Mechanism of Action and Target Identification: A Matter of Timing in Drug Discovery

Davis, Ronald L.

doi:10.1016/j.isci.2020.101487

Cited by 56 publications

(41 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Yet, despite advances in the complexity and sophistication of phenotypic screens (e.g. [4,5]), the unambiguous assessment of a drug's primary, secondary and tertiary effects, in vivo, remains a significant challenge. Successful implementation of chemogenomic assays and an analytical framework would help bridge the gap between bioactive compound discovery and drug target validation.…”

Section: Introductionmentioning

confidence: 99%

The cellular response to drug perturbation is limited: comparison of large-scale chemogenomic fitness signatures

Barazandeh

Kriti²,

Nislow

et al. 2022

BMC Genomics

View full text Add to dashboard Cite

Background Chemogenomic profiling is a powerful approach for understanding the genome-wide cellular response to small molecules. First developed in Saccharomyces cerevisiae, chemogenomic screens provide direct, unbiased identification of drug target candidates as well as genes required for drug resistance. While many laboratories have performed chemogenomic fitness assays, few have been assessed for reproducibility and accuracy. Here we analyze the two largest independent yeast chemogenomic datasets comprising over 35 million gene-drug interactions and more than 6000 unique chemogenomic profiles; the first from our own academic laboratory (HIPLAB) and the second from the Novartis Institute of Biomedical Research (NIBR). Results Despite substantial differences in experimental and analytical pipelines, the combined datasets revealed robust chemogenomic response signatures, characterized by gene signatures, enrichment for biological processes and mechanisms of drug action. We previously reported that the cellular response to small molecules is limited and can be described by a network of 45 chemogenomic signatures. In the present study, we show that the majority of these signatures (66%) are also found in the companion dataset, providing further support for their biological relevance as conserved systems-level, small molecule response systems. Conclusions Our results demonstrate the robustness of chemogenomic fitness profiling in yeast, while offering guidelines for performing other high-dimensional comparisons including parallel CRISPR screens in mammalian cells.

show abstract

Section: Introductionmentioning

confidence: 99%

The cellular response to drug perturbation is limited: comparison of large-scale chemogenomic fitness signatures

Barazandeh

Kriti²,

Nislow

et al. 2022

BMC Genomics

View full text Add to dashboard Cite

show abstract

“…As expected from the literature, [ [58] , [59] , [60] ] the effect of 6i on the above kinases could also play a partial role in inhibiting the replication of Influenza A and SARS-CoV-2 but the full understanding of its MOA is a complex endeavour and major efforts will be required to solve this challenge in the future. It is also important to remember that the precise knowledge of a drug's target is not an essential requirement in drug discovery and around 10–20% of approved drugs have unknown target or MOA [ 62 , 63 ]. Especially in the discovery of new BSAAs for emerging diseases, the right compromise between target identification and efficacy in multiple functional assays should probably drive the rapid development of new and efficient candidates for preclinical studies.…”

Section: Resultsmentioning

confidence: 99%

System-oriented optimization of multi-target 2,6-diaminopurine derivatives: Easily accessible broad-spectrum antivirals active against flaviviruses, influenza virus and SARS-CoV-2

Vicenti

Martina

Boccuto

et al. 2021

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

The worldwide circulation of different viruses coupled with the increased frequency and diversity of new outbreaks, strongly highlight the need for new antiviral drugs to quickly react against potential pandemic pathogens. Broad-spectrum antiviral agents (BSAAs) represent the ideal option for a prompt response against multiple viruses, new and re-emerging. Starting from previously identified anti-flavivirus hits, we report herein the identification of promising BSAAs by submitting the multi-target 2,6-diaminopurine chemotype to a system-oriented optimization based on phenotypic screening on cell cultures infected with different viruses. Among the synthesized compounds, 6i showed low micromolar potency against Dengue, Zika, West Nile and Influenza A viruses (IC 50 = 0.5–5.3 μM) with high selectivity index. Interestingly, 6i also inhibited SARS-CoV-2 replication in different cell lines, with higher potency on Calu-3 cells that better mimic the SARS-COV-2 infection in vivo (IC 50 = 0.5 μM, SI = 240). The multi-target effect of 6i on flavivirus replication was also analyzed in whole cell studies ( in vitro selection and immunofluorescence) and against isolated host/viral targets.

show abstract

“…While genomic and proteomic approaches have uncovered an increasing number of potential druggable proteins, compelling Pharma businesses to adopt target-based drug discovery strategies, many challenges still remain. These include poor understanding of the mode of action of the target protein and its interaction with the therapeutic agent, as well as difficulties associated with the manufacturing of high-quality protein-based biologics in terms of purity and stability ( Davis 2020 ; Emmerich et al, 2021 ). In this perspective, we sought to direct the reader’s attention to the application of conventional and simple biophysical methods within automated HTP settings that are able not only to assess protein stability and integrity in solution but also to probe protein behaviour in the presence of multi-parametric screens of buffers, excipients, additives, salts, osmolytes, and co-factors.…”

Section: Perspective Summarymentioning

confidence: 99%

Measuring Protein Aggregation and Stability Using High-Throughput Biophysical Approaches

Kwan

Kolek

Danson

et al. 2022

Front. Mol. Biosci.

View full text Add to dashboard Cite

Structure-function relationships of biological macromolecules, in particular proteins, provide crucial insights for fundamental biochemistry, medical research and early drug discovery. However, production of recombinant proteins, either for structure determination, functional studies, or to be used as biopharmaceutical products, is often hampered by their instability and propensity to aggregate in solution in vitro. Protein samples of poor quality are often associated with reduced reproducibility as well as high research and production expenses. Several biophysical methods are available for measuring protein aggregation and stability. Yet, discovering and developing means to improve protein behaviour and structure-function integrity remains a demanding task. Here, we discuss workflows that are made possible by adapting established biophysical methods to high-throughput screening approaches. Rapid identification and optimisation of conditions that promote protein stability and reduce aggregation will support researchers and industry to maximise sample quality, stability and reproducibility, thereby reducing research and development time and costs.

show abstract

Mechanism of Action and Target Identification: A Matter of Timing in Drug Discovery

Cited by 56 publications

References 29 publications

The cellular response to drug perturbation is limited: comparison of large-scale chemogenomic fitness signatures

The cellular response to drug perturbation is limited: comparison of large-scale chemogenomic fitness signatures

System-oriented optimization of multi-target 2,6-diaminopurine derivatives: Easily accessible broad-spectrum antivirals active against flaviviruses, influenza virus and SARS-CoV-2

Measuring Protein Aggregation and Stability Using High-Throughput Biophysical Approaches

Contact Info

Product

Resources

About