Early phase drug discovery: Cheminformatics and computational techniques in identifying lead series

Duffy, Bryan C.; Zhu, Lei; Decornez, Hélène; Kitchen, Douglas B.

doi:10.1016/j.bmc.2012.04.062

Cited by 67 publications

(37 citation statements)

References 112 publications

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“…Advances in robotic automation and liquid handling, coupled with the ever-shrinking scale at which these assays are performed have facilitated the ultra high throughput screening (HTS) of very large compound libraries [11]. Furthermore, the continued development of cheminformatics, which encompasses the ability to analyze, filter, and interpret the large datasets generated from these screens, has greatly contributed to the establishment of HTS technology as a staple in the drug discovery process [12]. The pharmaceutical industry has relied on two different methods of HTS.…”

Section: Identifying New Drug Candidatesmentioning

confidence: 99%

Phenotypic Screens in Antimalarial Drug Discovery

Hovlid

Winzeler

2016

Trends in Parasitology

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Phenotypic high throughput screens are a valuable tool for identifying new chemical compounds with antimalarial activity. Traditionally, these screens have focused solely on the symptomatic asexual blood stage of the parasite's lifecycle; however, in order to discover new medicines for malaria's treatment and prevention, robust screening technologies against other parasite lifecycle stages are required. This review highlights recent advances and progress toward phenotypic screening methodologies over the past several years, with a focus on exoerythrocytic stage screens.

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Section: Identifying New Drug Candidatesmentioning

confidence: 99%

Phenotypic Screens in Antimalarial Drug Discovery

Hovlid

Winzeler

2016

Trends in Parasitology

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“…Another approach used by pharmaceutical companies early in drug discovery is high throughput screening (HTS) [61,62]. This strategy leverages mechanical automation to quickly assay the biological or biochemical activity of a large number of drug-like compounds simultaneously under controlled experimental conditions.…”

Section: Novel Strategies For Drug Discovery In Pahmentioning

confidence: 99%

Novel approaches to pulmonary arterial hypertension drug discovery

Sung¹,

Yuan²,

Perez³

2016

Expert Opinion on Drug Discovery

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Introduction Pulmonary arterial hypertension (PAH) is a rare disorder associated with abnormally elevated pulmonary pressures that, if untreated, leads to right heart failure and premature death. The goal of drug development for PAH is to develop effective therapies that halt, or ideally, reverse the obliterative vasculopathy that results in vessel loss and obstruction of blood flow to the lungs. Areas Covered This review summarizes the current approach to candidate discovery in PAH and discusses the currently available drug discovery methods that should be implemented to prioritize targets and obtain a comprehensive pharmacological profile of promising compounds with well-defined mechanisms. Expert opinion To improve the successful identification of leading drug candidates, it is necessary that traditional pre-clinical studies are combined with drug screening strategies that maximize the characterization of biological activity and identify relevant off-target effects that could hinder the clinical efficacy of the compound when tested in human subjects. A successful drug discovery strategy in PAH will require collaboration of clinician scientists with medicinal chemists and pharmacologists who can identify compounds with an adequate safety profile and biological activity against relevant disease mechanisms.

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“…1 The drug discovery and development pathway from a novel drug target to a Food and Drug Administration (FDA) approved drug and to the marketing of a novel molecular entity is long and expensive, which prompts new pharmaceutical companies and laboratories to benefit from the usage of computational methods. 2,3 Computational methods now play an integral role in understanding intermolecular interactions and although algorithms are based on approximations and assumptions, molecular modeling has become the leading tool in modern drug discovery. 4,5 The ability of specialized virtual screening algorithms to filter molecular libraries into a manageable number of compounds for biological assays is the driving force for finding novel ligands.…”

Section: Introductionmentioning

confidence: 99%

Pyrazolyl-Tetrazoles and Imidazolyl-Pyrazoles as Potential Anticoagulants and their Integrated Multiplex Analysis Virtual Screening

Lourenço

Vegi

Faria

et al. 2018

J. Braz. Chem. Soc.

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This article reports a novel virtual screening algorithm seeking the rational identification of novel lead anticoagulants. Seven 5-(3-methyl-1-aryl-1H-pyrazol-4-yl)-1H-tetrazoles and seven novel 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-3-methyl-1H-pyrazoles were obtained in three steps starting from arylhydrazine hydrochlorides as raw materials in good yields: 50-72% and 50-85%, respectively. All compounds were submitted to an in silico target-base pipeline named integrated multiplex analysis virtual screening (IMA-VS), which comprises the evaluation of their (i) fitting physicochemical properties to the chemical environment of the target enzyme; (ii) active-site homing electrostatic potential to the target enzyme; (iii) structural fitting to the target active site through molecular docking; and (iv) overall absorption, distribution, metabolism, excretion and toxicity (ADMET) profile. After the virtual selection of potential anticoagulant hits, all molecules were synthesized and candidates were evaluated in vitro for their anticoagulant and hemolytic profile. The most promising candidate pointed out by IMA-VS was compound 1-(3',4'-dichlorophenyl)-4-(4,5-dihydro-1H-imidazol-2-yl)-3-methyl-1H-pyrazole that shown to display factor Xa (FXa)-specific inhibitory activity in vitro, acting as an uncompetitive inhibitor with an inhibition constant (Ki) = 61.16 ± 12.96 µM, in addition to the lowest hemolytic activity of the series. Further experiments revealed the antithrombotic activity of this compound in an in vivo model of arterial thrombosis induced by FeCl 3 .

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Early phase drug discovery: Cheminformatics and computational techniques in identifying lead series

Cited by 67 publications

References 112 publications

Phenotypic Screens in Antimalarial Drug Discovery

Phenotypic Screens in Antimalarial Drug Discovery

Novel approaches to pulmonary arterial hypertension drug discovery

Pyrazolyl-Tetrazoles and Imidazolyl-Pyrazoles as Potential Anticoagulants and their Integrated Multiplex Analysis Virtual Screening

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