scholarly journals Characterizing RNA-binding Ligands on Structures, Chemical Information, Binding Affinity and Drug-likeness

2022 ◽  
Author(s):  
Cong Fan ◽  
Xin Wang ◽  
Tianze Wang ◽  
Huiying Zhao
Keyword(s):  
Binding Affinity ◽  
Drug Targets ◽  
Rna Binding ◽  
Chemical Properties ◽  
P Value ◽  
Chemical Information ◽  
Ligand Interactions ◽  
Approved Drugs ◽  
2D And 3D ◽  
Fda Approved Drugs

Recent studies suggest RNAs playing essential roles in many cell activities and act as promising drug targets. However, limited development has been achieved in detecting RNA-ligand interactions. To guide the discovery of RNA-binding ligands, it is necessary to characterize them comprehensively. We established a database, RNALID that collects RNA-ligand interactions validated by low-throughput experiment. RNALID contains 358 RNA-ligand interactions. Comparing to other databases, 94.5% of ligands in RNALID are completely or partially novel collections, and 51.78% have novel two-dimensional (2D) structures. The ligand structure analysis indicated that multivalent ligands (MV), ligands binding with cellular mRNA (mRNA), ligands binding with RNA from virus (vRNA) and ligands binding with RNA containing repetitive sequence (rep RNA) are more structurally conserved in both 2D and 3D structures than other ligand types. Binding affinity analysis revealed that interactions between ligands and rep RNA were significantly stronger (two-tailed MW-U test P-value = 0.012) than the interactions between ligands and non-rep RNAs; the interactions between ligands and vRNA were significantly stronger (two-tailed MW-U test P-value = 0.012) than those between ligands and mRNA. Drug-likeness analysis indicated that small molecule (SM) ligands binding with non-rep RNA or vRNA may have higher probability to be drugs than other types of ligands. Comparing ligands in RNALID to FDA-approved drugs and ligands without bioactivity indicated that RNA-binding ligands are different from them in chemical properties, structural properties and drug-likeness. Thus, characterizing the RNA-ligand interactions in RNALID in multiple respects provides new insights into discovering and designing druggable ligands binding with RNA.

scholarly journals Drug Repurposing Commonly Against Dengue Virus Capsid and SARS-CoV-2 Nucleocapsid: An in Silico Approach

2020 ◽  
Author(s):  
Debica Mukherjee ◽  
Rupesh Roy ◽  
UPASANA RAY
Keyword(s):  
Dengue Virus ◽  
Capsid Protein ◽  
In Silico ◽  
Rna Binding ◽  
Drug Repurposing ◽  
Virus Capsid ◽  
Approved Drugs ◽  
Full Swing ◽  
Fda Approved Drugs ◽  
Virus Capsid Protein

<p></p><p>In the middle of SARS-CoV-2 pandemic, dengue virus (DENV) is giving a silent warning as the season approaches nearer. There is no specific antiviral against DENV for use in the clinics. Thus, considering these facts we can potentially face both these viruses together increasing the clinical burden. The search for anti-viral drugs against SARS-CoV-2 is in full swing and repurposing of already ‘in-use’ drugs against other diseases or COVID-19 has drawn significant attention. Earlier we had reported few FDA approved anti-viral and anti-microbial drugs that could be tested for binding with SARS-CoV-2 nucleocapsid N terminal domain. We explored the possibility of interactions of the drugs screened for SARS-CoV2 with Dengue virus capsid protein. We report five FDA approved drugs that were seen to be docking onto the SARS-CoV-2 nucleocapsid RNA binding domain, also docking well with DENV capsid protein on the RNA binding site and/or the capsid’s membrane fusion domain. Thus, the present study proposes these five drugs as common antiviral candidates against both SARS-CoV-2 and DENV although the <i>in silico</i> study is subject to further validations.</p><br><p></p>

Review and Prospect of Tissue-agnostic targeted Strategies in Anticancer therapies

2020 ◽  
Vol 20 ◽  
Author(s):  
Peng Yu ◽  
Tao Hongxun ◽  
Gao Yuanqing ◽  
Yang Yuanyuan ◽  
Chen Zhiyong
Keyword(s):  
Targeted Therapy ◽  
Drug Targets ◽  
Anatomical Location ◽  
Tumor Characteristics ◽  
Genetic Characteristics ◽  
Drug Candidates ◽  
Specific Tumor ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Prevalence Of Cancer

: Due to the increasing prevalence of cancer year by year, and the complexity and refractory nature of the disease itself, it is required to constantly innovate the development of new cancer treatment schemes. At the same time, the understanding of cancers has deepened, from the use of chemotherapy regimens with high toxicity and side effects, to the popularity of targeted drugs with specific targets, to precise treatments based on tumor characteristics rather than traditional anatomical location classification. In precision medical, in the view of the specific tumor diseases and their biological characteristics, it has great potential to develop tissue-agnostic targeted therapy with broad-spectrum anticancer significance. The present review has discussed tissue-agnostic targeted therapy based on the biological and genetic characteristics of cancers, expounded its theoretical basis and strategies for drug development. And the feasible drug targets, FDA-approved drugs, as well as drug candidates in clinical trials have also been summarized. In conclusion, the “tissue-agnostic targeted therapy” is a breakthrough in anticancer therapies.

Coronavirus Disease 2019: Virology and Drug Targets

2020 ◽  
Vol 20 ◽  
Author(s):  
Praveen Thaggikuppe Krishnamurthy
Keyword(s):  
High Throughput Screening ◽  
Drug Targets ◽  
Vaccine Development ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Structural Proteins ◽  
Current Status ◽  
Approved Drugs ◽  
Viral Target ◽  
Fda Approved Drugs

: The Coronavirus Disease 2019, a pandemic caused by novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is seriously affecting global health and the economy. As the vaccine development takes time, the current research is focused on repurposing FDA approved drugs against the viral target proteins. This review discusses the current understanding of SARS-CoV-2 virology, its target structural proteins (S- glycoprotein), non-structural proteins (3- chymotrypsin-like protease, papain-like protease, RNA-dependent RNA polymerase, and helicase) and accessory proteins, drug discovery strategies (drug repurposing, artificial intelligence, and high-throughput screening), and the current status of antiviral drug development.

scholarly journals Drug Repurposing Commonly Against Dengue Virus Capsid and SARS-CoV-2 Nucleocapsid: An in Silico Approach

2020 ◽  
Author(s):  
Debica Mukherjee ◽  
Rupesh Roy ◽  
UPASANA RAY
Keyword(s):  
Dengue Virus ◽  
Capsid Protein ◽  
In Silico ◽  
Rna Binding ◽  
Drug Repurposing ◽  
Virus Capsid ◽  
Approved Drugs ◽  
Full Swing ◽  
Fda Approved Drugs ◽  
Virus Capsid Protein

<p></p><p>In the middle of SARS-CoV-2 pandemic, dengue virus (DENV) is giving a silent warning as the season approaches nearer. There is no specific antiviral against DENV for use in the clinics. Thus, considering these facts we can potentially face both these viruses together increasing the clinical burden. The search for anti-viral drugs against SARS-CoV-2 is in full swing and repurposing of already ‘in-use’ drugs against other diseases or COVID-19 has drawn significant attention. Earlier we had reported few FDA approved anti-viral and anti-microbial drugs that could be tested for binding with SARS-CoV-2 nucleocapsid N terminal domain. We explored the possibility of interactions of the drugs screened for SARS-CoV2 with Dengue virus capsid protein. We report five FDA approved drugs that were seen to be docking onto the SARS-CoV-2 nucleocapsid RNA binding domain, also docking well with DENV capsid protein on the RNA binding site and/or the capsid’s membrane fusion domain. Thus, the present study proposes these five drugs as common antiviral candidates against both SARS-CoV-2 and DENV although the <i>in silico</i> study is subject to further validations.</p><br><p></p>

scholarly journals Variable dose analysis: A novel RNAi-based method for detection of synthetic lethal interactions

2017 ◽  
Author(s):  
Benjamin E. Housden ◽  
Zhongchi Li ◽  
Colleen Kelley ◽  
Yuanli Wang ◽  
Yanhui Hu ◽  
...  
Keyword(s):  
Drug Targets ◽  
Limited Range ◽  
Synthetic Lethal ◽  
Candidate Drug ◽  
Highly Sensitive ◽  
Synthetic Lethal Interactions ◽  
A Cell ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Variable Dose

AbstractSynthetic sick or synthetic lethal (SS/L) screens are a powerful way to identify candidate drug targets to specifically kill tumor cells but such screens generally suffer from low reproducibility. We found that many SS/L interactions involve essential genes and are therefore detectable within a limited range of knockdown efficiency. Such interactions are often missed by overly efficient RNAi reagents. We therefore developed an assay that measures viability over a range of knockdown efficiency within a cell population. This method, called variable dose analysis (VDA), is highly sensitive to viability phenotypes and reproducibly detects SS/L interactions. We applied the VDA method to search for SS/L interactions with TSC1 and TSC2, the two tumor suppressors underlying tuberous sclerosis complex (TSC) and generated a SS/L network for TSC. Using this network, we identified four FDA-approved drugs that selectively affect viability of TSC deficient cells, representing promising candidates for repurposing to treat TSC-related tumors.

scholarly journals Genomic analysis of human polymorphisms affecting drug-protein interactions

2017 ◽  
Author(s):  
Oriol Pich i Rosello ◽  
Anna V. Vlasova ◽  
Polina A. Shichkova ◽  
Yuri Markov ◽  
Peter K. Vlasov ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Protein Interactions ◽  
Low Frequency ◽  
Genomic Analysis ◽  
Binding Affinities ◽  
Using Data ◽  
Individual Drug Response ◽  
Approved Drugs ◽  
The Impact ◽  
Fda Approved Drugs

Human genetic variability is thought to account for a substantial fraction of individual biochemical characteristics – in biomedical sense, of individual drug response. However, only a handful of human genetic variants have been linked to medication outcomes. Here, we combine data on drug-protein interactions and human genome sequences to assess the impact of human variation on their binding affinity. Using data from the complexes of FDA-drugs and drug-like compounds, we predict SNPs substantially affecting the protein-ligand binding affinities. We estimate that an average individual carries ~6 SNPs affecting ~5 different FDA-approved drugs from among all of the approved compounds. SNPs affecting drug-protein binding affinity have low frequency in the population indicating that the genetic component for many ADEs may be highly personalized with each individual carrying a unique set of relevant SNPs. The reduction of ADEs, therefore, may primarily rely on the application of computational genome analysis in the clinic rather than the experimental study of common SNPs.

Recognizing drug targets using evolutionary information: implications for repurposing FDA-approved drugs against Mycobacterium tuberculosis H37Rv

2015 ◽  
Vol 11 (12) ◽  
pp. 3316-3331 ◽  
Author(s):  
Gayatri Ramakrishnan ◽  
Nagasuma R. Chandra ◽  
Narayanaswamy Srinivasan
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Drug Repurposing ◽  
Target Space ◽  
Evolutionary Information ◽  
Mycobacterium Tuberculosis H37rv ◽  
The Past ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Computational Drug Discovery

Drug repurposing to explore target space has been gaining pace over the past decade with the upsurge in the use of systematic approaches for computational drug discovery.

scholarly journals CaNDis: a web server for investigation of causal relationships between diseases, drugs and drug targets

2020 ◽  
Author(s):  
Blaž Škrlj ◽  
Nika Eržen ◽  
Nada Lavrač ◽  
Tanja Kunej ◽  
Janez Konc
Keyword(s):  
Drug Targets ◽  
Web Server ◽  
Interaction Network ◽  
Biological Data ◽  
Supplementary Information ◽  
Disease Network ◽  
Regulatory Pathways ◽  
Disease Mechanisms ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Motivation Causal biological interaction networks represent cellular regulatory pathways. Their fusion with other biological data enables insights into disease mechanisms and novel opportunities for drug discovery. Results We developed Causal Network of Diseases (CaNDis), a web server for the exploration of a human causal interaction network, which we expanded with data on diseases and FDA-approved drugs, on the basis of which we constructed a disease–disease network in which the links represent the similarity between diseases. We show how CaNDis can be used to identify candidate genes with known and novel roles in disease co-occurrence and drug–drug interactions. Availabilityand implementation CaNDis is freely available to academic users at http://candis.ijs.si and http://candis.insilab.org. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals In silico and in vitro screening of FDA-approved drugs for potential repurposing against tuberculosis

2017 ◽  
Author(s):  
Sridharan Brindha ◽  
Jagadish Chandrabose Sundaramurthi ◽  
Savariar Vincent ◽  
Devadasan Velmurugan ◽  
John Joel Gnanadoss
Keyword(s):  
In Silico ◽  
Drug Targets ◽  
Luciferase Reporter ◽  
Synergistic Activity ◽  
Resistant Strains ◽  
Approved Drugs ◽  
Clinical Conditions ◽  
Drug Resistant Strains ◽  
Fda Approved Drugs

AbstractMotivationRepurposing of known drugs to newer clinical conditions is a promising avenue for finding novel therapeutic applications for tuberculosis.MethodsWe performed docking-based virtual screening for 1554 known drugs against two of the potential drug targets, namely trpD and coaA of M. tuberculosis. In the first round of in silico screening we used rigid docking using Glide and AutoDock Vina. We subjected the consistently ranked drugs for induced-fit docking by these tools against the same target proteins. We performed luciferase reporter phage (LRP) assay to determine the biological activity of five selected drugs against M. tuberculosis.ResultsWe observed lymecycline and cefpodoxime to be active against drug susceptible and drug resistant strains of M. tuberculosis. In addition, lymecycline and cefpodoxime showed synergistic activity with rifampin and isoniazid against M. tuberculosis.ConclusionOur results suggest that lymecycline and cefpodoxime have potential to be repurposed for the treatment of tuberculosis.

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