The alternative NF-κB pathway from biochemistry to biology: Pitfalls and promises for future drug development

2006 ◽  
Vol 72 (9) ◽  
pp. 1161-1179 ◽  
Author(s):  
Emmanuel Dejardin
Keyword(s):  
Drug Development ◽  
Future Drug

Positron Emission Tomography for Future Drug Development

2011 ◽  
Vol 1 (2) ◽  
pp. 137-151
Author(s):  
Ryogo Minamimoto ◽  
Chumpol Theeraladanon ◽  
Akiko Suzuki ◽  
Tomio Inoue
Keyword(s):  
Positron Emission Tomography ◽  
Drug Development ◽  
Emission Tomography ◽  
Positron Emission ◽  
Future Drug

scholarly journals Multiscale simulations examining glycan shield effects on drug binding to influenza neuraminidase

2020 ◽  
Author(s):  
Christian Seitz ◽  
Lorenzo Casalino ◽  
Robert Konecny ◽  
Gary Huber ◽  
Rommie E. Amaro ◽  
...  
Keyword(s):  
Drug Development ◽  
Ligand Binding ◽  
Binding Site ◽  
Brownian Dynamics ◽  
Drug Binding ◽  
Binding Mechanism ◽  
Drug Effectiveness ◽  
Future Drug ◽  
Dynamics Simulations ◽  
Inhibit Antibody

AbstractInfluenza neuraminidase is an important drug target. Glycans are present on neuraminidase, and are generally considered to inhibit antibody binding via their glycan shield. In this work we studied the effect of glycans on the binding kinetics of antiviral drugs to the influenza neuraminidase. We created all-atom in silico systems of influenza neuraminidase with experimentally-derived glycoprofiles consisting of four systems with different glycan conformations and one system without glycans. Using Brownian dynamics simulations, we observe a two- to eight-fold decrease in the rate of ligand binding to the primary binding site of neuraminidase due to the presence of glycans. These glycans are capable of covering much of the surface area of neuraminidase, and the ligand binding inhibition is derived from glycans sterically occluding the primary binding site on a neighboring monomer. Our work also indicates that drugs preferentially bind to the primary binding site (i.e. the active site) over the secondary binding site, and we propose a binding mechanism illustrating this. These results help illuminate the complex interplay between glycans and ligand binding on the influenza membrane protein neuraminidase.Statement of SignificanceThe influenza glycoprotein neuraminidase is the target for three FDA-approved influenza drugs in the US. However, drug resistance and low drug effectiveness merits further drug development towards neuraminidase, which is hindered by our limited understanding of glycan effects on ligand binding. Generally, drug developers do not include glycans in their development pipelines. Here, we show that even though glycans can reduce drug binding towards neuraminidase, we recommend future drug development work to focus on strong binders with a long lifetime. Furthermore, we examine the binding competition between the primary and secondary binding sites on neuraminidase, leading us to propose a new, to the best of our knowledge, multivalent binding mechanism.

scholarly journals Recent advances in imaging and understanding interstitial cystitis

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1771 ◽  
Author(s):  
Pradeep Tyagi ◽  
Chan-Hong Moon ◽  
Joseph Janicki ◽  
Jonathan Kaufman ◽  
Michael Chancellor ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Drug Development ◽  
Interstitial Cystitis ◽  
Pain Syndrome ◽  
Bladder Pain Syndrome ◽  
Resonance Imaging ◽  
Bladder Pain ◽  
Prevalence Estimates ◽  
Recent Developments ◽  
Future Drug

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition associated with intense pelvic pain and bladder storage symptoms. Since diagnosis is difficult, prevalence estimates vary with the methodology used. There is also a lack of proven imaging tools and biomarkers to assist in differentiation of IC/BPS from other urinary disorders (overactive bladder, vulvodynia, endometriosis, and prostatitis). Current uncertainty regarding the etiology and pathology of IC/BPS ultimately impacts its timely and successful treatment, as well as hampers future drug development. This review will cover recent developments in imaging methods, such as magnetic resonance imaging, that advance the understanding of IC/BPS and guide drug development.

scholarly journals Trypanosoma brucei Homologue of Regulator of Ribosome Synthesis 1 (Rrs1) Has Direct Interactions with Essential Trypanosome-Specific Proteins

mSphere ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Daniel Jaremko ◽  
Martin Ciganda ◽  
Noreen Williams
Keyword(s):  
Drug Development ◽  
Trypanosoma Brucei ◽  
Ribosome Biogenesis ◽  
5S Rrna ◽  
Content Type ◽  
Animal African Trypanosomiasis ◽  
Rnp Complex ◽  
Future Drug ◽  
Specific Proteins ◽  
Additional Member

ABSTRACT Studies in eukaryotic ribosome biogenesis have largely been performed in yeast, where they have described a highly complex process involving numerous protein and RNA components. Due to the complexity and crucial nature of this process, a number of checkpoints are necessary to ensure that only properly assembled ribosomes are released into the cytoplasm. Assembly of the 5S ribonucleoprotein (RNP) complex is one of these checkpoints for late-stage 60S subunit maturation. Studies in Saccharomyces cerevisiae have identified the 5S rRNA and four proteins, L5, L11, Rpf2, and Rrs1, as comprising the ribosome-associated 5S RNP. Work from our laboratory has shown that in the eukaryotic pathogen Trypanosoma brucei, the 5S RNP includes trypanosome-specific proteins P34/P37, as well as homologues of L5, Rpf2, and 5S rRNA. In this study, we examine a homologue of Rrs1 and identify it as an additional member of the T. brucei 5S RNP. Using RNA interference, we show that TbRrs1 is essential for the survival of T. brucei and has an important role in ribosome subunit formation and, together with TbRpf2, plays a role in 25/28S and 5.8S rRNA processing. We further show that TbRrs1 is a member of the T. brucei 5S RNP through the identification of novel direct interactions with P34/P37 and 5S rRNA as well as with TbL5 and TbRpf2. These unique characteristics of TbRrs1 highlight the importance of studying ribosome biogenesis in the context of diverse organisms and identify interactions that could be targeted for future drug development. IMPORTANCE Trypanosoma brucei is a parasite responsible for human and animal African trypanosomiasis. Current treatments for these diseases have numerous problems, and the development of novel chemotherapeutics can be achieved by identifying targets that are parasite specific and part of essential processes. Ribosome biogenesis is the process of generating translation-competent ribosomes and is critical for survival in all organisms. Work from our laboratory has shown that the formation of the 5S RNP, a crucial checkpoint in ribosome biogenesis, requires trypanosome-specific proteins P34/P37 and homologues of Rpf2 and L5 which possess parasite-specific characteristics. In this study, we characterize TbRrs1, an additional member of the T. brucei 5S RNP, and show that it is essential for parasite survival and has unique interactions with P34/P37 and 5S rRNA. This expands our understanding of the 5S RNP in T. brucei and identifies new targets for future drug development.

scholarly journals A machine learning and network framework to discover new indications for small molecules

2019 ◽  
Author(s):  
Coryandar Gilvary ◽  
Jamal Elkhader ◽  
Neel Madhukar ◽  
Claire Henchcliffe ◽  
Marcus D. Goncalves ◽  
...  
Keyword(s):  
Drug Development ◽  
Small Molecules ◽  
Kinase Inhibitor ◽  
Drug Repurposing ◽  
Chemical Information ◽  
Respiratory Illnesses ◽  
Drug Classes ◽  
Future Drug ◽  
Drug Similarity

AbstractDrug repurposing, identifying novel indications for drugs, bypasses common drug development pitfalls to ultimately deliver therapies to patients faster. However, most repurposing discoveries have been led by anecdotal observations (e.g. Viagra) or experimental-based repurposing screens, which are costly, time-consuming, and imprecise. Recently, more systematic computational approaches have been proposed, however these rely on utilizing the information from the diseases a drug is already approved to treat. This inherently limits the algorithms, making them unusable for investigational molecules. Here, we present a computational approach to drug repurposing, CATNIP, that requires only biological and chemical information of a molecule. CATNIP is trained with 2,576 diverse small molecules and uses 16 different drug similarity features, such as structural, target, or pathway based similarity. This model obtains significant predictive power (AUC = 0.841). Using our model, we created a repurposing network to identify broad scale repurposing opportunities between drug types. By exploiting this network, we identified literature-supported repurposing candidates, such as the use of systemic hormonal preparations for the treatment of respiratory illnesses. Furthermore, we demonstrated that we can use our approach to identify novel uses for defined drug classes. We found that adrenergic uptake inhibitors, specifically amitriptyline and trimipramine, could be potential therapies for Parkinson’s disease. Additionally, using CATNIP, we predicted the kinase inhibitor, vandetanib, as a possible treatment for Type 2 Diabetes. Overall, this systematic approach to drug repurposing lays the groundwork to streamline future drug development efforts.

Mannich Bases: Centrality in Cytotoxic Drug Design

2021 ◽  
Vol 18 ◽  
Author(s):  
Neha V. Bhilare ◽  
Vinayak S. Marulkar ◽  
Pramodkumar J. Shirote ◽  
Shailaja A. Dombe ◽  
Vilas J. Pise ◽  
...  
Keyword(s):  
Drug Design ◽  
Drug Development ◽  
Cell Lines ◽  
Mannich Bases ◽  
Cytotoxic Agents ◽  
Structure Activity ◽  
Anti Cancer ◽  
Methods Of Synthesis ◽  
Future Drug ◽  
Clinical Conditions

: Mannich bases identified by Professor Carl Mannich have been the most extensively explored scaffolds for more than 100 years now. The versatile biological roles that they play have promoted their applications in many clinical conditions. The present review highlights the application of Mannich bases as cytotoxic agents, categorizing them into synthetic, semisynthetic and prodrugs classes and gives an exhaustive account of the work reported in the last two decades. The methods of synthesis of these cytotoxic agents, their anti-cancer potential in various cell lines and promising leads for future drug development have also been discussed. Structure-activity relationships along with the targets on which these cytotoxic Mannich bases act have been included as well.

scholarly journals TheMycobacterium tuberculosisFAS-II condensing enzymes: their role in mycolic acid biosynthesis, acid-fastness, pathogenesis and in future drug development

2007 ◽  
Vol 64 (6) ◽  
pp. 1442-1454 ◽  
Author(s):  
Apoorva Bhatt ◽  
Virginie Molle ◽  
Gurdyal S. Besra ◽  
William R. Jacobs ◽  
Laurent Kremer
Keyword(s):  
Drug Development ◽  
Mycolic Acid ◽  
Acid Biosynthesis ◽  
Future Drug
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