scholarly journals A Primary Evaluation of Potential Small‐Molecule Inhibitors of the Astacin Metalloproteinase Ovastacin, a Novel Drug Target in Female Infertility Treatment

ChemMedChem ◽  
2020 ◽  
Vol 15 (16) ◽  
pp. 1499-1504 ◽  
Author(s):  
Hagen Körschgen ◽  
Christian Jäger ◽  
Kathrin Tan ◽  
Mirko Buchholz ◽  
Walter Stöcker ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Infertility Treatment ◽  
Female Infertility ◽  
Primary Evaluation ◽  
Novel Drug

scholarly journals Small Molecule Inhibitors of Influenza Virus Entry

2021 ◽  
Vol 14 (6) ◽  
pp. 587
Author(s):  
Zhaoyu Chen ◽  
Qinghua Cui ◽  
Michael Caffrey ◽  
Lijun Rong ◽  
Ruikun Du
Keyword(s):  
Influenza Virus ◽  
Membrane Fusion ◽  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Virus Entry ◽  
Critical Role ◽  
Structural Basis ◽  
Future Directions ◽  
The Past

Hemagglutinin (HA) plays a critical role during influenza virus receptor binding and subsequent membrane fusion process, thus HA has become a promising drug target. For the past several decades, we and other researchers have discovered a series of HA inhibitors mainly targeting its fusion machinery. In this review, we summarize the advances in HA-targeted development of small molecule inhibitors. Moreover, we discuss the structural basis and mode of action of these inhibitors, and speculate upon future directions toward more potent inhibitors of membrane fusion and potential anti-influenza drugs.

scholarly journals Small Molecule Inhibitors of HSF1-Activated Pathways as Potential Next-Generation Anticancer Therapeutics

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2757 ◽  
Author(s):  
Chiranjeev Sharma ◽  
Young Seo
Keyword(s):  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Chemotherapeutic Agents ◽  
Heat Shock Factor 1 ◽  
Next Generation ◽  
Anticancer Activities ◽  
Cancer Cell Growth ◽  
Survival Studies ◽  
New Chemotherapeutic Agents

Targeted therapy is an emerging paradigm in the development of next-generation anticancer drugs. Heat shock factor 1 (HSF1) has been identified as a promising drug target because it regulates several pathways responsible for cancer cell growth, metastasis, and survival. Studies have clearly demonstrated that HSF1 is an effective drug target. Herein, we provide a concise yet comprehensive and integrated overview of progress in developing small molecule inhibitors of HSF1 as next-generation anticancer chemotherapeutics while critically evaluating their potential and challenges. We believe that this review will provide a better understanding of important concepts helpful for outlining the strategy to develop new chemotherapeutic agents with promising anticancer activities by targeting HSF1.

scholarly journals Primary Evaluation of Potential Small Molecule Inhibitors of the Astacin Metalloproteinase Ovastacin, A Novel Drug Target in Female Infertility Treatment

2019 ◽  
Author(s):  
Hagen Körschgen ◽  
Christian Jäger ◽  
Kathrin Tan ◽  
Mirko Buchholz ◽  
Walter Stöcker ◽  
...  
Keyword(s):  
In Vitro Fertilization ◽  
Infertility Treatment ◽  
Cortical Granule ◽  
Success Rates ◽  
Vitro Fertilization ◽  
Zona Hardening ◽  
Primary Evaluation ◽  
Novel Drug ◽  
Small Molecular Inhibitors

<p>Despite huge progress in hormonal therapy and improved in vitro fertilization methods, the success rates in infertility treatment are still limited. A recently discovered mechanism revealed the interplay between the plasma protein fetuin-B and the cortical granule-based proteinase ovastacin as novel key-mechanism in the regulation of fertilization. Upon sperm-egg fusion, cleavage of a distinct zona pellucida component by ovastacin destroys the sperm receptor, enhances zona robustness and eventually provides a definitive block against polyspermy. An untimely onset of this zona hardening prior to fertilization would consequently result in infertility. Physiologically, this process is controlled by fetuin-B, an endogenous ovastacin inhibitor. Here we aimed at the discovery of small molecular inhibitors of ovastacin that could mimic the effect of fetuin-B. Hence, these compounds could be useful lead structures for the development of specific ovastacin inhibitors that can be utilized in infertility treatment or in vitro fertilization.</p>

scholarly journals Detection of the ATPase Activity of the Molecular Chaperones Hsp90 and Hsp72 Using the Transcreener™ ADP Assay Kit

2010 ◽  
Vol 15 (3) ◽  
pp. 279-286 ◽  
Author(s):  
Martin Rowlands ◽  
Craig McAndrew ◽  
Chris Prodromou ◽  
Laurence Pearl ◽  
Andrew Kalusa ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Atpase Activity ◽  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Heat Shock Protein 90 ◽  
Cancer Drug ◽  
Cell Growth Inhibition ◽  
Client Proteins

The molecular chaperone heat shock protein 90 (Hsp90) is required for the correct folding and stability of a number of client proteins that are important for the growth and maintenance of cancer cells. Heat shock protein 72 (Hsp72), a co-chaperone of Hsp90, is also emerging as an attractive cancer drug target. Both proteins bind and hydrolyze adenosine triphosphate (ATP), and ATPase activity is essential for their function. Inhibition of Hsp90 ATPase activity leads to the degradation of client proteins, resulting in cell growth inhibition and apoptosis. Several small-molecule inhibitors of the ATPase activity of Hsp90 have been described and are currently being evaluated clinically for the treatment of cancer. A number of methods for the measurement of ATPase activity have been previously used, but not all of these are ideally suited to screening cascades in drug discovery projects. The authors have evaluated the use of commercial reagents (Transcreener™ ADP) for the measurement of ATPase activity of both yeast and human Hsp90 (ATP Km ~500 µM) and human Hsp72 (ATP Km ~1 µM). The low ATPase activity of human Hsp90 and its stimulation by the co-chaperone Aha1 was measured with ease using reduced incubation times, generating robust data (Z′ = 0.75). The potency of several small-molecule inhibitors of both Hsp90 and Hsp72 was determined using the Transcreener™ reagents and compared well to that determined using other assay formats.

scholarly journals A pharmacophore model for SARS-CoV-2 3CLpro small molecule inhibitors and in vitro experimental validation of computationally screened inhibitors

2021 ◽  
Author(s):  
Enrico Glaab ◽  
Ganesh Babu Manoharan ◽  
Daniel Abankwa
Keyword(s):  
Machine Learning ◽  
Molecular Dynamics ◽  
Virtual Screening ◽  
Small Molecule ◽  
Drug Target ◽  
Experimental Validation ◽  
Small Molecule Inhibitors ◽  
Pharmacophore Model ◽  
Computational Screening

AbstractAmong the biomedical efforts in response to the current coronavirus (COVID-19) pandemic, pharmacological strategies to reduce viral load in patients with severe forms of the disease are being studied intensively. One of the main drug target proteins proposed so far is the SARS-CoV-2 viral protease 3CLpro (also called Mpro), an essential component for viral replication. Ongoing ligand- and receptor-based computational screening efforts would be facilitated by an improved understanding of the electrostatic, hydrophobic and steric features that characterize small molecule inhibitors binding stably to 3CLpro, as well as by an extended collection of known binders.Here, we present combined virtual screening, molecular dynamics simulation, machine learning and in vitro experimental validation analyses which have led to the identification of small molecule inhibitors of 3CLpro with micromolar activity, and to a pharmacophore model that describes functional chemical groups associated with the molecular recognition of ligands by the 3CLpro binding pocket. Experimentally validated inhibitors using a ligand activity assay include natural compounds with available prior knowledge on safety and bioavailability properties, such as the natural compound rottlerin (IC50 = 37 μM), and synthetic compounds previously not characterized (e.g. compound CID 46897844, IC50 = 31 μM). In combination with the developed pharmacophore model, these and other confirmed 3CLpro inhibitors may provide a basis for further similarity-based screening in independent compound databases and structural design optimization efforts, to identify 3CLpro ligands with improved potency and selectivity.Overall, this study suggests that the integration of virtual screening, molecular dynamics simulations and machine learning can facilitate 3CLpro-targeted small molecule screening investigations. Different receptor-, ligand- and machine learning-based screening strategies provided complementary information, helping to increase the number and diversity of identified active compounds. Finally, the resulting pharmacophore model and experimentally validated small molecule inhibitors for 3CLpro provide resources to support follow-up computational screening efforts for this drug target.

scholarly journals Primary Evaluation of Potential Small Molecule Inhibitors of the Astacin Metalloproteinase Ovastacin, A Novel Drug Target in Female Infertility Treatment

2019 ◽  
Author(s):  
Hagen Körschgen ◽  
Christian Jäger ◽  
Kathrin Tan ◽  
Mirko Buchholz ◽  
Walter Stöcker ◽  
...  
Keyword(s):  
In Vitro Fertilization ◽  
Infertility Treatment ◽  
Cortical Granule ◽  
Success Rates ◽  
Vitro Fertilization ◽  
Zona Hardening ◽  
Primary Evaluation ◽  
Novel Drug ◽  
Small Molecular Inhibitors

<p>Despite huge progress in hormonal therapy and improved in vitro fertilization methods, the success rates in infertility treatment are still limited. A recently discovered mechanism revealed the interplay between the plasma protein fetuin-B and the cortical granule-based proteinase ovastacin as novel key-mechanism in the regulation of fertilization. Upon sperm-egg fusion, cleavage of a distinct zona pellucida component by ovastacin destroys the sperm receptor, enhances zona robustness and eventually provides a definitive block against polyspermy. An untimely onset of this zona hardening prior to fertilization would consequently result in infertility. Physiologically, this process is controlled by fetuin-B, an endogenous ovastacin inhibitor. Here we aimed at the discovery of small molecular inhibitors of ovastacin that could mimic the effect of fetuin-B. Hence, these compounds could be useful lead structures for the development of specific ovastacin inhibitors that can be utilized in infertility treatment or in vitro fertilization.</p>

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