scholarly journals An integrative network-based approach for drug target indication expansion

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0253614
Author(s):  
Yingnan Han ◽  
Clarence Wang ◽  
Katherine Klinger ◽  
Deepak K. Rajpal ◽  
Cheng Zhu
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Interaction Network ◽  
Superior Performance ◽  
Systematic Evaluation ◽  
Network Algorithms ◽  
Drug Discovery And Development ◽  
Traditional Drug ◽  
Literature Evidence ◽  
State Of Art

Background The identification of a target-indication pair is regarded as the first step in a traditional drug discovery and development process. Significant investment and attrition occur during discovery and development before a molecule is shown to be safe and efficacious for the selected indication and becomes an approved drug. Many drug targets are functionally pleiotropic and might be good targets for multiple indications. Methodologies that leverage years of scientific contributions on drug targets to allow systematic evaluation of other indication opportunities are critical for both patients and drug discovery and development scientists. Methods We introduced a network-based approach to systematically screen and prioritize disease indications for drug targets. The approach fundamentally integrates disease genomics data and protein interaction network. Further, the methodology allows for indication identification by leveraging state-of-art network algorithms to generate and compare the target and disease subnetworks. Results We first evaluated the performance of our method on recovering FDA approved indications for 15 randomly selected drug targets. The results showed superior performance when compared with other state-of-art approaches. Using this approach, we predicted novel indications supported by literature evidence for several highly pursued drug targets such as IL12/IL23 combination. Conclusions Our results demonstrated a potential global approach for indication expansion strategies. The proposed methodology enables rapid and systematic evaluation of both individual and combined drug targets for novel indications. Additionally, this approach provides novel insights on expanding the role of genes and pathways for developing therapeutic intervention strategies.

scholarly journals Small Molecule Modulation of Microbiome Ecosystem: A Systems Pharmacology Perspective

2020 ◽  
Author(s):  
Qiao Liu ◽  
Bohyun Lee ◽  
Lei Xie
Keyword(s):  
Drug Discovery ◽  
Human Health ◽  
Small Molecule ◽  
Drug Targets ◽  
Outer Membrane Proteins ◽  
Human Microbiome ◽  
Interaction Network ◽  
Fine Tune ◽  
Potential Drug Targets ◽  
Pathogenic Microbe

AbstractAn increasing body of evidence suggests that microbes are not only strongly associated with many human diseases but also responsible for the efficacy, resistance, and toxicity of drugs. Small-molecule drugs which can precisely fine-tune the microbial ecosystem on the basis of individual patients may revolutionize biomedicine. However, emerging endeavors in small-molecule microbiome drug discovery continue to follow a conventional “one-drug-one-target-one-disease” process. It is often insufficient and less successful in tackling complex systematic diseases. A systematic pharmacology approach that intervenes multiple interacting pathogenic species in the microbiome, could offer an attractive alternative solution. Advances in the Human Microbiome Project have provided numerous genomics data to study microbial interactions in the complex microbiome community. Integrating microbiome data with chemical genomics and other biological information enables us to delineate the landscape for the small molecule modulation of the human microbiome network. In this paper, we construct a disease-centric signed microbe-microbe interaction network using metabolite information of microbes and curated microbe effects on human health from published work. We develop a Signed Random Walk with Restart algorithm for the accurate prediction of pathogenic and commensal species. With a survey on the druggable and evolutionary space of microbe proteins, we find that 8-10% of them can be targeted by existing drugs or drug-like chemicals and that 25% of them have homologs to human proteins. We also demonstrate that drugs for diabetes are enriched in the potential inhibitors that target pathogenic microbe without affecting the commensal microbe, thus can be repurposed to modulate the microbiome ecosystem. We further show that periplasmic and cellular outer membrane proteins are overrepresented in the potential drug targets set in pathogenic microbe, but not in the commensal microbe. The systematic studies of polypharmacological landscape of the microbiome network may open a new avenue for the small-molecule drug discovery of microbiome.Author SummaryAs one of the most abundant components in human bodies, the microbiome has an extensive impact on human health. Pathogenic-microbes have become emerging potential therapeutic targets. Small-molecule drugs that only intervene in the growth of a specific pathogenic microbe without considering the interacting dynamics of the microbiome community may disrupt the ecosystem homeostasis, thus can cause drug side effect or prompt drug resistance. To discover novel drugs for safe and effective microbe-targeting therapeutics, a systematic approach is needed to fine-tune the microbiome ecosystem. To this end, we built a disease-centric signed microbe-microbe interaction network which accurately predicts the pathogenic or commensal effect of microbe on human health. Based on annotated and predicted pathogens and commensal species, we performed a systematic survey on therapeutic space and target landscape of existing drugs for modulating the microbiome ecosystem. Enrichment analysis on potential microbe-targeting drugs shows that drugs for diabetes could be repurposed to maintain the healthy state of microbiome. Furthermore, periplasmic and cellular outer membrane proteins are overrepresented in the potential drug targets of pathogenic-microbes, but not in proteins that perturb commensal-microbes. Our study may open a new avenue for the small molecule drug discovery of microbiome.

The impact of molecular biology on drug discovery

2006 ◽  
Vol 34 (2) ◽  
pp. 313-316 ◽  
Author(s):  
G.P. Belfield ◽  
S.J. Delaney
Keyword(s):  
Drug Discovery ◽  
Molecular Biology ◽  
Clinical Efficacy ◽  
Drug Targets ◽  
Safety Data ◽  
Vital Role ◽  
Drug Discovery And Development ◽  
New Drug ◽  
Whole Process ◽  
The Impact

The discipline of molecular biology has become increasingly important in recent times for the process of drug discovery. We describe the impact of molecular biology across the whole process of drug discovery and development, including (i) the identification and validation of new drug targets, (ii) the development of molecular screens to find new candidate drugs, and (iii) the generation of safety data and competences leading to enhanced clinical efficacy. We also speculate on emerging developments in drug discovery where it seems likely that molecular biology will play an even more vital role in the generation of future therapies.

scholarly journals Conference 2015: Drug Discovery and Development in the Post Genomic Era. An international symposium held jointly by CSPS and CC-CRS, May 26-28, 2015, Toronto, ON, Canada

2015 ◽  
Vol 18 (3) ◽  
pp. 1
Author(s):  
Beverley Berekoff
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
New Technologies ◽  
Pharmaceutical Sciences ◽  
Drug Discovery And Development ◽  
University Of Toronto ◽  
Genome Wide ◽  
Lifetime Achievement ◽  
New Methodologies ◽  
University Of Manitoba

Plenaries and Special Presentations:Shana Kelley, University of Toronto:  "New Technologies for Ultrasensitive Analysis of Clinically-relevant Biomolecules"Richard Hargreaves, BIOGEN IDEC:  "Imaging in CNS Drug Discovery and Development"Roger Williams:  CSPS Lifetime Achievement Award - "0.5 X 102:  Looking Back and Forward"Neal Davies, University of Manitoba:  CSPS Award of Leadership in Canadian Pharmaceutical Sciences - "30 Years of Coffee, Beer and Serendipity in Pharmacy Research"Conference Sessions:Special CSPS Session: The Future of Pharmaceutical Sciences1. The Evolving Business of Pharmaceuticals2. Analysis of Peptide and Protein Drug Targets by LC/MS/MS3. Mucosal Drug Delivery4. New Methodologies of Genome Wide Target Validation5. Regulatory Updates and Developments6. Antibody-based Therapeutics7. Imaging in Drug Delivery8. Nuclear Receptors in Drug Discovery9. IV-IVC Modeling and Simulation as a Tool to Facilitate Drug Development and Marketing10. Pharmacogenomics in Drug Development11. Bioavailability of Novel Dosage Forms

scholarly journals Academic Discovery of Anticancer Drugs: Historic and Future Perspectives

2019 ◽  
Vol 3 (1) ◽  
pp. 385-408 ◽  
Author(s):  
Alessandro Carugo ◽  
Giulio F. Draetta
Keyword(s):  
Drug Discovery ◽  
Anticancer Drug ◽  
Cancer Biology ◽  
Drug Targets ◽  
Nonprofit Sector ◽  
Critical Issue ◽  
Drug Discovery And Development ◽  
New Horizons ◽  
Innovation Research ◽  
History Of

The identification and prosecution of meritorious anticancer drug targets and the discovery of clinical candidates represent an extraordinarily time- and resource-intensive process, and the current failure rate of late-stage drugs is a critical issue that must be addressed. Relationships between academia and industry in drug discovery and development have continued to change over time as a result of technical and financial challenges and, most importantly, to the objective of translating impactful scientific discoveries into clinical opportunities. This Golden Age of anticancer drug discovery features an increased appreciation for the high-risk, high-innovation research conducted in the nonprofit sector, with the goals of infusing commercial drug development with intellectual capital and curating portfolios that are financially tenable and clinically meaningful. In this review, we discuss the history of academic-industry interactions in the context of antidrug discovery and offer a view of where these interactions are likely headed as we continue to reach new horizons in our understanding of the immense complexities of cancer biology.

Schizophrenia drug discovery and development in an evolving era: Are new drug targets fulfilling expectations?

2015 ◽  
Vol 29 (2) ◽  
pp. 230-238 ◽  
Author(s):  
John Dunlop ◽  
Nicholas J Brandon
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Negative Symptoms ◽  
Metabotropic Glutamate Receptor ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Therapeutic Benefit ◽  
Receptor Subtype ◽  
Drug Discovery And Development ◽  
Alpha7 Nicotinic Acetylcholine Receptor

Current therapeutics for schizophrenia, the typical and atypical antipsychotic class of drugs, derive their therapeutic benefit predominantly by antagonism of the dopamine D2 receptor subtype and have robust clinical benefit on positive symptoms of the disease with limited to no impact on negative symptoms and cognitive impairment. Driven by these therapeutic limitations of current treatments and the recognition that transmitter systems beyond the dopaminergic system in particular glutamatergic transmission contribute to the etiology of schizophrenia significant recent efforts have focused on the discovery and development of novel treatments for schizophrenia with mechanisms of action that are distinct from current drugs. Specifically, compounds selectively targeting the metabotropic glutamate receptor 2/3 subtype, phosphodiesterase subtype 10, glycine transporter subtype 1 and the alpha7 nicotinic acetylcholine receptor have been the subject of intense drug discovery and development efforts. Here we review recent clinical experience with the most advanced drug candidates targeting each of these novel mechanisms and discuss whether these new agents are living up to expectations.

scholarly journals Mapping the SARS-CoV-2–Host Protein–Protein Interactome by Affinity Purification Mass Spectrometry and Proximity-Dependent Biotin Labeling: A Rational and Straightforward Route to Discover Host-Directed Anti-SARS-CoV-2 Therapeutics

2021 ◽  
Vol 22 (2) ◽  
pp. 532
Author(s):  
Rosa Terracciano ◽  
Mariaimmacolata Preianò ◽  
Annalisa Fregola ◽  
Corrado Pelaia ◽  
Tiziana Montalcini ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Drug Discovery ◽  
Protein Interactions ◽  
Drug Targets ◽  
Affinity Purification ◽  
Drug Repurposing ◽  
Host Protein ◽  
Host Cells ◽  
Traditional Drug ◽  
Approved Drugs

Protein–protein interactions (PPIs) are the vital engine of cellular machinery. After virus entry in host cells the global organization of the viral life cycle is strongly regulated by the formation of virus-host protein interactions. With the advent of high-throughput -omics platforms, the mirage to obtain a “high resolution” view of virus–host interactions has come true. In fact, the rapidly expanding approaches of mass spectrometry (MS)-based proteomics in the study of PPIs provide efficient tools to identify a significant number of potential drug targets. Generation of PPIs maps by affinity purification-MS and by the more recent proximity labeling-MS may help to uncover cellular processes hijacked and/or altered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), providing promising therapeutic targets. The possibility to further validate putative key targets from high-confidence interactions between viral bait and host protein through follow-up MS-based multi-omics experiments offers an unprecedented opportunity in the drug discovery pipeline. In particular, drug repurposing, making use of already existing approved drugs directly targeting these identified and validated host interactors, might shorten the time and reduce the costs in comparison to the traditional drug discovery process. This route might be promising for finding effective antiviral therapeutic options providing a turning point in the fight against the coronavirus disease-2019 (COVID-19) outbreak.

Proteomics-based Anticancer Drug Discovery and Development

2002 ◽  
Vol 1 (4) ◽  
pp. 231-236 ◽  
Author(s):  
K. K. Jain
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Protein Structure Determination ◽  
Protein Microarrays ◽  
Cancer Drug ◽  
Drug Discovery And Development ◽  
Cancer Drug Discovery ◽  
Laser Capture ◽  
Personalized Medicines ◽  
Important Drug

Proteins are important targets for drug discovery and this applied to cancer as well because there is a defect in the protein machinery of the cell in malignancy. Proteomic technologies are now being integrated with genomic approaches for cancer drug discovery and target validation. Among the large number of proteomic technologies available for this purpose, the most important ones are 3-D protein structure determination, protein microarrays, laser capture microdissection and study of protein-protein and protein-drug interactions. Cancer biomarkers and several cell pathways are important drug targets. Several companies are involved in using proteomic technologies for drug discovery. Finally, proteomic approaches will play an important role in the discovery and development of personalized medicines.

From Target Identification to Drug Development in Space: Using the Microgravity Assist

2020 ◽  
Vol 17 (1) ◽  
pp. 45-56 ◽  
Author(s):  
Martin Braddock
Keyword(s):  
Drug Discovery ◽  
Drug Development ◽  
Drug Targets ◽  
Space Shuttle ◽  
Target Identification ◽  
Space Station ◽  
Space Environment ◽  
Drug Discovery And Development ◽  
Unique Nature ◽  
Microarray Analyses

The unique nature of microgravity encountered in space provides an opportunity for drug discovery and development that cannot be replicated on Earth. From the production of superior protein crystals to the identification and validation of new drug targets to microarray analyses of transcripts attenuated by microgravity, there are numerous examples which demonstrate the benefit of exploiting the space environment. Moreover, studies conducted on Space Shuttle missions, the International Space Station and other craft have had a direct benefit for drug development programmes such as those directed against reducing bone and muscle loss or increasing bone formation. This review will highlight advances made in both drug discovery and development and offer some future insight into how drug discovery and associated technologies may be further advanced using the microgravity assist.

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