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Phenotypic Screening

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 40140

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Special Issue Editors

Dr. Maria Chatzopoulou

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Guest Editor

UCB, 216 Bath Rd, Slough SL1 3WE, UK
Interests: medicinal chemistry; drug discovery; phenotypic screening; biotransformation; drug metabolism; diabetes; Duchenne muscular dystrophy

Prof. Dr. Angela Russell

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Guest Editor

1. Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
2. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3PQ, UK
Interests: medicinal chemistry; drug discovery; phenotypic screening; target identification; regenerative medicine; neuromuscular disease; cancer; inflammation

Special Issue Information

Dear Colleagues,

Phenotypic screening and more broadly phenotypic drug discovery (PDD) rely on methods where the molecular mechanism is not known or assumed and uses empirical lead generation to deliver novel drug candidates in the clinic. Though target-based approaches, supported by the rapid progress in genetics and molecular biology, have dominated drug discovery in the past 30 years, there is recently a resurgence of PDD. The relative simplicity of target-based approaches facilitated testing of increasing numbers of compounds, initially thought of as increasing diversity and furthering the odds of successful drug discovery. However, a disconnect between in vitro and in vivo systems was often observed, as a result of stirring away from physiologically relevant conditions that cease to accurately simulate disease. PDD, on the other hand, is more costly and slow in the early stages, requiring rigorous validation and/or target identification, but with a better understanding of the risks and challenges, it can be a powerful tool leading to increased probabilty of success for drug candidates, but also to the identification of novel drug targets that can be used alone or in combination with existing therapeutics.

The present Special Issue is aimed at covering improvements in library design, screening, assay cascade, and chemoinformatics tools that expedite modern PDD, presenting successful medicinal chemistry efforts in PDD, and further target identification campaigns that originated from PDD. We look forward to receiving these and other relevant contributions.

Dr. Maria Chatzopoulou
Prof. Dr. Angela Russell
Guest Editors

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Keywords

phenotypic screening
drug discovery
high-throughput screening
high-content screening
hit triage
lead identification
lead optimisation
assay cascade
chemoinformatics
apparent activity
assay interference
structure–activity relationships
library design
target identification/validation

Published Papers (12 papers)

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21 pages, 1127 KiB

Open AccessArticle

Identifying Protein Features and Pathways Responsible for Toxicity Using Machine Learning and Tox21: Implications for Predictive Toxicology

by Lama Moukheiber, William Mangione, Mira Moukheiber, Saeed Maleki, Zackary Falls, Mingchen Gao and Ram Samudrala

Molecules 2022, 27(9), 3021; https://doi.org/10.3390/molecules27093021 - 08 May 2022

Cited by 5 | Viewed by 3031

Abstract

Humans are exposed to numerous compounds daily, some of which have adverse effects on health. Computational approaches for modeling toxicological data in conjunction with machine learning algorithms have gained popularity over the last few years. Machine learning approaches have been used to predict toxicity-related biological activities using chemical structure descriptors. However, toxicity-related proteomic features have not been fully investigated. In this study, we construct a computational pipeline using machine learning models for predicting the most important protein features responsible for the toxicity of compounds taken from the Tox21 dataset that is implemented within the multiscale Computational Analysis of Novel Drug Opportunities (CANDO) therapeutic discovery platform. Tox21 is a highly imbalanced dataset consisting of twelve in vitro assays, seven from the nuclear receptor (NR) signaling pathway and five from the stress response (SR) pathway, for more than 10,000 compounds. For the machine learning model, we employed a random forest with the combination of Synthetic Minority Oversampling Technique (SMOTE) and the Edited Nearest Neighbor (ENN) method (SMOTE+ENN), which is a resampling method to balance the activity class distribution. Within the NR and SR pathways, the activity of the aryl hydrocarbon receptor (NR-AhR) and the mitochondrial membrane potential (SR-MMP) were two of the top-performing twelve toxicity endpoints with AUCROCs of 0.90 and 0.92, respectively. The top extracted features for evaluating compound toxicity were analyzed for enrichment to highlight the implicated biological pathways and proteins. We validated our enrichment results for the activity of the AhR using a thorough literature search. Our case study showed that the selected enriched pathways and proteins from our computational pipeline are not only correlated with AhR toxicity but also form a cascading upstream/downstream arrangement. Our work elucidates significant relationships between protein and compound interactions computed using CANDO and the associated biological pathways to which the proteins belong for twelve toxicity endpoints. This novel study uses machine learning not only to predict and understand toxicity but also elucidates therapeutic mechanisms at a proteomic level for a variety of toxicity endpoints. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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16 pages, 3870 KiB

Open AccessArticle

Developing CRISPR/Cas9-Mediated Fluorescent Reporter Human Pluripotent Stem-Cell Lines for High-Content Screening

by Kinga Vojnits, Mio Nakanishi, Deanna Porras, Yeonjoon Kim, Zhuohang Feng, Diana Golubeva and Mick Bhatia

Molecules 2022, 27(8), 2434; https://doi.org/10.3390/molecules27082434 - 09 Apr 2022

Cited by 2 | Viewed by 3771

Abstract

Application of the CRISPR/Cas9 system to knock in fluorescent proteins to endogenous genes of interest in human pluripotent stem cells (hPSCs) has the potential to facilitate hPSC-based disease modeling, drug screening, and optimization of transplantation therapy. To evaluate the capability of fluorescent reporter hPSC lines for high-content screening approaches, we targeted EGFP to the endogenous OCT4 locus. Resulting hPSC–OCT4–EGFP lines generated expressed EGFP coincident with pluripotency markers and could be adapted to multi-well formats for high-content screening (HCS) campaigns. However, after long-term culture, hPSCs transiently lost their EGFP expression. Alternatively, through EGFP knock-in to the AAVS1 locus, we established a stable and consistent EGFP-expressing hPSC–AAVS1–EGFP line that maintained EGFP expression during in vitro hematopoietic and neural differentiation. Thus, hPSC–AAVS1–EGFP-derived sensory neurons could be adapted to a high-content screening platform that can be applied to high-throughput small-molecule screening and drug discovery campaigns. Our observations are consistent with recent findings indicating that high-frequency on-target complexities appear following CRISPR/Cas9 genome editing at the OCT4 locus. In contrast, we demonstrate that the AAVS1 locus is a safe genomic location in hPSCs with high gene expression that does not impact hPSC quality and differentiation. Our findings suggest that the CRISPR/Cas9-integrated AAVS1 system should be applied for generating stable reporter hPSC lines for long-term HCS approaches, and they underscore the importance of careful evaluation and selection of the applied reporter cell lines for HCS purposes. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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21 pages, 4063 KiB

Open AccessArticle

Image-Based Annotation of Chemogenomic Libraries for Phenotypic Screening

by Amelie Tjaden, Apirat Chaikuad, Eric Kowarz, Rolf Marschalek, Stefan Knapp, Martin Schröder and Susanne Müller

Molecules 2022, 27(4), 1439; https://doi.org/10.3390/molecules27041439 - 21 Feb 2022

Cited by 16 | Viewed by 3185

Abstract

Phenotypical screening is a widely used approach in drug discovery for the identification of small molecules with cellular activities. However, functional annotation of identified hits often poses a challenge. The development of small molecules with narrow or exclusive target selectivity such as chemical probes and chemogenomic (CG) libraries, greatly diminishes this challenge, but non-specific effects caused by compound toxicity or interference with basic cellular functions still pose a problem to associate phenotypic readouts with molecular targets. Hence, each compound should ideally be comprehensively characterized regarding its effects on general cell functions. Here, we report an optimized live-cell multiplexed assay that classifies cells based on nuclear morphology, presenting an excellent indicator for cellular responses such as early apoptosis and necrosis. This basic readout in combination with the detection of other general cell damaging activities of small molecules such as changes in cytoskeletal morphology, cell cycle and mitochondrial health provides a comprehensive time-dependent characterization of the effect of small molecules on cellular health in a single experiment. The developed high-content assay offers multi-dimensional comprehensive characterization that can be used to delineate generic effects regarding cell functions and cell viability, allowing an assessment of compound suitability for subsequent detailed phenotypic and mechanistic studies. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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14 pages, 1282 KiB

Open AccessArticle

Compounds from the Medicines for Malaria Venture Box Inhibit In Vitro Growth of Babesia divergens, a Blood-Borne Parasite of Veterinary and Zoonotic Importance

by Mohamed Abdo Rizk, Shimaa Abd El-Salam El-Sayed, Mahmoud S. Alkhoudary, Khalaf F. Alsharif, Mohamed M. Abdel-Daim and Ikuo Igarashi

Molecules 2021, 26(23), 7118; https://doi.org/10.3390/molecules26237118 - 24 Nov 2021

Cited by 12 | Viewed by 1812

Abstract

Babesiosis is an infectious disease with an empty drug pipeline. A search inside chemical libraries for novel potent antibabesial candidates may help fill such an empty drug pipeline. A total of 400 compounds (200 drug-like and 200 probe-like) from the Malaria Box were evaluated in the current study against the in vitro growth of Babesia divergens (B. divergens), a parasite of veterinary and zoonotic importance. Novel and more effective anti-B. divergens drugs than the traditionally used ones were identified. Seven compounds (four drug-like and three probe-like) revealed a highly inhibitory effect against the in vitro growth of B. divergens, with IC₅₀s ≤ 10 nanomolar. Among these hits, MMV006913 exhibited an IC₅₀ value of 1 nM IC₅₀ and the highest selectivity index of 32,000. The atom pair fingerprint (APfp) analysis revealed that MMV006913 and MMV019124 showed maximum structural similarity (MSS) with atovaquone and diminazene aceturate (DA), and with DA and imidocarb dipropionate (ID), respectively. MMV665807 and MMV665850 showed MMS with each other and with ID. Of note, a high concentration (0.75 IC₅₀) of MMV006913 caused additive inhibition of B. divergens growth when combined with DA at 0.75 or 0.50 IC₅₀. The Medicines for Malaria Venture box is a treasure trove of anti-B. divergens candidates according to the obtained results. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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13 pages, 1338 KiB

Open AccessArticle

The Discovery of Actinospene, a New Polyene Macrolide with Broad Activity against Plant Fungal Pathogens and Pathogenic Yeasts

by Ying Tang, Cuiyang Zhang, Tianqi Cui, Ping Lei, Zhaohui Guo, Hailong Wang and Qingshu Liu

Molecules 2021, 26(22), 7020; https://doi.org/10.3390/molecules26227020 - 20 Nov 2021

Cited by 3 | Viewed by 1879

Abstract

Phytopathogenic fungi infect crops, presenting a worldwide threat to agriculture. Polyene macrolides are one of the most effective antifungal agents applied in human therapy and crop protection. In this study, we found a cryptic polyene biosynthetic gene cluster in Actinokineospora spheciospongiae by genome mining. Then, this gene cluster was activated via varying fermentation conditions, leading to the discovery of new polyene actinospene (1), which was subsequently isolated and its structure determined through spectroscopic techniques including UV, HR-MS, and NMR. The absolute configuration was confirmed by comparing the calculated and experimental electronic circular dichroism (ECD) spectra. Unlike known polyene macrolides, actinospene (1) demonstrated more versatile post-assembling decorations including two epoxide groups and an unusual isobutenyl side chain. In bioassays, actinospene (1) showed a broad spectrum of antifungal activity against several plant fungal pathogens as well as pathogenic yeasts with minimum inhibitory concentrations ranging between 2 and 10 μg/mL. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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28 pages, 8098 KiB

Open AccessEditor’s ChoiceArticle

Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro

by Laia Josa-Culleré, Thomas J. Cogswell, Irene Georgiou, Morgan Jay-Smith, Thomas R. Jackson, Carole J. R. Bataille, Stephen G. Davies, Paresh Vyas, Thomas A. Milne, Graham M. Wynne and Angela J. Russell

Molecules 2021, 26(21), 6648; https://doi.org/10.3390/molecules26216648 - 02 Nov 2021

Viewed by 2704

Abstract

Acute myeloid leukemia (AML) is the most aggressive type of blood cancer, and there is a continued need for new treatments that are well tolerated and improve long-term survival rates in patients. Induction of differentiation has emerged as a promising alternative to conventional cytotoxic chemotherapy, but known agents lack efficacy in genetically distinct patient populations. Previously, we established a phenotypic screen to identify small molecules that could stimulate differentiation in a range of AML cell lines. Utilising this strategy, a 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one hit compound was identified. Herein, we report the hit validation in vitro, structure-activity relationship (SAR) studies and the pharmacokinetic profiles for selected compounds. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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12 pages, 2396 KiB

Open AccessFeature PaperArticle

Actions of Camptothecin Derivatives on Larvae and Adults of the Arboviral Vector Aedes aegypti

by Frederick A. Partridge, Beth C. Poulton, Milly A. I. Lake, Rebecca A. Lees, Harry-Jack Mann, Gareth J. Lycett and David B. Sattelle

Molecules 2021, 26(20), 6226; https://doi.org/10.3390/molecules26206226 - 15 Oct 2021

Cited by 4 | Viewed by 1755

Abstract

Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and Onchocerca volvulus endanger health and economic security around the globe, and emerging mosquito-borne pathogens have pandemic potential. However, the rapid spread of insecticide resistance threatens our ability to control mosquito vectors. Larvae of Aedes aegypti were screened with the Medicines for Malaria Venture Pandemic Response Box, an open-source compound library, using INVAPP, an invertebrate automated phenotyping platform suited to high-throughput chemical screening of larval motility. We identified rubitecan (a synthetic derivative of camptothecin) as a hit compound that reduced A. aegypti larval motility. Both rubitecan and camptothecin displayed concentration dependent reduction in larval motility with estimated EC₅₀ of 25.5 ± 5.0 µM and 22.3 ± 5.4 µM, respectively. We extended our investigation to adult mosquitoes and found that camptothecin increased lethality when delivered in a blood meal to A. aegypti adults at 100 µM and 10 µM, and completely blocked egg laying when fed at 100 µM. Camptothecin and its derivatives are inhibitors of topoisomerase I, have known activity against several agricultural pests, and are also approved for the treatment of several cancers. Crucially, they can inhibit Zika virus replication in human cells, so there is potential for dual targeting of both the vector and an important arbovirus that it carries. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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13 pages, 1383 KiB

Open AccessArticle

In Vitro Phenotypic Activity and In Silico Analysis of Natural Products from Brazilian Biodiversity on Trypanosoma cruzi

by Raiza B. Peres, Ludmila F. de A. Fiuza, Patrícia B. da Silva, Marcos M. Batista, Flávia da C. Camillo, André M. Marques, Lavínia de C. Brito, Maria R. Figueiredo and Maria de N. C. Soeiro

Molecules 2021, 26(18), 5676; https://doi.org/10.3390/molecules26185676 - 18 Sep 2021

Cited by 4 | Viewed by 1610

Abstract

Chagas disease (CD) affects more than 6 million people worldwide. The available treatment is far from ideal, creating a demand for new alternative therapies. Botanical diversity provides a wide range of novel potential therapeutic scaffolds. Presently, our aim was to evaluate the mammalian host toxicity and anti-Trypanosoma cruzi activity of botanic natural products including extracts, fractions and purified compounds obtained from Brazilian flora. In this study, 36 samples of extracts and fractions and eight pure compounds obtained from seven plant species were evaluated. The fraction dichloromethane from Aureliana fasciculata var. fasciculata (AFfPD) and the crude extract of Piper tectoniifolium (PTFrE) showed promising trypanosomicidal activity. AFfPD and PTFrE presented EC₅₀ values 10.7 ± 2.8 μg/mL and 12.85 ± 1.52 μg/mL against intracellular forms (Tulahuen strain), respectively. Additionally, both were active upon bloodstream trypomastigotes (Y strain), exhibiting EC₅₀ 2.2 ± 1.0 μg/mL and 38.8 ± 2.1 μg/mL for AFfPD and PTFrE, respectively. Importantly, AFfPD is about five-fold more potent than Benznidazole (Bz), the reference drug for CD, also reaching lower EC₉₀ value (7.92 ± 2.2 μg/mL) as compared to Bz (23.3 ± 0.6 μg/mL). Besides, anti-parasitic effect of eight purified botanic substances was also investigated. Aurelianolide A and B (compounds 1 and 2) from A. fasciculata and compound 8 from P. tuberculatum displayed the best trypanosomicidal effect. Compounds 1, 2 and 8 showed EC₅₀ of 4.6 ± 1.3 μM, 1.6 ± 0.4 μM and 8.1 ± 0.9 μM, respectively against intracellular forms. In addition, in silico analysis of these three biomolecules was performed to predict parameters of absorption, distribution, metabolism and excretion. The studied compounds presented similar ADMET profile as Bz, without presenting mutagenicity and hepatotoxicity aspects as predicted for Bz. Our findings indicate that these natural products have promising anti-T. cruzi effect and may represent new scaffolds for future lead optimization. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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7 pages, 619 KiB

Open AccessArticle

Practical High-Throughput Method to Screen Compounds for Anthelmintic Activity against Caenorhabditis elegans

by Aya C. Taki, Joseph J. Byrne, Peter R. Boag, Abdul Jabbar and Robin B. Gasser

Molecules 2021, 26(14), 4156; https://doi.org/10.3390/molecules26144156 - 08 Jul 2021

Cited by 12 | Viewed by 2495

Abstract

In the present study, we established a practical and cost-effective high throughput screening assay, which relies on the measurement of the motility of Caenorhabditis elegans by infrared light-interference. Using this assay, we screened 14,400 small molecules from the “HitFinder” library (Maybridge), achieving a hit rate of 0.3%. We identified small molecules that reproducibly inhibited the motility of C. elegans (young adults) and assessed dose relationships for a subset of compounds. Future work will critically evaluate the potential of some of these hits as candidates for subsequent optimisation or repurposing as nematocides or nematostats. This high throughput screening assay has the advantage over many previous assays in that it is cost- and time-effective to carry out and achieves a markedly higher throughput (~10,000 compounds per week); therefore, it is suited to the screening of libraries of tens to hundreds of thousands of compounds for subsequent evaluation and development. The present phenotypic whole-worm assay should be readily adaptable to a range of socioeconomically important parasitic nematodes of humans and animals, depending on their dimensions and motility characteristics in vitro, for the discovery of new anthelmintic candidates. This focus is particularly important, given the widespread problems associated with drug resistance in many parasitic worms of livestock animals globally. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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10 pages, 4674 KiB

Open AccessArticle

Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against Haemonchus contortus In Vitro

by Aya C. Taki, Abdul Jabbar, Thomas Kurz, Beate Lungerich, Guangxu Ma, Joseph J. Byrne, Marc Pflieger, Yodita Asfaha, Fabian Fischer, Bill C. H. Chang, Brad E. Sleebs and Robin B. Gasser

Molecules 2021, 26(9), 2819; https://doi.org/10.3390/molecules26092819 - 10 May 2021

Cited by 2 | Viewed by 2960

Abstract

Due to widespread multi-drug resistance in parasitic nematodes of livestock animals, there is an urgent need to discover new anthelmintics with distinct mechanisms of action. Extending previous work, here we screened a panel of 245 chemically-diverse small molecules for anti-parasitic activity against Haemonchus contortus—an economically important parasitic nematode of livestock. This panel was screened in vitro against exsheathed third-stage larvae (xL3) of H. contortus using an established phenotypic assay, and the potency of select compounds to inhibit larval motility and development assessed in dose-response assays. Of the 245 compounds screened, three—designated MPK18, MPK334 and YAK308—induced non-wildtype larval phenotypes and repeatedly inhibited xL3-motility, with IC₅₀ values of 45.2 µM, 17.1 µM and 52.7 µM, respectively; two also inhibited larval development, with IC₅₀ values of 12.3 µM (MPK334) and 6.5 µM (YAK308), and none of the three was toxic to human liver cells (HepG2). These findings suggest that these compounds deserve further evaluation as nematocidal candidates. Future work should focus on structure–activity relationship (SAR) studies of these chemical scaffolds, and assess the in vitro and in vivo efficacies and safety of optimised compounds against adults of H. contortus. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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Review

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15 pages, 464 KiB

Open AccessReview

Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses

by Ahmed Morsy, Angelica V. Carmona and Paul C. Trippier

Molecules 2021, 26(20), 6235; https://doi.org/10.3390/molecules26206235 - 15 Oct 2021

Cited by 3 | Viewed by 2075

Abstract

Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1–CLN8, CLN10–CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Some common symptoms include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Currently, all forms of NCL are fatal, and no curative treatments are available. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type of the human body. Cells reprogrammed from a patient have the advantage of acquiring disease pathogenesis along with recapitulation of disease-associated phenotypes. They serve as practical model systems to shed new light on disease mechanisms and provide a phenotypic screening platform to enable drug discovery. Herein, we provide an overview of available iPSC models for a number of different NCLs. More specifically, we highlight findings in these models that may spur target identification and drug development. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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27 pages, 4250 KiB

Open AccessReview

RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays

by Zhichao Tang, Junxing Zhao, Zach J. Pearson, Zarko V. Boskovic and Jingxin Wang

Molecules 2021, 26(8), 2263; https://doi.org/10.3390/molecules26082263 - 14 Apr 2021

Cited by 21 | Viewed by 10815

Abstract

RNA splicing is an essential step in producing mature messenger RNA (mRNA) and other RNA species. Harnessing RNA splicing modifiers as a new pharmacological modality is promising for the treatment of diseases caused by aberrant splicing. This drug modality can be used for infectious diseases by disrupting the splicing of essential pathogenic genes. Several antisense oligonucleotide splicing modifiers were approved by the U.S. Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Recently, a small-molecule splicing modifier, risdiplam, was also approved for the treatment of SMA, highlighting small molecules as important warheads in the arsenal for regulating RNA splicing. The cellular targets of these approved drugs are all mRNA precursors (pre-mRNAs) in human cells. The development of novel RNA-targeting splicing modifiers can not only expand the scope of drug targets to include many previously considered “undruggable” genes but also enrich the chemical-genetic toolbox for basic biomedical research. In this review, we summarized known splicing modifiers, screening methods for novel splicing modifiers, and the chemical space occupied by the small-molecule splicing modifiers. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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