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Understanding Brain Delivery
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Joana Bicker, Ana Fortuna, Gilberto Alves, Amílcar Falcäo
This occurs because making go/no-go decisions during CNS drug development is particularly difficult (Fig. 2.1). For instance, the high complexity of the human CNS contributes to an insufficient understanding of the aetiology and pathophysiology of many CNS disorders, making it difficult to develop targeted and validated therapies [9]. However, even the optimisation of a molecule with affinity for an identified target does not necessarily ensure success, because the target may not be as relevant in the disease process as it was initially anticipated [10]. The solution may reside in the simultaneous modulation of more than one relevant target [10, 11]. In this context, phenotypic screening was pointed out as an alternative strategy to target-based screening, because it does not require previous knowledge about the molecular targets involved in CNS diseases. Nevertheless, it is still necessary to continue the investigation of disease-relevant cellular phenotypes with improved assay throughput, and the target(s) must be identified later in the process (target deconvolution) [12, 13]. A recent phenotype-based screen was developed for the discovery of drugs directed at multiple sclerosis [14].
Marine Natural Products for Human Health Care
Published in Hafiz Ansar Rasul Suleria, Megh R. Goyal, Health Benefits of Secondary Phytocompounds from Plant and Marine Sources, 2021
Analysis of the origin of new FDA approved drugs between 1999 and 2008 suggests that phenotypic screening strategies have been more productive than target-based approaches in drug discovery. It has been shown that utilization of phenotypic assays early in the screening cascade generates hits of higher quality, as opposed to target-based screening. This is because many other factors, in addition to compound-target interactions, come into play when a compound is to be used as a drug. Examples of these are: membrane permeability, unspecific protein binding, and metabolism.
Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Theodora Calogeropoulou, George E. Magoulas, Ina Pöhner, Joanna Panecka-Hofman, Pasquale Linciano, Stefania Ferrari, Nuno Santarem, Ma Dolores Jiménez-Antón, Ana Isabel Olías-Molero, José María Alunda, Anabela Cordeiro da Silva, Rebecca C. Wade, Maria Paola Costi
Usually, drug discovery for NTDs is carried out using classical ligand-based approaches, target-based approaches and phenotypic screening. Ligand-based approaches, which are discussed later in the chapter, are typically focused on the development of new compounds on the basis of already known active compounds, natural compounds or marketed drugs. Chemical structure modifications are then applied on the basis of classical medicinal chemistry strategies (Wermuth et al. 2015). Target-based approaches involve screening a library of compounds against a protein target and then optimizing the compounds for potency against the enzyme, selectivity, cellular activity, and pharmacokinetic properties. However, there are relatively few validated drug targets for trypanosomiatidic infections (Frearson et al. 2007). Targets of major interest in the field of drug discovery are reported in Gilbert et al. (2013) and, in this chapter, we focus on targets relevant for ergosterol biosynthesis, folate metabolism, phosphodiesterases, cysteine proteases and trypanothione metabolism. On the other hand, phenotypic screening has the advantage of identifying compounds that are active against the whole cell, meaning issues such as cell uptake and cell efflux have already been addressed (Haasen et al. 2017). There has been a major emphasis on phenotypic approaches to drug discovery for neglected diseases and a number of notable successes have been reported, like the above mentioned fexinidazole and acoziborole (Eperon et al. 2014). Nonetheless, a balanced portfolio of carefully selected ligand- and target-based approaches together with phenotypic approaches is probably the best strategy for drug discovery for NTDs. This must be complemented by studies in animal models, which are reviewed in the final section of this chapter.
Parasite and host kinases as targets for antimalarials
Published in Expert Opinion on Therapeutic Targets, 2023
Han Wee Ong, Jack Adderley, Andrew B. Tobin, David H. Drewry, Christian Doerig
Historically, due to limited number of validated targets in Plasmodium, phenotypic screening has been a popular method to discover novel antimalarials. One major advantage of phenotypic screening is that the starting point has already demonstrated efficacy against the parasite, thereby overcoming hurdles in physiochemical properties that may limit target exposure. However, target-based drug discovery offers numerous key advantages over traditional phenotypic screening. Firstly, an identified target facilitates structure-guided rational compound optimization efforts, especially to gain selectivity over undesired off-targets (such as a human orthologue of an essential Plasmodium kinase). Target-based drug discovery also enables (i) the development of in vitro biochemical screens, which may identify hits that may lack sufficient potency to be identified in a phenotypic screen, and (ii) the utilization of novel screening technologies such as virtual screening, fragment-based screening, and DNA-encoded library screening technologies, which cover a larger proportion of chemical space to increase the likelihood of discovery of novel chemical matter. From a clinical development perspective, knowledge of the target is also crucial for developing combination therapies and for resistance monitoring. For an in-depth discussion of target-based antimalarial drug discovery, readers are encouraged to consult publications by the Malaria Drug Accelerator (MalDA), a consortium aiming to improve and accelerate early antimalarial drug discovery process by identifying novel targets [11,12].
Strategies for targeting undruggable targets
Published in Expert Opinion on Drug Discovery, 2022
Gong Zhang, Juan Zhang, Yuting Gao, Yangfeng Li, Yizhou Li
Throughout history, people have been seeking natural products and drugs to cure diseases. In ancient times, they sought an empirical linkage between the disease ‘phenotype’ and the unknown mixture of herbals. Modern medicinal science originates from aspirin, the first chemically pure therapeutic compound[1]. Nonetheless, the early stage of drug discovery still relied on phenotypic screening, that is, to establish a correlation between drug treatment and phenotypes. Although phenotypic screening is an integral part of drug discovery, more efforts have been made to investigate the molecular and pathological pathways involved in diseases generation in recent decades. Target-based drug discoveries have emerged, which symbolized the new era of drug discovery. ‘Drug target’ is defined as a biomacromolecule that plays an essential role in disease development and can be accessed to cure disease by treating with exogeneous molecules [2,3].
Drug discovery for primary amebic meningoencephalitis: from screen to identification of leads
Published in Expert Review of Anti-infective Therapy, 2021
The conventional route of drug development is a long and expensive process and involves about $2.6 billion to bring a drug to the market [61]. The use of clinically developed compounds can reduce the development time and allows to cost-effectively repurpose these drugs for the treatment of PAM. Considering the rarity of the disease and more than a quarter of all annotated drugs are associated with off-label uses [62,63], PAM drug discovery strategies are continuously exploring the repurposing opportunities. Repurposing may employ both phenotypic screening and target-based approaches. Despite the availability of molecular biology and genomic tools, a handful of druggable targets (pore forming protein, cysteine protease, CYP51, 24-SMT, ERG2) were identified in N. fowleri [15,25,28,64–66]. The development of robust assay based on phenotypic screening led to the reliance on this screen to identify new leads. Earlier analysis of first-in-class small-molecule drugs approved by the FDA between 1999 and 2008 showed that the phenotypic screening contributed more to the discovery of new leads than that of target-based approaches, demonstrating the utility of the phenotypic screening strategy [67]. A mechanism-based discovery of new anti-Naegleria compounds can be explored in conjunction with the phenotypic screening to identify target-based inhibitors.