Photoaffinity Labelling Strategies for Mapping the Small Molecule-Protein Interactome

2021 ◽  
Author(s):  
Nikolas R Burton ◽  
Phillip Kim ◽  
Keriann M. Backus
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Atomic Level ◽  
Photoaffinity Labelling ◽  
Protein Interactome ◽  
Approved Drugs ◽  
Fda Approved Drugs

Nearly all FDA approved drugs and bioactive small molecules exert their effects by binding to and modulating proteins. Consequently, understanding how small molecules interact with proteins at an atomic level...

scholarly journals A New Big-Data Paradigm for Target Identification and Drug Discovery

2017 ◽  
Author(s):  
Neel S. Madhukar ◽  
Prashant K. Khade ◽  
Linda Huang ◽  
Kaitlyn Gayvert ◽  
Giuseppe Galletti ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Clinical Application ◽  
Small Molecule ◽  
Target Identification ◽  
Clinical Development ◽  
Data Types ◽  
Public Data ◽  
Drug Target Identification ◽  
Approved Drugs

AbstractDrug target identification is one of the most important aspects of pre-clinical development yet it is also among the most complex, labor-intensive, and costly. This represents a major issue, as lack of proper target identification can be detrimental in determining the clinical application of a bioactive small molecule. To improve target identification, we developed BANDIT, a novel paradigm that integrates multiple data types within a Bayesian machine-learning framework to predict the targets and mechanisms for small molecules with unprecedented accuracy and versatility. Using only public data BANDIT achieved an accuracy of approximately 90% over 2000 different small molecules – substantially better than any other published target identification platform. We applied BANDIT to a library of small molecules with no known targets and generated ∼4,000 novel molecule-target predictions. From this set we identified and experimentally validated a set of novel microtubule inhibitors, including three with activity on cancer cells resistant to clinically used anti-microtubule therapies. We next applied BANDIT to ONC201 – an active anti- cancer small molecule in clinical development – whose target has remained elusive since its discovery in 2009. BANDIT identified dopamine receptor 2 as the unexpected target of ONC201, a prediction that we experimentally validated. Not only does this open the door for clinical trials focused on target-based selection of patient populations, but it also represents a novel way to target GPCRs in cancer. Additionally, BANDIT identified previously undocumented connections between approved drugs with disparate indications, shedding light onto previously unexplained clinical observations and suggesting new uses of marketed drugs. Overall, BANDIT represents an efficient and highly accurate platform that can be used as a resource to accelerate drug discovery and direct the clinical application of small molecule therapeutics with improved precision.

scholarly journals Emerging Therapeutic Modalities against COVID-19

2020 ◽  
Vol 13 (8) ◽  
pp. 188 ◽  
Author(s):  
Shipra Malik ◽  
Anisha Gupta ◽  
Xiaobo Zhong ◽  
Theodore P. Rasmussen ◽  
Jose E. Manautou ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Small Molecules ◽  
Therapeutic Interventions ◽  
Pharmaceutical Companies ◽  
The Novel ◽  
Comprehensive Overview ◽  
Therapeutic Modalities ◽  
Academic Researchers ◽  
Approved Drugs ◽  
Fda Approved Drugs

The novel SARS-CoV-2 virus has quickly spread worldwide, bringing the whole world as well as the economy to a standstill. As the world is struggling to minimize the transmission of this devastating disease, several strategies are being actively deployed to develop therapeutic interventions. Pharmaceutical companies and academic researchers are relentlessly working to investigate experimental, repurposed or FDA-approved drugs on a compassionate basis and novel biologics for SARS-CoV-2 prophylaxis and treatment. Presently, a tremendous surge of COVID-19 clinical trials are advancing through different stages. Among currently registered clinical efforts, ~86% are centered on testing small molecules or antibodies either alone or in combination with immunomodulators. The rest ~14% of clinical efforts are aimed at evaluating vaccines and convalescent plasma-based therapies to mitigate the disease's symptoms. This review provides a comprehensive overview of current therapeutic modalities being evaluated against SARS-CoV-2 virus in clinical trials.

scholarly journals Computational Search for Potential COVID-19 Drugs from FDA-Approved Drugs and Small Molecules of Natural Origin Identifies Several Anti-Virals and Plant Products

2020 ◽  
Author(s):  
Abhishek Sharma ◽  
Vikas Tiwari ◽  
Ramanathan Sowdhamini
Keyword(s):  
Molecular Dynamics ◽  
Small Molecules ◽  
Natural Origin ◽  
Drug Identification ◽  
The World ◽  
Computational Search ◽  
Simple Molecules ◽  
Human Coronaviruses ◽  
Approved Drugs ◽  
Fda Approved Drugs

<div>The world is facing COVID-19 pandemic at the present time, for which mild symptoms include fever and dry cough. In severe cases it could lead to pneumonia and ultimately death in some instances. The pathogen, SARS-CoV-2, is one of the human coronaviruses which was identified to infect humans first in December 2019. We have interrogated the capacity to repurpose around 2300 FDA-approved drugs and more than 300,000 small molecules of natural origin towards drug identification through virtual screening and molecular dynamics. Interestingly, we observed simple molecules like lactose, previously known anti-virals and few secondary metabolites of plants as promising hits.</div><div><br></div><div></div>

Drug discovery of small molecules for the treatment of COVID-19: A review on clinical studies

2020 ◽  
Vol 21 ◽  
Author(s):  
Bharat Goel ◽  
Nivedita Bhardwaj ◽  
Nancy Tripathi ◽  
Shreyans K. Jain
Keyword(s):  
Small Molecules ◽  
Clinical Studies ◽  
Ebola Virus ◽  
Viral Infections ◽  
New Drugs ◽  
Zoonotic Virus ◽  
Traditional Medicines ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Fda Approved Drugs

: Recently, a sudden outbreak of novel coronavirus disease (COVID-19) was caused by a zoonotic virus known as severe acute respiratory syndrome coronavirus (SARS-CoV-2). It has caused pandemic situations around the globe and affecting the lives of millions of people. So far, no drug has been approved for the treatment of SARS-CoV-2 infected patients. As of now, more than 1000 clinical trials are going on for repurposing of FDA approved drugs and for evaluating the safety & efficiency of experimental antiviral molecules to combat COVID-19. Since the development of new drugs may require months to years to reach the market, this review focusses on the potentials of existing small molecule FDA approved drugs and the molecules already in the clinical pipeline against viral infections like HIV, hepatitis B, Ebola virus, and other viruses of coronavirus family (SARS-CoV and MERS-CoV). The review also discusses the natural products and traditional medicines in clinical studies against COVID-19. Currently, 1978 studies are active, 143 completed and 4 posted results (as on June 13, 2020) on clinicaltrials.gov.

scholarly journals Ceftazidime Is a Potential Drug to Inhibit SARS-CoV-2 Infection In Vitro by Blocking Spike Protein-ACE2 Interaction

2020 ◽  
Author(s):  
ChangDong Lin ◽  
Yue Li ◽  
MengYa Yuan ◽  
MengWen Huang ◽  
Cui Liu ◽  
...  
Keyword(s):  
Small Molecules ◽  
High Throughput Screening ◽  
Inhibitory Concentration ◽  
Cell Entry ◽  
Host Cells ◽  
First Line ◽  
Angiotensin Converting Enzyme 2 ◽  
Approved Drugs ◽  
Fda Approved Drugs

SUMMARYCoronavirus Disease 2019 (COVID-19) spreads globally as a sever pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cell entry of SARS-CoV-2 mainly depends on binding of the viral spike (S) proteins to angiotensin converting enzyme 2 (ACE2) on host cells. Therefore, repurposing of known drugs to inhibit S protein-ACE2 interaction could be a quick way to develop effective therapy for COVID-19. Using a high-throughput screening system to investigate the interaction between spike receptor binding domain (S-RBD) and ACE2 extracellular domain, we screened 3581 FDA-approved drugs and natural small molecules and identified ceftazidime as a potent compound to inhibit S-RBD–ACE2 interaction by binding to S-RBD. In addition to significantly inhibit S-RBD binding to HPAEpiC cells, ceftazidime efficiently prevented SARS-CoV-2 pseudovirus to infect ACE2-expressing 293T cells. The inhibitory concentration (IC50) was 113.2 μM, which is far below the blood concentration (over 300 μM) of ceftazidime in patients when clinically treated with recommended dose. Notably, ceftazidime is a drug clinically used for the treatment of pneumonia with minimal side effects compared with other antiviral drugs. Thus, ceftazidime has both anti-bacterial and anti-SARS-CoV-2 effects, which should be the first-line antibiotics used for the clinical treatment of COVID-19.

Small-molecule kinase inhibitors: an analysis of FDA-approved drugs

2016 ◽  
Vol 21 (1) ◽  
pp. 5-10 ◽  
Author(s):  
Peng Wu ◽  
Thomas E. Nielsen ◽  
Mads H. Clausen
Keyword(s):  
Small Molecule ◽  
Kinase Inhibitors ◽  
Approved Drugs ◽  
Fda Approved Drugs

scholarly journals An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications

2019 ◽  
Author(s):  
Yihui Shi ◽  
Walter Bray ◽  
Alexander J. Smith ◽  
Wei Zhou ◽  
Joy Calaoagan ◽  
...  
Keyword(s):  
Small Molecule ◽  
Exon Skipping ◽  
Mrna Splicing ◽  
Luciferase Reporter ◽  
Antitumor Drugs ◽  
Small Molecule Ligands ◽  
A Cell ◽  
Displacement Assay ◽  
Approved Drugs ◽  
Fda Approved Drugs

ABSTRACTAgents that modulate pre-mRNA splicing are of interest in multiple therapeutic areas, including cancer. We report our recent screening results with the application of a cell-based Triple Exon Skipping Luciferase Reporter (TESLR) using a library that is composed of FDA approved drugs, clinical compounds, and mechanistically characterized tool compounds. Confirmatory assays showed that three clinical antitumor therapeutic candidates (milciclib, PF-3758309 and PF-030871) are potent splicing modulators and that these drugs are, in fact, nanomolar inhibitors of multiple kinases involved in the regulation the spliceosome. We also report the identification of new SF3B1 antagonists (sudemycinol C and E) and show that these antagonists can be used to develop a displacement assay for SF3B1 small molecule ligands. These results further supports the broad potential for the development of agents that target the spliceosome for the treatment of cancer and other diseases, as well as new avenues for chemotherapeutic discovery.

scholarly journals A Compendium of Kinetic Cell Death Modulatory Profiles Identifies Ferroptosis Regulators

2019 ◽  
Author(s):  
Megan Conlon ◽  
Carson Poltorack ◽  
Giovanni C. Forcina ◽  
Alex Wells ◽  
Melodie Mallais ◽  
...  
Keyword(s):  
Cell Death ◽  
Amino Acid ◽  
Small Molecules ◽  
Mtor Inhibitors ◽  
Bioactive Compound ◽  
Time Lapse ◽  
Approved Drugs ◽  
Amino Acid Sensing ◽  
Investigational Agents ◽  
Fda Approved Drugs

AbstractCell death can be executed by regulated apoptotic and non-apoptotic pathways, including the iron-dependent process of ferroptosis. Small molecules are essential tools for studying the regulation of cell death. Using live-cell, time-lapse imaging, and a library of 1,833 small molecules including FDA-approved drugs and investigational agents, we assemble a large compendium of kinetic cell death ‘modulatory profiles’ for inducers of apoptosis and ferroptosis. From this dataset we identified dozens of small molecule inhibitors of ferroptosis, including numerous investigational and FDA-approved drugs with unexpected off-target antioxidant or iron chelating activities. ATP-competitive mechanistic target of rapamycin (mTOR) inhibitors, by contrast, were on-target ferroptosis inhibitors. Further investigation revealed both mTOR-dependent and mTOR-independent mechanisms linking amino acid levels to the regulation of ferroptosis sensitivity in cancer cells. These results highlight widespread bioactive compound pleiotropy and link amino acid sensing to the regulation of ferroptosis.

scholarly journals Molecular basis of small-molecule binding to α-synuclein

2021 ◽  
Author(s):  
Paul Robustelli ◽  
Alain Ibanez-de-Opakua ◽  
Cecily Campbell-Bezat ◽  
Fabrizio Giordanetto ◽  
Stefan Becker ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Rational Design ◽  
Intrinsically Disordered Proteins ◽  
Md Simulations ◽  
Structural Features ◽  
Atomic Level ◽  
Disordered Proteins ◽  
Structure Based Drug Design ◽  
Intrinsically Disordered

AbstractIntrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of their binding to small molecules. Here we present long-timescale, atomic-level molecular dynamics (MD) simulations of monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson’s disease) binding the small-molecule drug fasudil in which the observed protein-ligand interactions were found to be in good agreement with previously reported NMR chemical shift data. In our simulations, fasudil, when bound, favored certain charge-charge and π-stacking interactions near the C terminus of α-synuclein, but tended not to form these interactions simultaneously, rather breaking one of these interactions and forming another nearby (a mechanism we term dynamic shuttling). Further simulations with small molecules chosen to modify these interactions yielded binding affinities and key structural features of binding consistent with subsequent NMR experiments, suggesting the potential for MD-based strategies to facilitate the rational design of small molecules that bind with disordered proteins.

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