linked to a ligand for the BET family of proteins or the Cdk2/7/9 family of kinases result in ubiquitin-independent degradation of some of these target proteins. We use this system, the first that allows facile degradation of native proteins in a ubiquitin-independent fashion, to probe two issues: the effect of varying the length of the linker connecting the chloroalkane and the target ligand and the selectivity of degradation within the protein families engaged by the target ligand.

Exploring the material basis and molecular targets of Changma Xifeng tablet in treating Tourette syndrome: an integrative approach of network pharmacology and miRNA analysis.

This study was to investigate the mechanism of Changma Xifeng tablet, a traditional Chinese medicine in the treatment of Tourette syndrome. Network pharmacology was utilized to pinpoint blood-entering constituents of Changma Xifeng and explore their potential targets. Additionally, differential microRNA expression analysis was conducted to predict Tourette syndrome-associated targets, complemented by molecular docking and dynamics simulations to support the interactions of the active compounds with these targets. The study identified 98 common targets between Changma Xifeng and Tourette syndrome, which may be involved in the treatment process. A protein-protein interaction network and a drug-active ingredient-disease target network highlighted the formulation's multi-component, multi-target therapeutic approach. Eight pivotal targets-AR, GRM5, MET, RORA, HTR2A, CNR1, PDE4B, and TOP1-were identified at the intersection of microRNA and drug targets. Molecular docking revealed 12 complexes with favorable binding energies below - 7kcal/mol, specifically: AR with Alfacalcidol, TOP1 with Albiflorin, GRM5 with Arachidic Acid, GRM5 with Palmitic Acid, AR with Arachidic Acid, AR with 2-Hydroxyoctadecanoic Acid, RORA with Pinellic Acid, RORA with Palmitic Acid, AR with Acoronene, AR with Epiacoronene, AR with 4,4'-Methylenediphenol, and HTR2A with Calycosin. Our molecular docking and molecular dynamics simulations suggest potential stable interactions between the formulation's active components and target proteins. These computational methods provide a preliminary theoretical framework that will guide our future experimental work. The study provides a scientific rationale for the use of traditional Chinese medicine in Tourette syndrome management and offers new insights for drug development.

Chronic constipation

Chronic constipation is one of the most common health disorders in all of medicine. Its extent ranges from mild discomfort, which is usually easy to improve, to severe functional limitations that may significantly reduce quality of life and may be refractory to various treatment approaches. Our understanding of the pathomechanism has grown considerably in recent years and has also led to important new therapeutic developments. The resulting treatment options and recommendations are presented in the current update of the S2k constipation guideline in an evidence-based and practical manner. The respective significance of traditional and recent drug developments is classified and categorized in modern "step-up" treatment strategies. In particular, numerous important aspects of everyday practice are addressed, such as questions on long-term treatment and therapeutic options in specific constellations (adequate treatment of constipation in older people, constipation during pregnancy, and drug-induced [especially opioid-induced]constipation).The most important new developments (i.e. new therapeutic approaches, but also re-evaluations of "traditional" laxatives and the importance of careful diagnostics in therapy-refractory patients) are summarized in this article.

Association between Fat-Soluble Vitamin Metabolic Process and Glioma Progression.

Although multimodality therapy has recently advanced, patients with glioblastoma, one of the most aggressive and deadly types of central nervous system cancer, have a very poor prognosis and rare long-term survival. Vitamins are essential organic nutrients that play a pivotal role in maintaining homeostasis, and various studies have demonstrated the implication of vitamins in the pathophysiology of gliomas. Herein, we aimed to investigate the association of the vitamin metabolic pathway and the corresponding candidate genes for the malignancy, aggressiveness, and poor prognosis of gliomas using The Cancer Genome Atlas database of patients with gliomas. We demonstrated that fat-soluble vitamin metabolic processes are prominently associated with glioma grade, molecular biomarkers, molecular subtypes, and clinical outcomes. Moreover, we identified the key genes related to the fat-soluble metabolic pathway in gliomas using differentially expressed gene analysis. Among them, the expression of the vitamin K epoxide reductase complex subunit 1 (VKORC1), encoding VKOR essential for the vitamin K-dependent γ-carboxylation of target proteins, was prominently associated with not only malignancy, aggressiveness, and poor prognosis of gliomas but also the representative signal pathways related to glioma pathogenesis. Moreover, the inactivation of Vkorc1 by RNA interference decreased the proliferation and migration potential of glioma cells in vitro. Collectively, these findings reveal the pivotal role of fat-soluble vitamin and vitamin K metabolic processes in the pathophysiology of gliomas, thereby identifying a potential target for drug development for the treatment of malignant gliomas.

Utility of common in vitro systems for predicting circulating metabolites.

In vitro systems such as cultured hepatocytes are used early in drug development as a proxy for in vivo data to predict metabolites in human and the potential pre-clinical species. These data support preclinical species selection for toxicology studies as well as provide early evidence for potential active and reactive metabolites that can be generated in human. While in vivo data would be best to select preclinical species for a given compound, only in vitro systems are available when selecting tox species. However, as with any in vitro system, the correlation to actual in vivo results can be variable. Understanding the predictivity of a given in vitro assay for in vivo metabolism would help drug development teams appreciate the significance of early cross-species metabolite profiles relative to the eventual clinical outcomes. In a retrospective analysis of historic metabolite profiling data from Abbott/AbbVie, in vitro systems predicted ~50% of circulating metabolites present in vivo, across preclinical species and human, with no correlation between apparent exposures in vitro vs in vivo A direct comparison of five common in vitro systems using commercial compounds with known metabolism resulted in suspension hepatocytes and co-cultured hepatocytes slightly outperforming the other systems in successfully generating major human circulating metabolites. Current in vitro systems have value early in development when in vivo studies are not feasible and are required for regulatory filings to support pre-clinical toxicology species selection but should not be treated as wholly representative of a given drug's in vivo metabolism. Significance Statement This is a comprehensive assessment of historic metabolism data quantitating the success rate of in vitro to in vivo predictivity. Reliability of in vitro systems for metabolite profiling is important for early drug development, and understanding predictivity will help give appropriate context to the data. New data were also generated to compare common in vitro liver models to determine whether any could be definitively identified as more predictive of human circulating metabolites than others.

Mucormycosis: Current Perspectives on Treatment, Diagnosis, and Advancements

Objective: This review study examines mucormycosis treatment challenges, gaps in medicines, and COVID-19-related effects. This paper examines diagnostic and drug development advances while addressing safety and specificity. Methods: This review study searches PubMed, Web Science, and Scopus for relevant material. Keywords associated with mucormycosis, therapy, diagnosis, medication advancement, and COVID- 19 are used to identify pertinent articles. Data extraction summarizes therapeutic obstacles, diagnostic advances, and innovative drug options. Results: This review article covers mucormycosis therapy, diagnostics, and drug development. It reveals limitations in present medicines, such as selectivity, safety, and resistance mechanisms. Diagnostic advances and mucormycosis in COVID-19 have also been explored. Conclusion: This review emphasizes the need for more secure, specific mucormycosis therapies. It discusses therapy obstacles, diagnostic advances, and new drug techniques. Overall, this research emphasizes improving mucormycosis therapy to enhance patient outcomes.

Molecular docking, network pharmacology, and QSAR modelling studies of benzo[c]phenanthridines - novel antileishmaniasis agents.

Leishmaniasis treatment primarily relies on chemotherapy due to lack of vaccines. However, the low efficacy, parasite resistance, and toxicity associated with existing drugs necessitate the development of effective and safer therapies. Fuchino etal. reported promising leishmanicidal activity in a series of benzo[c]phenanthridines against L. major promastigotes. To progress these compounds towards drug development, it is crucial to understand their molecular targets, mechanisms of action, binding interactions, and structural requirements. In this research, molecular docking, network pharmacology, 2D-QSAR, and 3D-QSAR CoMFA studies were performed on 30 benzo[c]phenanthridines. Docking analysis showed that all molecules had a strong binding affinity to L. major-nucleoside diphosphate kinase (NDPK) compared to the other targets. 10-isopropoxy sanguinarine had the highest binding affinity (-10.6 kcal/mol) and formed ionic and hydrophobic interactions. Network pharmacology analysis of the most active compounds identified serine/threonine-protein kinase Mtor as a potential antileishmaniasis target in humans for benzo[c]phenanthridines. This was confirmed with high-affinity scores > -7.0 kcal/mol for all the compounds docked. GO and KEGG pathway enrichment identified Reg. of fatty acid oxidation (BP), TORC1 complex (CC), RNA polymerase III type 1 promoter sequence-specific DNA binding (MF), and Acute myeloid leukemia (KEGG pathway) to be highly enriched with the hub genes. Both 2D and 3D-QSAR CoMFA models satisfied the internal and external validation tests as follows: 2D-QSAR: R2Train = 0.9040, Q2cv = 0.8648, R2adj = 0.8838, and R2Test = 0.8740; and 3D-QSAR: r2 = 0.998, q2 = 0.526, and SDEP = 0.856. The molecules can be practically evaluated as superior antileishmaniasis agents.

Ubiquitin-proteasome system in Plasmodium: a potential antimalarial target to overcome resistance – a systematic review

BackgroundMalaria is a devasting parasitic disease that causes over half a million deaths every year. The necessity for prompt and thorough antimalarial drug discovery and development is accelerated by the rise in multidrug resistance and the lack of an effective vaccine. The Plasmodium spp. proteasome represents a prospective target for antimalarial treatment since several chemotherapy types have been shown to potently and selectively limit the growth of parasites. Combined with first-line artemisinin medicines, it creates synergy, even in the artemisinin-resistant parasites.MethodsPRISMA guidelines were used in the development of this systematic review. A literature search was performed in March 2024 in PubMed, Science Direct, and Scopus databases, with the following keywords: ((antimalarial resistance) AND (plasmodium OR malaria) AND (proteasome)) NOT (cancer [Title/Abstract]). Only articles with the susceptibility assessment were included.ResultsHerein, 35 articles were included in the systematic review, which was divided into two subcategories: those that studied the UPS inhibitors, which accounted for 25 articles, and those that studied genetic modifications, including knockouts, knockdowns, and mutations, in the UPS toward antimalarial resistance, accounting for 16 articles. 6 articles included both subcategories. In total, 16 categories of inhibitors were analyzed, together with two knockdowns, one knockout, and 35 mutations.ConclusionIn this study, we reviewed the literature for available inhibitors and their respective susceptibility and ability to develop resistance toward Plasmodium spp. 26 s proteasome. The proteasome was highlighted as a potential antimalarial target and as an artemisinin partner drug. However, host toxicity and susceptibility to resistance appear as the main obstacle in the development of highly potent drugs, indicating a need for additional scrutiny during any further drug development efforts.

Acquired Bortezomib Resistance in Multiple Myeloma:From Mechanisms to Strategy.

Multiple myeloma (MM) is a heterogeneous plasma cell tumor with a survival period of several months to over ten years. Despite the development of various new drugs, MM is still incurable and recurs repeatedly. Bortezomib, a landmark event in the history of MM treatment, has dramatically improved the prognosis of patients with MM. Although proteasome inhibitors (PIs) represented by bortezomib, have greatly prolonged MM survival, unfortunately, almost all MM will develop bortezomib resistance, leading to relapse with a shorter survival. It has been reported that both the tumor microenvironment and myeloma cells drive bortezomib resistance. Multiple treatment methods have been attempted to overcome bortezomib resistance, but unfortunately, there has been no breakthrough. It is believed that the key resistance mechanism has not yet been discovered. A deeper understanding of the mechanism of bortezomib resistance and strategies to overcome it can help identify key resistance mechanisms and further improve the prognosis of MM.

Structural analysis and accelerating wound healing function of a novel galactosylated glycosaminoglycan from the snail Helix lucorum

Diabetic foot ulcers (DFUs) as a nonhealing wound remain a clinical challenge, and the development of pro-healing and cost-effective drugs is in urgent need. Herein, we reported a novel galactosylated glycosaminoglycan (GAG) from the snail Helix lucorum, as an effective pro-healing compound. The snail GAG is composed of a heparan sulfate-like main chain and galactose side chains at C-3 of GlcNAc residue. Its main chain has a repeating disaccharide structure of → 4)-α-D-GlcNAc-(1 → 4)-α-L-IdoA2S(1 →. This is the first example of glycosaminoglycan with galactose branches from mollusks. Pharmacological experiments showed that the H. lucorum GAG significantly promoted skin wound healing in both healthy and diabetic mice by accelerating granulation tissue regeneration, angiogenesis, and collagen deposition. The distinctive galactosylated substitution may play an important role on its pro-healing activity. Our discovery enriches the diversity of non-anticoagulant heparan sulfate-like glycosaminoglycans, and provides a potential candidate of pro-healing drug for treating diabetic wound.

The progress of Mycobacterium tuberculosis drug targets

Tuberculosis (TB) has been troubling humans for hundreds of years, is a highly infectious disease caused by Mycobacterium tuberculosis (Mtb) infection, Mtb can infect almost all organs of the body and is one of the deadly infectious diseases in the world. At present, the first-line treatment regimen has a long treatment cycle and is prone to multiple drug resistance. Anti-tuberculosis drugs and latent tuberculosis infection (LTBI) resistance are increasing year by year, and new targets and new bioactive compounds are urgently needed to treat this disease. This review focuses on the latest reported anti-TB drug targets and related compounds in recent years, reviews the current TB drug regimen and major defects, outlines the key drug targets developed to date in Mtb, and the current situation of newly discovered anti-TB resistant forms of drugs. To provide a reference for the research and development of new anti-TB drugs and bring new treatment strategies for TB patients.

The future of metronomic chemotherapy: experimental and computational approaches of drug repurposing.

Metronomic chemotherapy (MC), long-term continuous administration of anticancer drugs, is gaining attention as an alternative to the traditional maximum tolerated dose (MTD) chemotherapy. By combining MC with other treatments, the therapeutic efficacy is enhanced while minimizing toxicity. MC employs multiple mechanisms, making it a versatile approach against various cancers. However, drug resistance limits the long-term effectiveness of MC, necessitating ongoing development of anticancer drugs. Traditional drug discovery is lengthy and costly due to processes like target protein identification, virtual screening, lead optimization, and safety and efficacy evaluations. Drug repurposing (DR), which screens FDA-approved drugs for new uses, is emerging as a cost-effective alternative. Both experimental and computational methods, such as protein binding assays, in vitro cytotoxicity tests, structure-based screening, and several types of association analyses (Similarity-Based, Network-Based, and Target Gene), along with retrospective clinical analyses, are employed for virtual screening. This review covers the mechanisms of MC, its application in various cancers, DR strategies, examples of repurposed drugs, and the associated challenges and future directions.

Method Development and Validation of Luliconazole Bulk Drug Using Reverse Phase - HPLC Technique

Objective: To develop and validate the RP- HPLC method for determining Luliconazole in bulk and pharmaceutical formulations. Methods: Following the International Conference on Harmonization (ICH) guidelines, a sensitive, accurate, and specific reversed-phase HPLC technique was created and validated for the detection of Luliconazole. Using high-performance liquid chromatography, this drug was examined. A better separation of the drug was achieved by using Agilent Eclipse XDB C (4.6mm x 250mm, 5µm) with a mobile phase consisting of a mixture of Acetonitrile and Buffer in HPLC water. The ratio of 30:70 v/v (Formic acid and Acetonitrile) at a flow rate of 1.0 ml/ min and the detection was at the wavelength 295 nm using a Photodiode Arrays Detector. The planned method was able to produce good quality separation of the drug and its degradation products with sharp peaks. Findings: Luliconazole had a retention time of 2.38 ± 0.127 minutes. The technique was linear in the range of 10-100 µg/ml, with a correlation (r2) of 0.9995 and a run duration of 4 minutes. The method limit of detection (LOD) and limit of quantification (LOQ) were set at 0.1 and 1 g/ml, respectively. The method accuracy and system precision were estimated, and the findings were calculated as percentage RSD values, which were found to be limitations. Luliconazole recovery was 100% confirming the method's efficiency. Novelty: The presented approach was innovative and successfully fulfilled all validation requirements, including linearity, robustness, accuracy, reduced retention, and run time. This suggests that the method is appropriate for identifying the stability of luliconazole in bulk and pharmaceutical formulations. Keywords: RP-HPLC, Transferosome, ICH guidelines, Validation, Luliconazole

How to drug a cloud? Targeting intrinsically disordered proteins.

Biologically active proteins/regions without stable structure (i.e., intrinsically disordered proteins and regions (IDPs and IDRs)) are commonly found in all proteomes. They have a unique functional repertoire that complements the functionalities of ordered proteins and domains. IDPs/IDRs are multifunctional promiscuous binders capable of folding at interaction with specific binding partners on a template- or context-dependent manner, many of which undergo liquid-liquid phase separation, leading to the formation of membrane-less organelles and biomolecular condensates. Many of them are frequently related to the pathogenesis of various human diseases. All this defines IDPs/IDRs as attractive targets for the development of novel drugs. However, their lack of unique structures, multifunctionality, binding promiscuity, and involvement in unusual modes of action preclude direct use of traditional structure-based drug design approaches for targeting IDPs/IDRs, and make disorder-based drug discovery for these "protein clouds" challenging. Despite all these complexities there is continuing progress in the design of small molecules affecting IDPs/IDRs. This article describes the major structural features of IDPs/IDRs and the peculiarities of the disorder-based functionality. It also discusses the roles of IDPs/IDRs in various pathologies, and shows why the approaches elaborated for finding drugs targeting ordered proteins cannot be directly used for the intrinsic disorder-based drug design, and introduces some novel methodologies suitable for these purposes. Finally, it emphasizes that regardless of their multifunctionality, binding promiscuity, lack of unique structures, and highly dynamic nature, "protein clouds" are principally druggable. Significance Statement Intrinsically disordered proteins and regions are highly abundant in nature, have multiple important biological functions, are commonly involved in the pathogenesis of a multitude of human diseases, and are therefore considered as very attractive drug targets. Although dealing with these unstructured multifunctional protein/regions is a challenging task, multiple innovative approaches have been designed to target them by small molecules.

How many drugs are repositioned each year in Europe?

AbstractFor two decades, commentators have argued for law and policy reform to incentivise organisations to develop new indications for (already) authorised drugs, an area of drug development known as ‘repositioning’. In short, they argue that hurdles in patent and pharmaceutical law hinder repositioning and, therefore, reform is required to increase its use. Yet, these arguments are made primarily on anecdotes; the empirical evidence is scant. One foundational question is how many drugs are repositioned each year in Europe. This study develops a method to examine the number authorised each year. The results show a marked increase in repositioning over the last 3 years, and that the number per year is comparable, though slightly fewer than, the number of new compounds, indicating modest to higher‐than‐expected activity. This study considers what the results mean for four suggested reform options, including the EU Commission's recent proposal. We conclude that the reforms may not achieve their goals or that further evidence is required before we can know whether they will be effective. Lastly, this paper explains how the method and data in this study could serve as a benchmark for evaluating the success of future reforms.

MetaCGRP is a high-precision meta-model for large-scale identification of CGRP inhibitors using multi-view information

Migraine is considered one of the debilitating primary headache conditions with an estimated worldwide occurrence of approximately 14–15%, contributing highly to factors responsible for global disability. Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a crucial role in the pathophysiology of migraines and thus, its inhibition can help relieve migraine symptoms. However, conventional process of CGRP drug development has been laborious and time-consuming with incurred costs exceeding one billion dollars. On the other hand, machine learning (ML)-based approaches that are capable of accurately identifying CGRP inhibitors could greatly facilitate in expediting the discovery of novel CGRP drugs. Therefore, this study proposes a novel and high-accuracy meta-model, namely MetaCGRP, that can precisely identify CGRP inhibitors. To the best of our knowledge, MetaCGRP is the first SMILES-based approach that has been developed to identify CGRP inhibitors without the use of 3D structural information. In brief, we initially employed different molecular representation methods coupled with popular ML algorithms to construct a pool of baseline models. Then, all baseline models were optimized and used to generate multi-view features. Finally, we employed the feature selection method to optimize the multi-view features and determine the best feature subset to enable the construction of the meta-model. Both cross-validation and independent tests indicated that MetaCGRP clearly outperforms several conventional ML classifiers, with accuracies of 0.898 and 0.799 on the training and independent test datasets, respectively. In addition, MetaCGRP in conjunction with molecular docking was utilized to identify five potential natural product candidates from Thai herbal pharmacopoeia and analyze their binding affinity and interactions to CGRP. To facilitate community-wide efforts in expediting the discovery of novel CGRP inhibitors, a user-friendly web server for MetaCGRP is freely available at https://pmlabqsar.pythonanywhere.com/MetaCGRP.