scholarly journals Structure-Activity-Relationship and Bioactivity of Neurotrophic trans-Banglene

2021 ◽  
Author(s):  
Khyati Gohil ◽  
M. Zain Kazmi ◽  
Florence Williams
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Signaling Proteins ◽  
Neurotrophic Activity ◽  
Structure Activity ◽  
Cyclohexene Ring ◽  
Pharmacokinetic Properties ◽  
Pkc Inhibitors ◽  
Cis And Trans ◽  
Phenotypic Responses

Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, the pharmacokinetic properties of neurotrophins present challenges to their administration. Therefore, neurotrophic small molecules such as the cis- and trans-banglenes offer attractive alternatives. We describe the synthesis and testing of banglene derivatives and establish a structure-activity response for the banglene family. We demonstrate that (–) trans-banglene is the primarily active enantiomer, and that select modifications on the cyclohexene ring of trans-banglene do not significantly impair its bioactivity. Finally, we demonstrate that (–) trans-banglene potentiation of NGF induced neuritogenesis is unaffected by the presence of these Erk1/2, Akt and Pkc inhibitors. Our structure-activity results also suggest that (–) trans-banglene neurotrophic activity and its potentiation of NGF activity might be distinct unassociated processes.

scholarly journals Structure-Activity Relationship and Bioactivity Studies of Neurotrophic trans-Banglene

2021 ◽  
Author(s):  
Khyati Gohil ◽  
M. Zain Kazmi ◽  
Florence Williams
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Signaling Proteins ◽  
Neurotrophic Activity ◽  
Structure Activity ◽  
Cyclohexene Ring ◽  
Pharmacokinetic Properties ◽  
Pkc Inhibitors ◽  
Cis And Trans ◽  
Phenotypic Responses

Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, the pharmacokinetic properties of neurotrophins present challenges to their administration. Therefore, neurotrophic small molecules such as the cis- and trans-banglenes offer attractive alternatives. We describe the synthesis and testing of banglene derivatives and establish a structure-activity response for the banglene family. We demonstrate that (–) trans-banglene is the primarily active enantiomer, and that select modifications on the cyclohexene ring of trans-banglene do not significantly impair its bioactivity. Finally, we demonstrate that (–) trans-banglene potentiation of NGF induced neuritogenesis is unaffected by the presence of these Erk1/2, Akt and Pkc inhibitors. Our structure-activity results also suggest that (–) trans-banglene neurotrophic activity and its potentiation of NGF activity might be distinct unassociated processes.

scholarly journals Structure-Activity-Relationship and Bioactivity of Neurotrophic trans-Banglene

2021 ◽  
Author(s):  
Khyati Gohil ◽  
M. Zain Kazmi ◽  
Florence Williams
Keyword(s):  
Kinase Inhibitors ◽  
Signaling Proteins ◽  
Structure Activity ◽  
Cyclohexene Ring ◽  
Pharmacokinetic Properties ◽  
Living Organisms ◽  
Neurotrophic Signaling ◽  
Cis And Trans ◽  
The Relationship ◽  
Phenotypic Responses

Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, neurotrophin proteins possess pharmacokinetic properties that present challenges to their administration in living organisms, whether in biomedical studies or as therapeutics. Small molecules such as the cis- and trans-banglenes offer attractive alternatives to activate neurotrophic responses. We describe the synthesis and testing of banglene derivatives to establish a structure-activity response for the banglene family. Notably, during the course of our studies trans-banglene was shown to cause nerve growth factor (NGF)-potentiated neuritogenesis that was markedly stronger than the neuritogenic effects of trans-banglene alone. We demonstrate that only (–) trans-banglene is active, while its (+) enantiomer is not, and further demonstrate that select modifications on the cyclohexene ring of trans-banglene does not impair its bioactivity. Finally, to probe the relationship between (–) trans-banglene’s mechanism of ac-tion and canonical NGF signal transduction pathways, we employed kinase inhibitors targeting Pkc, Akt1/2/3 and Erk1/2, designed to inhibit NGF-induced neurotrophic signaling. Interestingly, (–) trans-banglene potentiation of NGF-induced neuri-togenesis was unaffected by the presence of these kinase inhibitors. Collectively, these results suggest a dual-mode of action for (–) trans-banglene (both neurotrophic alone and strongly potentiating of NGF activity), and an independence of its po-tentiating action on Pkc and Erk1/2 enzymatic activity.

Quantitative Structure Activity Relationship (QSAR) study predicts small molecule binding to RNA structure

2021 ◽  
Author(s):  
Zhengguo Cai ◽  
Martina Zafferani ◽  
Olanrewaju Akande ◽  
Amanda Hargrove
Keyword(s):  
High Resolution ◽  
Small Molecules ◽  
Small Molecule ◽  
Rna Structure ◽  
Quantitative Structure ◽  
Rna Structures ◽  
Qsar Study ◽  
Structure Activity ◽  
Qsar Models ◽  
Hiv 1

The diversity of RNA structural elements and their documented role in human diseases make RNA an attractive therapeutic target. However, progress in drug discovery and development has been hindered by challenges in the determination of high-resolution RNA structures and a limited understanding of the parameters that drive RNA recognition by small molecules, including a lack of validated quantitative structure-activity relationships (QSAR). Herein, we developed QSAR models that quantitatively predict both thermodynamic and kinetic-based binding parameters of small molecules and the HIV-1 TAR model RNA system. A set of small molecules bearing diverse scaffolds was screened against the HIV-1-TAR construct using surface plasmon resonance, which provided the binding kinetics and affinities. The data was then analyzed using multiple linear regression (MLR) combined with feature selection to afford robust models for binding of diverse RNA-targeted scaffolds. The predictivity of the model was validated on untested small molecules. The QSAR models presented herein represent the first application of validated and predictive 2D-QSAR using multiple scaffolds against an RNA target. We expect the workflow to be generally applicable to other RNA structures, ultimately providing essential insight into the small molecule descriptors that drive selective binding interactions and, consequently, providing a platform that can exponentially increase the efficiency of ligand design and optimization without the need for high-resolution RNA structures.

scholarly journals Identification of Small Molecule Modulators of Diguanylate Cyclase by FRET-based High-Throughput-Screening

2018 ◽  
Author(s):  
Matthias Christen ◽  
Cassandra Kamischke ◽  
Hemantha D. Kulasekara ◽  
Kathleen C. Olivas ◽  
Bridget R. Kulasekara ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
High Throughput ◽  
Biofilm Formation ◽  
High Throughput Screening ◽  
Diguanylate Cyclase ◽  
Chronic Infections ◽  
Structure Activity ◽  
Diguanylate Cyclases ◽  
Small Molecule Modulators

The bacterial second messenger cyclic diguanosine monophosphate (c-di-GMP) is a key regulator of cellular motility, the cell cycle, and biofilm formation with its resultant antibiotic tolerance, which may make chronic infections difficult to treat. Therefore, diguanylate cyclases, which regulate the spatiotemporal production of c-di-GMP, may be attractive drug targets to control biofilm formation that is part of chronic infections. In this paper, we present a FRET-based biochemical high-throughput screening approach coupled with detailed structure-activity studies to identify synthetic small molecule modulators of the diguanylate cyclase, DgcA, from Caulobacter crescentus. We identified a set of 7 small molecules that in the low µM range regulate DgcA enzymatic activity. Subsequent structure activity studies on selected scaffolds revealed a remarkable diversity of modulatory behaviors, including slight chemical substitutions that revert the effects from allosteric enzyme inhibition to activation. The compounds identified represent novel chemotypes and are potentially developable into chemical genetic tools for the dissection of c-di-GMP signaling networks and alteration of c-di-GMP associated phenotypes. In sum, our studies underline the importance for detailed mechanism of action studies for inhibitors of c-di-GMP signaling and demonstrate the complex interplay between synthetic small molecules and the regulatory mechanisms that control the activity of diguanylate cyclases.

ChemInformatics Model Explorer (CIME): Exploratory analysis of chemical model explanations

2021 ◽  
Author(s):  
Christina Humer ◽  
Henry Heberle ◽  
Floriane Montanari ◽  
Thomas Wolf ◽  
Florian Huber ◽  
...  
Keyword(s):  
Machine Learning ◽  
Small Molecules ◽  
Small Molecule ◽  
Daily Basis ◽  
Data Sets ◽  
Visualization Tool ◽  
Web Based ◽  
Pharmacokinetic Properties ◽  
Opening Up ◽  
Web Based System

The introduction of machine learning to small molecule research – an inherently multidisciplinary field in which chemists and data scientists combine their expertise and collaborate – has been vital to making screening processes more efficient. In recent years, numerous models that predict pharmacokinetic properties or bioactivity have been published, and these are used on a daily basis by chemists to make decisions and prioritize ideas. The emerging field of explainable artificial intelligence is opening up new possibilities for understanding the reasoning that underlies a model. In small molecule research, this means relating contributions of substructures of compounds to their predicted properties, which in turn also allows the areas of the compounds that have the greatest influence on the outcome to be identified. However, there is no interactive visualization tool that facilitates such interdisciplinary collaborations towards interpretability of machine learning models for small molecules. To fill this gap, we present CIME (ChemInformatics Model Explorer), an interactive web-based system that allows users to inspect chemical data sets, visualize model explanations, compare interpretability techniques, and explore subgroups of compounds. The tool is model-agnostic and can be run on a server or a workstation.

Trypanocidal Structure-Activity Relationshipfor Cis- and Trans-methylpluviatolide

Planta Medica ◽  
2008 ◽  
Vol 74 (03) ◽  
Author(s):  
R Silva ◽  
J Saraiva ◽  
S Albuquerque ◽  
C Curti ◽  
PM Donate ◽  
...  
Keyword(s):  
Structure Activity ◽  
Cis And Trans

Synthesis, Antimalarial Evaluation and SAR Study of Some 1,3,5-Trisubstituted Pyrazoline Derivatives

2019 ◽  
Vol 16 (10) ◽  
pp. 807-817 ◽  
Author(s):  
Shilpy Aggarwal ◽  
Deepika Paliwal ◽  
Dhirender Kaushik ◽  
Girish Kumar Gupta ◽  
Ajay Kumar
Keyword(s):  
Antimalarial Activity ◽  
Analysis Data ◽  
Docking Study ◽  
Maximum Activity ◽  
Elemental Analysis Data ◽  
Mass Spectral ◽  
Structure Activity ◽  
Pharmacokinetic Properties ◽  
Sar Study

The synthesis of a novel series of 1,3,5-trisubstitiuted pyrazoline was achieved by refluxing chalcone derivative with different heteroaryl hydrazines. The newly synthesized compounds were characterized by 1H NMR, 13CNMR, mass spectral and elemental analysis data. The synthetic series of novel pyrazoline hybrids was screened for in vitro schizont maturation assay against chloroquine sensitive 3D7 strain of Plasmodium falciparum. Most of the compounds showed promising in vitro antimalarial activity against CQ sensitive strain. The preliminary structure-activity relationship study showed that quinoline substituted analog at position N-1 showed maximum activity followed by benzothiazole substitution, while phenyl substitution lowers the antimalarial activity. The observed activity was persistent by the docking study on P. falciparum cystein protease falcipain-2. The pharmacokinetic properties were also studied using ADME prediction.

A Review on Camptothecin Analogs with Promising Cytotoxic Profile

2019 ◽  
Vol 18 (13) ◽  
pp. 1796-1814 ◽  
Author(s):  
Sk. Abdul Amin ◽  
Nilanjan Adhikari ◽  
Tarun Jha ◽  
Shovanlal Gayen
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Structure Property ◽  
Cytotoxic Potential ◽  
Structure Property Relationships ◽  
Structure Activity ◽  
Camptothecin Analogs ◽  
Pharmacokinetic Properties ◽  
Quantitative Structure Activity Relationships

Camptothecin (CPT), obtained from Camptotheca acuminata (Nyssaceae), is a quinoline type of alkaloid. Apart from various traditional uses, it is mainly used as a potential cytotoxic agent acting against a variety of cancer cell lines. Though searches have been continued for last six decades, still it is a demanding task to design potent and cytotoxic CPTs. Different CPT analogs are synthesized to enhance the cytotoxic potential as well as to increase the pharmacokinetic properties of these analogs. Some of these analogs were proven to be clinically effective in different cancer cell lines. In this article, different CPT analogs have been highlighted extensively to get a detail insight about the structure-property relationships as well as different quantitative structure-activity relationships (QSARs) modeling of these analogs are also discussed. This study may be beneficial for designing newer CPT analogs in future.

Sign in / Sign up

Export Citation Format

Share Document