Harnessing Allostery: A Novel Approach to Drug Discovery

2014 ◽  
Vol 34 (6) ◽  
pp. 1242-1285 ◽  
Author(s):  
Shaoyong Lu ◽  
Shuai Li ◽  
Jian Zhang
Keyword(s):  
Drug Discovery ◽  
Novel Approach

[P2-143]: SCREENING FOR INHIBITORS OF APOE4-CATALYZED Aβ OLIGOMER/FILAMENT FORMATION: A NOVEL APPROACH TO ALZHEIMER's DISEASE DRUG DISCOVERY

2017 ◽  
Vol 13 (7S_Part_13) ◽  
pp. P662-P663
Author(s):  
Christina M. Coughlan ◽  
Athena Wang ◽  
Lisa Viltz ◽  
Heidi J. Chial ◽  
Huntington Potter
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Discovery ◽  
Filament Formation ◽  
Novel Approach ◽  
Aβ Oligomer

scholarly journals Development of a Fragment-Based Screening Assay for the Focal Adhesion Targeting Domain Using SPR and NMR

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3352 ◽  
Author(s):  
Carlos Alvarado ◽  
Erik Stahl ◽  
Karissa Koessel ◽  
Andrew Rivera ◽  
Brian R. Cherry ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Focal Adhesion ◽  
High Throughput Screening ◽  
Quantum Coherence ◽  
Focal Adhesions ◽  
Scaffolding Protein ◽  
Screening Assay ◽  
Binding Interface ◽  
Novel Approach ◽  
Fragment Library

The Focal Adhesion Targeting (FAT) domain of Focal Adhesion Kinase (FAK) is a promising drug target since FAK is overexpressed in many malignancies and promotes cancer cell metastasis. The FAT domain serves as a scaffolding protein, and its interaction with the protein paxillin localizes FAK to focal adhesions. Various studies have highlighted the importance of FAT-paxillin binding in tumor growth, cell invasion, and metastasis. Targeting this interaction through high-throughput screening (HTS) provides a challenge due to the large and complex binding interface. In this report, we describe a novel approach to targeting FAT through fragment-based drug discovery (FBDD). We developed two fragment-based screening assays—a primary SPR assay and a secondary heteronuclear single quantum coherence nuclear magnetic resonance (HSQC-NMR) assay. For SPR, we designed an AviTag construct, optimized SPR buffer conditions, and created mutant controls. For NMR, resonance backbone assignments of the human FAT domain were obtained for the HSQC assay. A 189-compound fragment library from Enamine was screened through our primary SPR assay to demonstrate the feasibility of a FAT-FBDD pipeline, with 19 initial hit compounds. A final total of 11 validated hits were identified after secondary screening on NMR. This screening pipeline is the first FBDD screen of the FAT domain reported and represents a valid method for further drug discovery efforts on this difficult target.

Virogenomics: a novel approach to antiviral drug discovery

2001 ◽  
Vol 6 (12) ◽  
pp. 621-627 ◽  
Author(s):  
Klaus Früh ◽  
Kenneth Simmen ◽  
B.G.Mattias Luukkonen ◽  
Yolanda C Bell ◽  
Peter Ghazal
Keyword(s):  
Drug Discovery ◽  
Antiviral Drug ◽  
Novel Approach

Ethnopharmacology-A Novel Approach for Drug Discovery

2015 ◽  
Vol 2 (4) ◽  
pp. 222 ◽  
Author(s):  
Ajita D. Khamkar ◽  
V. M. Motghare ◽  
Rushikesh Deshpande
Keyword(s):  
Drug Discovery ◽  
Novel Approach

Molecular topology as a novel approach for drug discovery

2012 ◽  
Vol 7 (2) ◽  
pp. 133-153 ◽  
Author(s):  
Jorge Gálvez ◽  
María Gálvez-Llompart ◽  
Ramón García-Domenech
Keyword(s):  
Drug Discovery ◽  
Molecular Topology ◽  
Novel Approach

scholarly journals Improving drug discovery using image-based multiparametric analysis of epigenetic landscape

2019 ◽  
Author(s):  
Chen Farhy ◽  
Luis Orozco ◽  
Fu-Yue Zeng ◽  
Ian Pass ◽  
Jarkko Ylanko ◽  
...  
Keyword(s):  
Machine Learning ◽  
Drug Discovery ◽  
Nuclear Staining ◽  
Response Curves ◽  
Efficient Detection ◽  
Novel Approach ◽  
Novel Drug ◽  
Multiple Cells ◽  
Screening Approaches ◽  
Target Effects

AbstractWith the advent of automatic cell imaging and machine learning, high-content phenotypic screening has become the approach of choice for drug discovery due to its ability to extract drug specific multilayered data and compare it to known profiles. In the field of epigenetics such screening approaches has suffered from the lack of tools sensitive to selective epigenetic perturbations. Here we describe a novel approach Microscopic Imaging of Epigenetic Landscapes (MIEL) that captures patterns of nuclear staining of epigenetic marks (e.g. acetylated and methylated histones) and employs machine learning to accurately distinguish between such patterns (1). We demonstrated that MIEL has superior resolution compared to conventional intensity thresholding techniques and enables efficient detection of epigenetically active compounds, function-based classification, flagging possible off-target effects and even predict novel drug function. We validated MIEL platform across multiple cells lines and using dose-response curves to insure the robustness of this approach for the high content high throughput drug discovery.

scholarly journals Drug discovery for psychiatric disorders using high-content single-cell screening of signaling network responses ex vivo

2019 ◽  
Vol 5 (5) ◽  
pp. eaau9093 ◽  
Author(s):  
Santiago G. Lago ◽  
Jakub Tomasik ◽  
Geertje F. van Rees ◽  
Hannah Steeb ◽  
David A. Cox ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Single Cell ◽  
Drug Targets ◽  
Ex Vivo ◽  
Signaling Network ◽  
Antipsychotic Treatment ◽  
Channel Blockers ◽  
Functional Responses ◽  
Novel Approach

There is a paucity of efficacious new compounds to treat neuropsychiatric disorders. We present a novel approach to neuropsychiatric drug discovery based on high-content characterization of druggable signaling network responses at the single-cell level in patient-derived lymphocytes ex vivo. Primary T lymphocytes showed functional responses encompassing neuropsychiatric medications and central nervous system ligands at established (e.g., GSK-3β) and emerging (e.g., CrkL) drug targets. Clinical application of the platform to schizophrenia patients over the course of antipsychotic treatment revealed therapeutic targets within the phospholipase Cγ1–calcium signaling pathway. Compound library screening against the target phenotype identified subsets of L-type calcium channel blockers and corticosteroids as novel therapeutically relevant drug classes with corresponding activity in neuronal cells. The screening results were validated by predicting in vivo efficacy in an independent schizophrenia cohort. The approach has the potential to discern new drug targets and accelerate drug discovery and personalized medicine for neuropsychiatric conditions.

Drug Discovery for Covid-19 – A Multidimensional Perspective

2021 ◽  
Vol 11 (SPL4) ◽  
pp. 900-905
Author(s):  
Satish Kumar Sharma ◽  
Omprakash Goshain
Keyword(s):  
Drug Discovery ◽  
Secondary Metabolites ◽  
Plant Secondary Metabolites ◽  
Cost Effective ◽  
Fungal Species ◽  
The Body ◽  
Pharmaceutical Ingredients ◽  
Corona Virus ◽  
Global Pandemic ◽  
Novel Approach

Covid-19, a disease caused by severe acute respiratory syndrome corona virus (SARS-CoV) has challenged pharmaceutical science against viruses, globally. The disease has become a global pandemic beginning the race of new therapeutic strategies against novel corona virus (nCoV). Therefore, management of such pandemic issue is a need of the hour. Drug delivery refers to an approach adopted to transfer drug particles within the body to obtain a potent therapeutic effect. In the present study, an attempt has been taken to discuss about plant secondary metabolites (PSMs) and fungal bioactive compounds which are potent antiviral pharmaceutical agents. Also, a discussion about allopathic ingredient of plant secondary metabolites have also been done. The unique repository of Indian plants and versatility of fungal species provide broad spectrum to screen for pharmaceutical ingredients against novel corona virus. Further, screening of plant secondary metabolites by molecular docking can be a cost effective way to combat from novel corona virus. Thus, it can be said that, Multidimensional approach discussed herein may provide insights to combat antimicrobial resistance in the future. The present review will promote further research horizons in plants and fungal based therapeutics and a novel approach towards drug discovery thereby preventing the humans from suffering through severe adversities.

A Novel Evolutionary Approach Provides Hope for Limiting Future Drug Resistance in Malaria

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 420-420
Author(s):  
Theresa L. Coetzer ◽  
Kubendran Naidoo ◽  
Pierre Durand
Keyword(s):  
Drug Resistance ◽  
Drug Discovery ◽  
Dihydrofolate Reductase ◽  
Drug Target ◽  
Purifying Selection ◽  
Evolutionary Change ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Novel Approach ◽  
Target Sites

Abstract Malaria continues to be the most lethal protozoan disease of humans and the pathogenesis is fundamentally associated with the infection and hemolysis of red blood cells. Due to the emergence of resistance to most current drugs, there is an urgent need to develop a new generation of anti-parasitic agents. Drug development programs are expensive, long-term endeavors with numerous bottlenecks that exhibit a high rate of attrition. A major concern following the scientific and financial investment in drug discovery is the emergence of drug resistance. This is a well documented problem in malaria, and may be exceedingly rapid, classically demonstrated by pyrimethamine-resistant Plasmodium falciparum malaria. Strategies therefore that identify the most suitable drug target sites to minimize resistance are of major interest. In this study, a novel approach to select such sites based on the evolutionary rate of change is described, using the P. falciparum glycerol kinase (PfGK) as an example. The ratio of non-synonymous (dN) to synonymous (dS) nucleotide substitutions is defined as omega and was used to identify the patterns of evolutionary change at individual codons in the parasite and orthologous human (HsGK) coding sequences. The omega value of a particular codon reflects the evolutionary forces acting on the corresponding amino acid in the protein sequence. Natural selection will retain mutations that are beneficial to the organism and eliminate those that are detrimental. Omega values typically fall into three categories: positive selection (omega>1.0), neutral (omega=1.0), or purifying selection (omega<1.0). In this study, we quantified the relative intensity of selection and introduced the category of extreme purifying selection (omega≤0.1) to identify sites under the most severe evolutionary constraints. We have termed this novel approach to drug target selection “evolutionary patterning” (EP). EP describes the pattern of evolutionary change across a coding sequence, thereby identifying residues that make the most (omega<0.1) and least (omega>1.0) suitable drug target sites based on their potential to produce viable mutations. The EP approach was validated using the P. falciparum dihydrofolate reductase gene. Pyrimethamine targets the dihydrofolate reductase enzyme and five mutations conferring drug resistance have been identified. We hypothesized that none of these mutations would be under extreme purifying selection and our EP investigation confirmed this. EP analysis was thus applied to PfGK, which could be a potential novel drug target. PfGK is annotated as a putative glycerol kinase in the PlasmoDB database and to confirm this predicted function, the full length gene of 1506bp was cloned into a pGEX-4T2 expression vector, the recombinant GST-fusion protein was expressed in E coli and an in vitro assay showed that the enzyme was active and could phosphorylate glycerol. Glycerol-3-phosphate is a multifunctional metabolite that is essential for glycerolipid synthesis and also feeds into glycolysis, highlighting its essential role in parasite metabolism. EP analysis of the PfGK and HsGK genes was conducted separately as part of protozoan and metazoan clades, respectively, and key differences in the evolutionary patterns of the two molecules were identified. These differences were exploited to target the parasite selectively and six potential drug target sites were chosen, which contained residues under extreme purifying selection. To assess the functional and structural significance of these regions, as well as their accessibility to potential therapeutic molecules, they were mapped onto a 3D model of PfGK. This analysis ruled out three of the potential sites, since they were either not essential for enzyme activity or were embedded in the hydrophobic core of the enzyme. In collaboration with medicinal chemists the remaining three potential drug target sites will be used for in silico drug design and docking studies. The strategy of EP and refinement with structural modeling is generic in nature and will limit the development of drug resistance. This represents a significant advance for drug discovery programs in malaria and other infectious diseases.

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