Abstract:
:The high level of attrition of drugs in clinical development has led pharmaceutical companies to increase the efficiency of their lead identification and development through techniques such as combinatorial chemistry and high-throughput (HTP) screening. Since the major reasons for clinical drug candidate failure other than efficacy are pharmacokinetics and toxicity, attention has been focused on assessing properties such as metabolic stability, drug-drug interactions (DDI), and absorption earlier in the drug discovery process. Animal studies are simply too labor-intensive and expensive to use for evaluating every hit, so it has been necessary to develop and implement higher throughput in vitro ADME screens to manage the large number of compounds of interest. The antimalarial drug development program at the Walter Reed Army Institute of Research, Division of Experimental Therapeutics (WRAIR/ET) has adopted this paradigm in its search for a long-term prophylactic for the prevention of malaria. The overarching goal of this program is to develop new, long half-life, orally bioavailable compounds with potent intrinsic activity against liver- and blood-stage parasites. From the WRAIR HTP antimalarial screen, numerous compounds are regularly identified with potent activity. These hits are now immediately evaluated using a panel of in vitro ADME screens to identify and predict compounds that will meet our specific treatment criteria. In this review, the WRAIR ADME screening program for antimalarial drugs is described as well as how we have implemented it to predict the ADME properties of small molecule for the identification of promising drug candidates.
journal_name
Comb Chem High Throughput Screenjournal_title
Combinatorial chemistry & high throughput screeningauthors
Shearer TW,Smith KS,Diaz D,Asher C,Ramirez Jdoi
10.2174/1386207053328129subject
Has Abstractpub_date
2005-02-01 00:00:00pages
89-98issue
1eissn
1386-2073issn
1875-5402journal_volume
8pub_type
杂志文章,评审abstract:Aims & Objective:Corona Virus Disease 2019 (COVID-19) caused by the human coronavirus 2019 (HCoV-19, also known as SARS-CoV-2) infection is currently in a global outbreak. COVID-19 has posed a huge threat to public health and economic stability worldwide. CR3022, a human monoclonal neutralizing antibody isolated from a...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207323666201026160500
更新日期:2020-10-26 00:00:00
abstract:AIM AND OBJECTIVE:This study was designed to explore the active compounds and significant pathways of Guizhi-Shaoyao-Zhimu decoction (GSZD) for treating diabetes mellitus using molecular docking combined with network pharmacology. MATERIALS AND METHODS:Chemical constituents of GSZD and diabetes-related target proteins...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207322666191022101613
更新日期:2019-01-01 00:00:00
abstract::A new and simple high-performance liquid chromatography method was developed and validated for the simultaneous determination of retinol, retinyl palmitate, β-carotene, α-tocopherol and vitamin C in rat serum treated with Plantago Major L. and 7,12 dimethylbenz[a]anthracene. High-performance liquid chromatography anal...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:
更新日期:2013-02-01 00:00:00
abstract::Multiplexing of GFP based and immunofluorescence translocation assays enables easy acquisition of multiple readouts from the same cell in a single assay run. Immunofluorescence assays monitor translocation, phosphorylation, and up/down regulation of endogenous proteins. GFP-based assays monitor translocation of stably...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章,评审
doi:10.2174/138620708785204081
更新日期:2008-08-01 00:00:00
abstract:AIM AND OBJECTIVE:The importance of Chromeno[4,3-b]pyridines in bioactive compounds, highlighted the ongoing research on developing novel methods for the construction of this heterocyclic scaffold. Regarding the advantageous features of multi-component reactions in organic synthesis, we will try to synthesize pyridocou...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207321666180524110635
更新日期:2018-01-01 00:00:00
abstract:BACKGROUND:A set of antibiotic fluoroquinolones with confirmed antimicrobial activity were analyzed with the use of two types of quantum chemical calculation methods and quantitative structure-activity relationships (QSAR). OBJECTIVE:The purpose of this study was to demonstrate the common and differentiating character...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207321666180827105856
更新日期:2018-01-01 00:00:00
abstract:AIM AND OBJECTIVE:The present method is simple, green and highly efficient for the synthesis of 2-amino-4H-pyran derivatives which are achieved by a one pot three component cyclocondensation of aldehyde, malanonitrile and ethyl acetoacetate or methyl acetoacetate using DABCO under solvent free with grinding conditions ...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207321666180315095422
更新日期:2018-01-01 00:00:00
abstract::Combinatorial phage peptide libraries have been used to identify the ligands for specific target molecules. These libraries are also useful for identification of the specific substrates of various proteases. A substrate phage library has a random peptide sequence at the N-terminus of the phage coat protein and an addi...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207013330788
更新日期:2001-11-01 00:00:00
abstract::This paper aims to review recent developments in the synthesis of quinazolines and quinazolinone derivatives under conditions that include the application of microwave heating in the ring forming step. Recently, two reviews on the synthesis and chemistry of natural and synthetic quinazolines and quinazolinones have be...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章,评审
doi:10.2174/138620707783220356
更新日期:2007-12-01 00:00:00
abstract::The Emory Chemical Biology Discovery Center (ECBDC) aims to accelerate high throughput biology and translation of biomedical research discoveries into therapeutic targets and future medicines by providing high throughput research platforms to scientific collaborators worldwide. ECBDC research is focused at the interfa...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207317666140109125415
更新日期:2014-03-01 00:00:00
abstract:BACKGROUND:Clinical outcomes after rotator cuff repair associated with diabetes mellitus(DM) are generally favorable, but no study has attempted to establish the influence of DM on outcomes after rotator cuff repair. PURPOSE:To conduct a meta-analysis of clinical studies evaluating patient outcomes between people with...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: meta分析
doi:10.2174/1386207323666201020114034
更新日期:2020-10-20 00:00:00
abstract:AIM AND OBJECTIVE:4-Hydroxyphenylpyruvate dioxygenase (HPPD), converting phydroxyphenylpyruvate (HPPA) to homogentisate (HGA), is an important target for treating type I tyrosinemia and synthesizing novel herbicides due to its significant role in tyrosine catabolism. Hence, it is imperative to design novel HPPD inhibit...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207320666170622073738
更新日期:2017-01-01 00:00:00
abstract:AIM AND OBJECTIVE:Lysine acetylation, as one type of post-translational modifications (PTM), plays key roles in cellular regulations and can be involved in a variety of human diseases. However, it is often high-cost and time-consuming to use traditional experimental approaches to identify the lysine acetylation sites. ...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207320666170314093216
更新日期:2017-01-01 00:00:00
abstract::Mitochondria are the center of metabolism and the critical role of aberrant mitochondrial fission in the onset and progression of a wide range of human diseases such as neurodegenerative disorders, cardiovascular disease, ischemic stroke and diabetes, is slowly becoming recognized. Under physiological conditions, mito...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207311316010044
更新日期:2014-01-01 00:00:00
abstract:BACKGROUND:The Rab family proteins are involved in membrane trafficking, cell growth and differentiation. Rab38 is implicated in the biogenesis of melanosomes that help in the synthesis, storage and transport of melanin pigments. The Rab38 protein is overexpressed at the RNA level in melanoma cancer. AIM AND OBJECTIVE...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207319666161026153237
更新日期:2016-01-01 00:00:00
abstract::The electrochemical behavior of atorvastatin calcium at glassy carbon and boron-doped diamond electrodes has been studied using voltammetric techniques. The possible mechanism of oxidation was discussed with model compounds. The dependence of the peak current and potentials on pH, concentration, scan rate and nature o...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/138620707782152407
更新日期:2007-08-01 00:00:00
abstract:AIM AND OBJECTIVE:In this work, we synthesized and characterized a novel Brönsted acidic ionic liquid from the reaction of N, N, N', N'-tetramethylethylenediamine with chlorosulfonic acid and explored its catalytic activity in 1, 8-dioxo-octahydroxanthenes synthesis. MATERIALS AND METHODS:Dimedone, aryl aldehydes, and...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207321666180828092546
更新日期:2018-01-01 00:00:00
abstract::Plasmodium falciparum is the most lethal form of the genus Plasmodium which causes malaria, a 'disease of antiquity'. Globally it affects the health and socio-economic development of a large population especially in Sub-Saharan Africa and Southeast Asia. The Plasmodium falciparum dihydrofolate reductase-thymidylate sy...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207317666140521153305
更新日期:2014-01-01 00:00:00
abstract::In the present work, we report characterization studies of antigen(Ag)-antibody (Ab) interaction based on the multi-walled carbon nanotube array-modified gold electrode for label-free electrochemical immunosensor. -COOH functionalization of MWCNT was suggested by FTIR spectroscopy. Images from atomic force microscopy ...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207318666141212165513
更新日期:2015-01-01 00:00:00
abstract::Recent studies have suggested that both constitutive androstane receptor (CAR) and pregnane X-receptor (PXR) are involved in the induction of rat liver microsomal cytochrome P-450 (CYP) 2B and 3A through a mechanism called cross-talk. In this study we intend to determine if a PXR-reporter gene assay could be used for ...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207054020822
更新日期:2005-06-01 00:00:00
abstract::African trypanosomes are the causative agent of sleeping sickness. The therapeutics used to control and treat the disease are very ineffective and thus, the development of improved drugs is urgently needed. Recently, new strategies for the design of novel trypanocidals have been put forward. Among them are techniques ...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/138620708783398331
更新日期:2008-01-01 00:00:00
abstract::This review describes the design process from conception through realisation and optimisation of a minibody'--a minimised antibody. The result was a proteinaceous molecule of novel fold and metal binding activity. We explain how combinatorial approaches, using phage display libraries, were used to randomise loop regio...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章,评审
doi:10.2174/1386207013330986
更新日期:2001-08-01 00:00:00
abstract::African trypanosomes are extracellular blood parasites that cause sleeping sickness in humans and Nagana in cattle. The therapeutics used to control and treat these diseases are very ineffective and thus, the development of new drugs is urgently needed. We have previously suggested to use trypanosome-specific RNA apta...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/138620706777935324
更新日期:2006-08-01 00:00:00
abstract::In the present work, an analytical methodology based on molecularly imprinted solid-phase extraction (MISPE) has been developed for the determination of bisphenol A (BPA) in environmental and food samples. In order to select the optimum material, a combinatorial library of molecularly imprinted polymers in small-scale...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/138620706779026024
更新日期:2006-12-01 00:00:00
abstract:BACKGROUND:Camptothecin is a quinoline alkaloid, isolated from the Chinese tree Camptotheca acuminate which exhibits its cytotoxic activity by the inhibition of nuclear enzyme Topoisomerase I (topo I). Camptothecin and its analogues forms a covalent bond with DNA which can arrest the tumor growth by slowing the religat...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207319666160810154346
更新日期:2016-01-01 00:00:00
abstract::The Molecular Screening Shared Resource (MSSR) offers a comprehensive range of leading-edge high throughput screening (HTS) services including drug discovery, chemical and functional genomics, and novel methods for nano and environmental toxicology. The MSSR is an open access environment with investigators from UCLA a...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207317666140323134621
更新日期:2014-05-01 00:00:00
abstract::To meet growing needs for high throughput gene expression profiling, we established a new automated high throughput TaqMan RT-PCR method for quantitative mRNA expression analysis. In this method, the Allegro( trade mark ) (Zymark) system conducts all sample tracking and liquid handling steps, and ABI PRISM 7900 HT (Ap...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/138620704773120810
更新日期:2004-03-01 00:00:00
abstract::Human activities have introduced tens of thousands of chemicals into water systems around the world which has significantly impacted water quality and aquatic ecosystems. The aim of this study was to develop an in silico QSAR model, capable of predicting the aquatic toxicity of pesticides in terms of a lethal dose (LD...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207317666141021110738
更新日期:2014-01-01 00:00:00
abstract::Cervical cancer is the second largest form of cancer to infest the leading cause of death in women worldwide. There are many causes of cancer but viruses are the most common among them. Human papillomaviruses (HPVs) are found to be the causative organism in almost 99.7% of the cases. HPV16 is the most frequent HPV typ...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/13862073113166660066
更新日期:2014-01-01 00:00:00
abstract::The breast cancer resistant protein (BCRP) is an important transporter and its inhibitors play an important role in cancer treatment by improving the oral bioavailability as well as blood brain barrier (BBB) permeability of anticancer drugs. In this work, a computational model was developed to predict the compounds as...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
doi:10.2174/1386207318666150525094503
更新日期:2015-01-01 00:00:00