scholarly journals Design and development of drugs for Alzheimer’s dementia as a protein misfolding disorder

2015 ◽  
Vol 42 (S1) ◽  
pp. S16-S16
Author(s):  
C Barden ◽  
F Meier-Stephenson ◽  
MD Carter ◽  
S Banfield ◽  
EC Diez ◽  
...  
Keyword(s):  
Transgenic Mouse ◽  
Protein Misfolding ◽  
Large Scale ◽  
Beta Amyloid ◽  
Protein Oligomerization ◽  
Drug Candidates ◽  
Pharmacokinetic Properties ◽  
Disease Modifying Agents ◽  
Novel Drug

Background: There are no disease modifying agents for the treatment of Alzheimer’s disease (AD). Pathologically, AD is associated with the misfolding of two peptides: beta-amyloid (plaques) and tau (tangles). Methods: Using large-scale computer simulations, we modelled the misfolding of both beta-amyloid and tau, identifying a common conformational motif (CCM; i.e. an abnormal peptide shape), present in both beta-amyloid and tau, that promotes their misfolding. We screened a library of 11.8 million compounds against this in silico model of protein misfolding, identifying three novel molecular classes of putative therapeutics as anti-protein misfolding agents. We synthesized approximately 400 new chemical entity drug-like molecules in each of these three classes (i.e. 1200 potential drug candidates). These were comprehensively screened in a battery of five in vitro protein oligomerization assays. Selected compounds were next evaluated in the APP/PS1 doubly transgenic mouse model of AD. Results: Two new classes of molecules were identified with the ability to block the oligomerization of both beta-amyloid and tau. These compounds are drug-like with good pharmacokinetic properties and are brain-penetrant. They exhibit excellent efficacy in transgenic mouse models. Conclusion: Computer aided drug design has enabled the discovery of novel drug-like molecules able to inhibit both tau and beta-amyloid misfolding.

scholarly journals In Vitro Resistance against DNA Gyrase Inhibitor SPR719 in Mycobacterium avium and Mycobacterium abscessus

2022 ◽  
Author(s):  
Wassihun Wedajo Aragaw ◽  
Nicole Cotroneo ◽  
Suzanne Stokes ◽  
Michael Pucci ◽  
Ian Critchley ◽  
...  
Keyword(s):  
Mycobacterium Avium ◽  
Dna Gyrase ◽  
Mycobacterium Abscessus ◽  
Drug Candidates ◽  
New Antibiotics ◽  
Novel Drug ◽  
Emergence Of Resistance

Clinical emergence of resistance to new antibiotics affects their utility. Characterization of in vitro resistance is a first step in the profiling of resistance properties of novel drug candidates.

scholarly journals The Phenoxyalkyltriazine Antagonists for 5-HT6 Receptor with Promising Procognitive and Pharmacokinetic Properties In Vivo in Search for a Novel Therapeutic Approach to Dementia Diseases

2021 ◽  
Vol 22 (19) ◽  
pp. 10773
Author(s):  
Sylwia Sudoł ◽  
Agnieszka Cios ◽  
Magdalena Jastrzębska-Więsek ◽  
Ewelina Honkisz-Orzechowska ◽  
Barbara Mordyl ◽  
...  
Keyword(s):  
Therapeutic Approach ◽  
Cognitive Disorders ◽  
Drug Candidates ◽  
Piperazine Derivatives ◽  
Pharmacokinetic Properties ◽  
Chemical Class ◽  
Novel Therapeutic ◽  
Dementia Diseases

Among the serotonin receptors, one of the most recently discovered 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT6 receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT6 receptor.. Thus, a broader pharmacological profile for 1–3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT6 receptor target.

scholarly journals Repurposing Approved Drugs for Guiding COVID-19 Prophylaxis: A Systematic Review

2020 ◽  
Vol 11 ◽  
Author(s):  
Bruno Silva Andrade ◽  
Fernanda de Souza Rangel ◽  
Naiane Oliveira Santos ◽  
Andria dos Santos Freitas ◽  
Wagner Rodrigues de Assis Soares ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Large Scale ◽  
Post Exposure Prophylaxis ◽  
Drug Candidates ◽  
Global Pandemic ◽  
The World ◽  
Approved Drugs ◽  
Exposure Prophylaxis

The SARS-CoV-2 outbreak originally appeared in China in December 2019 and became a global pandemic in March 2020. This infectious disease has directly affected public health and the world economy. Several palliative therapeutic treatments and prophylaxis strategies have been used to control the progress of this viral infection, including pre-(PrEP) and post-exposure prophylaxis. On the other hand, research groups around the world are still studying novel drug prophylaxis and treatment using repurposing approaches, as well as vaccination options, which are in different pre-clinical and clinical testing phases. This systematic review evaluated 1,228 articles from the PubMed and Scopus indexing databases, following the Kitchenham bibliographic searching protocol, with the aim to list drug candidates, potentially approved to be used as new options for SARS-CoV-2 prophylaxis clinical trials and medical protocols. In searching protocol, we used the following keywords: “Covid-19 or SARS-CoV-2” or “Coronavirus or 2019 nCoV,” “prophylaxis,” “prophylactic,” “pre-exposure,” “COVID-19 or SARS-CoV-2 Chemoprophylaxis,” “repurposed,” “strategies,” “clinical,” “trials,” “anti-SARS-CoV-2,” “anti-covid-19,” “Antiviral,” “Therapy prevention in vitro,” in cells “and” human testing. After all protocol steps, we selected 60 articles that included: 15 studies with clinical data, 22 studies that used in vitro experiments, seven studies using animal models, and 18 studies performed with in silico experiments. Additionally, we included more 22 compounds between FDA approved drugs and drug-like like molecules, which were tested in large-scale screenings, as well as those repurposed approved drugs with new mechanism of actions. The drugs selected in this review can assist clinical studies and medical guidelines on the rational repurposing of known antiviral drugs for COVID-19 prophylaxis.

Molecular Modeling Approaches for the Prediction of Selected Pharmacokinetic Properties

2019 ◽  
Vol 18 (26) ◽  
pp. 2230-2238 ◽  
Author(s):  
Emilio S. Petito ◽  
David J.R. Foster ◽  
Michael B. Ward ◽  
Matthew J. Sykes
Keyword(s):  
Molecular Modeling ◽  
In Silico ◽  
Volume Of Distribution ◽  
Future Directions ◽  
Unbound Fraction ◽  
Drug Candidates ◽  
New Methods ◽  
Pharmacokinetic Properties

Poor profiles of potential drug candidates, including pharmacokinetic properties, have been acknowledged as a significant hindrance to the development of modern therapeutics. Contemporary drug discovery and development would be incomplete without the aid of molecular modeling (in-silico) techniques, allowing the prediction of pharmacokinetic properties such as clearance, unbound fraction, volume of distribution and bioavailability. As with all models, in-silico approaches are subject to their interpretability, a trait that must be balanced with accuracy when considering the development of new methods. The best models will always require reliable data to inform them, presenting significant challenges, particularly when appropriate in-vitro or in-vivo data may be difficult or time-consuming to obtain. This article seeks to review some of the key in-silico techniques used to predict key pharmacokinetic properties and give commentary on the current and future directions of the field.

scholarly journals In Vitro and In Vivo Activities of Synthetic Trioxolanes against Major Human Schistosome Species

2007 ◽  
Vol 51 (4) ◽  
pp. 1440-1445 ◽  
Author(s):  
Shu-Hua Xiao ◽  
Jennifer Keiser ◽  
Jacques Chollet ◽  
Jürg Utzinger ◽  
Yuxiang Dong ◽  
...  
Keyword(s):  
Motor Activity ◽  
Worm Burden ◽  
Female Worm ◽  
Infection Model ◽  
Drug Candidates ◽  
Pharmacokinetic Properties ◽  
Health Significance ◽  
Low Toxicity

ABSTRACT Schistosomiasis is a parasitic disease that remains of considerable public health significance in tropical and subtropical environments. Since the mainstay of schistosomiasis control is chemotherapy with a single drug, praziquantel, drug resistance is a concern. Here, we present new data on the antischistosomal properties of representative synthetic 1,2,4-trioxolanes (OZs). Exposure of adult Schistosoma mansoni for 24 h to a medium containing 20 μg/ml OZ209 reduced worm motor activity, induced tegumental alterations, and killed worms within 72 h. While exposure of S. mansoni to OZ78 had no apparent effect, addition of hemin reduced worm motor activity and caused tegumental damage. Administration of single 200-mg/kg of body weight oral doses of OZ78, OZ209, and OZ288 to mice harboring a juvenile S. mansoni infection resulted in worm burden reductions of 82.0 to 95.4%. In the adult infection model in mice, single 400-mg/kg doses of these compounds resulted in a maximum total worm burden reduction of 52.2%. High worm burden reductions (71.7 to 86.5%) were observed after administration of single 200-mg/kg doses of OZ78 and OZ288 to hamsters infected with either juvenile or adult S. mansoni. A single 200-mg/kg dose of OZ78 to hamsters infected with adult Schistosoma japonicum resulted in total and female worm burden reductions of 94.2 to 100%. Our results, along with the low toxicity, metabolic stability, and good pharmacokinetic properties of the OZs, indicate the potential for the development of novel broad-spectrum antischistosomal OZ drug candidates.

scholarly journals An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yiyue Ge ◽  
Tingzhong Tian ◽  
Suling Huang ◽  
Fangping Wan ◽  
Jingxin Li ◽  
...  
Keyword(s):  
Large Scale ◽  
Therapeutic Agent ◽  
Drug Repositioning ◽  
In Vitro Assays ◽  
In Silico Screening ◽  
N Protein ◽  
Drug Candidates ◽  
Global Spread ◽  
Wet Lab

AbstractThe global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). In this study, we developed an integrative drug repositioning framework, which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 can interact with the nucleocapsid (N) protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.

scholarly journals SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model

Science ◽  
2021 ◽  
pp. eabf1611
Author(s):  
Jingxin Qiao ◽  
Yue-Shan Li ◽  
Rui Zeng ◽  
Feng-Liang Liu ◽  
Rong-Hua Luo ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Transgenic Mouse Model ◽  
Global Public Health ◽  
Viral Loads ◽  
Main Protease ◽  
Pharmacokinetic Properties ◽  
Intraperitoneal Treatment

The COVID-19 pandemic caused by the SARS-CoV-2 virus continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either Boceprevir or Telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro with IC50 values ranging from 7.6 to 748.5 nM. The co-crystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a SARS-CoV-2 infection transgenic mouse model, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.

scholarly journals In vitro antineurodegenerative activity and in silico predictions of blood-brain barrier penetration of Helichrysum plicatum flower extract

2020 ◽  
pp. 45-51
Author(s):  
Miloš Jovanović ◽  
Zorica Drinić ◽  
Dubravka Bigović ◽  
Ana Alimpić-Aradski ◽  
Sonja Duletić-Laušević ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Blood Brain Barrier ◽  
In Silico ◽  
Brain Barrier ◽  
Pharmacokinetic Parameters ◽  
Drug Candidates ◽  
Flower Extract ◽  
Blood Brain ◽  
Pharmacokinetic Properties

This study aimed to assess the antineurodegenerative and antioxidant activity of Helichrysum plicatum flower extract, as well as to identify extract ingredients with acceptable pharmacokinetic parameters such as gastrointestinal absorption, blood-brain barrier permeation, and P-glycoprotein-mediated effusion for optimal therapeutic brain exposure. Antioxidant activity was evaluated by ABTS, FRAP, and b-carotene bleaching assays, while antineurodegenerative activity was tested using acetylcholinesterase (AChE) and tyrosinase (TYR) inhibitory activity assays. In the ABTS test, the dry extract at the highest applied concentration (500 µg/mL) showed better or similar antioxidant activity compared to the standards. In the b-carotene assay, all applied concentrations of the extract showed significantly higher activity than vitamin C. No concentration-dependent activity was observed in the AChE assay, while in the TYR assay the lowest extract concentration (100 µg/mL) showed the highest percentage of inhibition (27.92 %). Pharmacokinetic parameters of compounds were predicted by in silico SwissADME online tool in accordance by the rules of drug-likeness. According to the pharmacokinetic properties, we concluded that pentoxymethoxylated flavones may represent CNS drug candidates for further studies.

scholarly journals Discovery of 5-Chlorobenzimidazole-based as Promising Inhibitors of Chloroquine-Resistant Plasmodium Strains: Synthesis, Biological Evaluation, Molecular Docking and Computational Studies

2021 ◽  
pp. 136-147
Author(s):  
Jean Paul N’Guessan ◽  
Songuigama Coulibaly ◽  
Abdulrahim A. Alzain ◽  
Drissa Sissouma ◽  
William Yavo ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antimalarial Activity ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Antiplasmodial Activity ◽  
Sensitivity Threshold ◽  
Drug Candidates ◽  
Pharmacokinetic Properties ◽  
Experimental Findings

Background: To overcome drug resistance to current antimalarial drugs, we propose the synthesis and in vitro evaluation of the antiplasmodial activity of a series of 5-chlorobenzimidazolyl-chalcones against chloroquino sensitive (CQ-S) and chloroquino resistant (CQ-R) strains of P. falciparum. Objective: This study aimed to establish through structure-activity relationship studies and docking, the structural elements essential for antiplasmodial activities. Methods: The antiplasmodial activity of these benzimidazolylchalcones was carried out according to the Rieckmann microtest technique, followed by the determination of the concentrations inhibiting 50% of the production of parasitic HRP2 antigens (IC50) by ELISA. Chloroquine was used as a reference molecule with a sensitivity threshold set at 100 µM. Molecular docking was performed using sensitive (PDB ID: 1J3I) and resistant (PDB ID: 4DP3) dihydrofolate reductase-thymidylate synthase proteins (PfDHFR-TS). Results: All benzimidazolylchalcones tested expressed antiplasmodial activities especially against chloroquine resistant isolates (IC50 = 0.32-44.38 µM). The best profile against both isolates was the methoxylated derivative (3e) with an IC50 ranging from 0.32 to 1.96 µM. This compound had the best antimalarial activity against CQ-S isolates. On CQ-R isolates, the unsubstituted 5-chlorobenzimidazole derivative (3b) had exalted activity (IC50 = 0.78 µM).  We selected a weakly active non-chlorinated derivative 3a and chlorinated derivatives 3b, 3d, 3e and 3f) with IC50< 3µM against the chloroquine-resistant strain to perform docking studies. These revealed that the pyrrolic nitrogen of benzimidazole and the ketone of propenone are the main chemical entities involved in the interaction at the receptor. Moreover, ADMET studies showed favorable pharmacokinetic properties. Conclusion: Molecular docking studies confirmed the experimental findings and revealed the possible interactions pattern. Derivatives 3b and 3e, which showed promising binding affinities against PfDHFR-TS, can be proposed as lead compounds for the development of antimalarial drug candidates.

scholarly journals EgGLUT1 Is Crucial for the Viability of Echinococcus granulosus sensu stricto Metacestode: A New Therapeutic Target?

2021 ◽  
Vol 11 ◽  
Author(s):  
Kuerbannisha Amahong ◽  
Mingzhi Yan ◽  
Jintian Li ◽  
Ning Yang ◽  
Hui Liu ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Echinococcus Granulosus ◽  
Drug Targets ◽  
Glucose Transporter ◽  
Sensu Stricto ◽  
Reference Drug ◽  
Glucose Transporter 1 ◽  
Drug Candidates ◽  
Novel Drug

Cystic echinococcosis (CE) is a zoonotic parasitic disease caused by infection with the larvae of Echinococcus granulosus sensu lato (s.l.) cluster. It is urgent to identify novel drug targets and develop new drug candidates against CE. Glucose transporter 1 (GLUT1) is mainly responsible for the transmembrane transport of glucose to maintain its constant cellular availability and is a recent research hotspot as a drug target in various diseases. However, the role of GLUT1 in E. granulosus s.l. (EgGLUT1) was unknown. In this study, we cloned a conserved GLUT1 homology gene (named EgGLUT1-ss) from E. granulosus sensu stricto (s.s.) and found EgGLUT1-ss was crucial for glucose uptake and viability by the protoscoleces of E. granulosus s.s. WZB117, a GLUT1 inhibitor, inhibited glucose uptake by E. granulosus s.s. and the viability of the metacestode in vitro. In addition, WZB117 showed significant therapeutic activity in E. granulosus s.s.-infected mice: a 10 mg/kg dose of WZB117 significantly reduced the number and weight of parasite cysts (P &lt; 0.05) as efficiently as the reference drug, albendazole. Our results demonstrate that EgGLUT1-ss is crucial for glucose uptake by the protoscoleces of E. granulosus s.s., and its inhibitor WZB117 has a therapeutic effect on CE.

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