scholarly journals Computational Drug Repositioning: Current Progress and Challenges

2020 ◽  
Vol 10 (15) ◽  
pp. 5076
Author(s):  
Younhee Ko
Keyword(s):  
Drug Repositioning ◽  
Attrition Rate ◽  
Drug Candidates ◽  
Disease Mechanisms ◽  
High Investment ◽  
Experimental Approaches ◽  
Approved Drugs ◽  
Investment Process ◽  
Novel Drug ◽  
High Attrition Rate

Novel drug discovery is time-consuming, costly, and a high-investment process due to the high attrition rate. Therefore, many trials are conducted to reuse existing drugs to treat pressing conditions and diseases, since their safety profiles and pharmacokinetics are already available. Drug repositioning is a strategy to identify a new indication of existing or already approved drugs, beyond the scope of their original use. Various computational and experimental approaches to incorporate available resources have been suggested for gaining a better understanding of disease mechanisms and the identification of repurposed drug candidates for personalized pharmacotherapy. In this review, we introduce publicly available databases for drug repositioning and summarize the approaches taken for drug repositioning. We also highlight and compare their characteristics and challenges, which should be addressed for the future realization of drug repositioning.

Developing novel chemical entities for the treatment of lysosomal storage disorders: an academic perspective

2015 ◽  
Vol 309 (12) ◽  
pp. F996-F999 ◽  
Author(s):  
James A. Shayman
Keyword(s):  
Drug Targets ◽  
Lysosomal Storage ◽  
Federal Drug Administration ◽  
Drug Candidates ◽  
Gaucher Disease Type 1 ◽  
Biotechnology Companies ◽  
Approved Drugs ◽  
Novel Drug ◽  
Early Drug

Historically, most Federal Drug Administration-approved drugs were the result of “in-house” efforts within large pharmaceutical companies. Over the last two decades, this paradigm has steadily shifted as the drug industry turned to startups, small biotechnology companies, and academia for the identification of novel drug targets and early drug candidates. This strategic pivot has created new opportunities for groups less traditionally associated with the creation of novel therapeutics, including small academic laboratories, for engagement in the drug discovery process. A recent example of the successful development of a drug that had its origins in academia is eliglustat tartrate, an oral agent for Gaucher disease type 1.

scholarly journals PS4DR: A multimodal workflow for identification and prioritization of drugs based on pathway signatures

2020 ◽  
Author(s):  
Mhammad Asif Emon ◽  
Daniel Domingo-Fernández ◽  
Charles Tapley Hoyt ◽  
Martin Hofmann-Apitius
Keyword(s):  
Gene Expression ◽  
Genome Wide Association Study ◽  
Drug Repositioning ◽  
Heterogeneous Data ◽  
New Drugs ◽  
Gwas Data ◽  
Drug Candidates ◽  
Gene Expression Signatures ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Background: During the last decade, there has been a surge towards computational drug repositioning owing to constantly increasing -omics data in the biomedical research field. While numerous existing methods focus on the integration of heterogeneous data to propose candidate drugs, it is still challenging to substantiate their results with mechanistic insights of these candidate drugs. Therefore, there is a need for more innovative and efficient methods which can enable better integration of data and knowledge for drug repositioning. Results: Here, we present a customizable workflow ( PS4DR) which not only integrates high-throughput data such as genome-wide association study (GWAS) data and gene expression signatures from disease and drug perturbations but also takes pathway knowledge into consideration to predict drug candidates for repositioning. We have collected and integrated publicly available GWAS data and gene expression signatures for several diseases and hundreds of FDA-approved drugs or those under clinical trial in this study. Additionally, different pathway databases were used for mechanistic knowledge integration in the workflow. Using this systematic consolidation of data and knowledge, the workflow computes pathway signatures that assist in the prediction of new indications for approved and investigational drugs. Conclusion: We showcase PS4DR with applications demonstrating how this tool can be used for repositioning and identifying new drugs as well as proposing drugs that can simulate disease dysregulations. We were able to validate our workflow by demonstrating its capability to predict FDA-approved drugs for their known indications for several diseases. Further, PS4DR returned many potential drug candidates for repositioning that were backed up by epidemiological evidence extracted from scientific literature. Source code is freely available at https://github.com/ps4dr/ps4dr .

scholarly journals Comparative Microsomal Proteomics of A Model Lung Cancer Cell Line NCI-H23 Reveals Distinct Differences Between Molecular Profiles of 3D and 2D Cultured Cells

2020 ◽  
Author(s):  
Josip Blonder ◽  
Jan A. Kaczmarczyk ◽  
Rhonda R. Roberts ◽  
Brian T. Luke ◽  
King C. Chan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
3D Culture ◽  
Culture Conditions ◽  
Attrition Rate ◽  
Dependent Manner ◽  
Drug Candidates ◽  
High Attrition Rate ◽  
Culture Dependent

Abstract Background: Lung cancer is the leading cause of cancer-related deaths in the USA and worldwide. Yet, about 95% of new drug candidates validated in preclinical phase eventually fail in clinical trials. Such a high attrition rate is attributed mostly to the inability of conventional two-dimensionally (2D) cultured cancer cells to mimic native three-dimensional (3D) growth of malignant cells in human tumors. Thus, it is expected that 3D cell culture systems would more accurately represent the phenotype of cancer cells growing in tumors. To ascertain phenotypical differences between these two distinct culture conditions, we carried out a comparative proteomic analysis of membrane fraction obtained from 3D- and 2D-cultured NSCLC model cell line NCI-H23. Methods: Global shotgun membrane (SGM) proteomics that relies on strong cation exchange (SCX)-based peptide fractionation and accurate-mass, liquid chromatography mass spectrometry (HR/AM LC-MS) was employed to analyze microsomal fractions obtained from the NCI-H23 cells grown in both 2D and 3D culture conditions. Results: Comparative proteomics revealed a map of 1,166 (24%) nonredundant protein species regulated in culture dependent manner in NCI-H23 cell line. Of these, a subset of 234 (i.e., 21 %) proteins were found significantly dysregulated (p-value ≤ 0.05) under both culture conditions whereas a total of 334 (27.8%) and 598 (51,2%) proteins were uniquely identified in 3D and 2D culture, respectively. The Ingenuity Pathway Analysis revealed extensive metabolic changes and differential regulation of a subset of CD molecules in culture-dependent manner. Using western blotting we verified exclusive 3D-culture expression of CD99, CD146 and CD239, involved in development of malignant stroma extracellular matrix, neo-angiogenesis and metastasis. Furthermore, using label-free quantitation we unambiguously confirmed upregulation of wild type and monoallelic KRas4B G12C mutant in 3D cultured NCI-H23 cells, targeting exclusively proteoform-specific tryptic peptides. Conclusions: In this study we generated a large-scale proteomic resource/atlas of a preclinical testing model NCI-H23 cell line grown in 3D- and 2D-culture, providing insight into phenotypical/proteomic changes unique to each culture type, that would not have been discovered using only conventional 2D-culture. To reduce high attrition rate of new drug candidates it is critical to profile a large number of patient-derived NSCLC cell lines.

scholarly journals Computational guided approach for drug repurposing against SARS-CoV-2

2021 ◽  
Author(s):  
Jigisha Anand ◽  
Tanmay Ghildiyal ◽  
Aakanksha Madhwal ◽  
Rishabh Bhatt ◽  
Devvret Verma ◽  
...  
Keyword(s):  
Drug Targets ◽  
De Novo ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Computational Docking ◽  
Drug Candidates ◽  
Docking Tool ◽  
Inhibitory Potential ◽  
Approved Drugs ◽  
Tract Infections

Background: In the current SARS-CoV-2 outbreak, drug repositioning emerges as a promising approach to develop efficient therapeutics in comparison to de novo drug development. The present investigation screened 130 US FDA-approved drugs including hypertension, cardiovascular diseases, respiratory tract infections (RTI), antibiotics and antiviral drugs for their inhibitory potential against SARS-CoV-2. Materials & methods: The molecular drug targets against SARS-CoV-2 proteins were determined by the iGEMDOCK computational docking tool. The protein homology models were generated through SWISS Model workspace. The pharmacokinetics of all the ligands was determined by ADMET analysis. Results: The study identified 15 potent drugs exhibiting significant inhibitory potential against SARS-CoV-2. Conclusion: Our investigation has identified possible repurposed drug candidates to improve the current modus operandi of the treatment given to COVID-19 patients.

scholarly journals Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Sangeun Jeon ◽  
Meehyun Ko ◽  
Jihye Lee ◽  
Inhee Choi ◽  
Soo Young Byun ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Drug Repositioning ◽  
Antiviral Drug ◽  
Drug Candidates ◽  
Global Challenge ◽  
Feasible Option ◽  
Approved Drugs ◽  
Fda Approved Drugs

ABSTRACT Drug repositioning is the only feasible option to immediately address the COVID-19 global challenge. We screened a panel of 48 FDA-approved drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which were preselected by an assay of SARS-CoV. We identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low 50% inhibitory concentrations (IC50s), and in particular, two FDA-approved drugs—niclosamide and ciclesonide—were notable in some respects.

In Silico Chemogenomics Drug Repositioning Strategies for Neglected Tropical Diseases

2019 ◽  
Vol 26 (23) ◽  
pp. 4355-4379 ◽  
Author(s):  
Carolina Horta Andrade ◽  
Bruno Junior Neves ◽  
Cleber Camilo Melo-Filho ◽  
Juliana Rodrigues ◽  
Diego Cabral Silva ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Drug Targets ◽  
Neglected Tropical Diseases ◽  
Drug Repositioning ◽  
Tropical Diseases ◽  
Systematic Screening ◽  
Drug Candidates ◽  
Lead Compounds ◽  
The One ◽  
Approved Drugs

Only ~1% of all drug candidates against Neglected Tropical Diseases (NTDs) have reached clinical trials in the last decades, underscoring the need for new, safe and effective treatments. In such context, drug repositioning, which allows finding novel indications for approved drugs whose pharmacokinetic and safety profiles are already known, emerging as a promising strategy for tackling NTDs. Chemogenomics is a direct descendent of the typical drug discovery process that involves the systematic screening of chemical compounds against drug targets in high-throughput screening (HTS) efforts, for the identification of lead compounds. However, different to the one-drug-one-target paradigm, chemogenomics attempts to identify all potential ligands for all possible targets and diseases. In this review, we summarize current methodological development efforts in drug repositioning that use state-of-the-art computational ligand- and structure-based chemogenomics approaches. Furthermore, we highlighted the recent progress in computational drug repositioning for some NTDs, based on curation and modeling of genomic, biological, and chemical data. Additionally, we also present in-house and other successful examples and suggest possible solutions to existing pitfalls.

scholarly journals Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs

2020 ◽  
Author(s):  
Sangeun Jeon ◽  
Meehyun Ko ◽  
Jihye Lee ◽  
Inhee Choi ◽  
Soo Young Byun ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Drug Repositioning ◽  
Antiviral Drug ◽  
Drug Candidates ◽  
Global Challenge ◽  
Feasible Option ◽  
Antiviral Activities ◽  
Approved Drugs ◽  
Near Future ◽  
Fda Approved Drugs

AbstractCOVID-19 is an emerging infectious disease and was recently declared as a pandemic by WHO. Currently, there is no vaccine or therapeutic available for this disease. Drug repositioning represents the only feasible option to address this global challenge and a panel of 48 FDA-approved drugs that have been pre-selected by an assay of SARS-CoV was screened to identify potential antiviral drug candidates against SARS-CoV-2 infection. We found a total of 24 drugs which exhibited antiviral efficacy (0.1 μM < IC50 < 10 μM) against SARS-CoV-2. In particular, two FDA-approved drugs - niclosamide and ciclesonide – were notable in some respects. These drugs will be tested in an appropriate animal model for their antiviral activities. In near future, these already FDA-approved drugs could be further developed following clinical trials in order to provide additional therapeutic options for patients with COVID-19.

A Nanoinformatics Approach to Evaluate the Pharmacological Properties of Nanoparticles for the treatment of Alzheimer’s Disease

2021 ◽  
Vol 24 ◽  
Author(s):  
Muhammad Zohaib Nawaz ◽  
Syed Awais Attique ◽  
Qurat-ul-Ain ◽  
Fahdah Ayed Alshammari ◽  
Heba Waheeb Alhamdi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Carbon Nanotubes ◽  
Alzheimer's Disease ◽  
Nervous System ◽  
Drug Targets ◽  
Kinase Domain ◽  
New Drugs ◽  
Drug Candidates ◽  
Experimental Approaches ◽  
Novel Drug

Background: Alzheimer’s disease is a nervous system destructive disease which causes structural, biochemical and electrical abnormalities inside the human brain and results due to genetic and various environmental factors. Traditional therapeutic agents of Alzheimer’s disease such as tacrine and physostigmine has been found causing adverse effects to the nervous system and gastrointestinal tract. Nanomaterials like graphene, metals, carbon-nanotubes and metal-oxides are gaining attention as potential drugs against Alzheimer’s disease due to their properties such as large surface area which provides clinical efficiency, targeted drug designing and delivery. Objectives: Designing new drugs by using experimental approaches are time-consuming, tedious and laborious processes which also require advanced technologies. This study aims to identify the novel drug candidates against Alzheimer’s disease with no or less associated side effects using molecular docking approaches. Methods: In this study, we utilized nanoinformatics based approaches for evaluating the interaction properties of various nanomaterials and metal nanoparticles with the drug targets including TRKB kinase domain, EphA4 and histone deacetylase. Furthermore, drug-likeness of carbon nanotubes was confirmed through ADME analysis. Results: Carbon nanotubes, either single or double-walled in all the three-configuration including zigzag, chiral, and armchair forms are found to interact with the target receptors with varying affinities. Conclusion: This study provides a novel and clearer insights into the interaction properties and drug suitability of known putative nanoparticles as potential agents for the treatment of Alzheimer’s disease.

Prodrug Strategies for Critical Drug Developability Issues: Part I

2021 ◽  
Vol 21 (24) ◽  
pp. 2155-2156
Author(s):  
Xingyue Ji
Keyword(s):  
Drug Development ◽  
Chemical Entity ◽  
Attrition Rate ◽  
Drug Candidate ◽  
Structure Property ◽  
Drug Candidates ◽  
Fda Approval ◽  
Cns Drugs ◽  
Approved Drugs ◽  
Preclinical And Clinical Studies

Drug development is a very time, capital, and labor-intensive process. It was anticipated that bringing a novel chemical entity to market would take over a billion dollars and around 14 years [1]. In addition, drug development is characterized by a very high attrition rate both in preclinical and clinical studies. It was reported that only 40% of drug candidates with the most drug-like properties could make their way into clinical trials, and only 10% of these can eventually reach FDA approval [2]. After analyzing the data from seven UK‐based pharmaceutical companies from 1964 through 1985, Prentis et al. found that 39% of failure was attributed to poor pharmacokinetic (PK) profiles in humans, 29% was attributed to a lack of clinical efficacy, 21% was attributed to toxicity and adverse effects, and about 6% was attributed to commercial limitations [3]. When a drug candidate is identified with one of these issues (except the commercial limitations), normally, a new round of structureactivity or structure-property relationship (SAR/SPR) studies is carried out to generate a new chemical entity with improved profiles, and in most cases, such a process is time and labor-intensive. Alternatively, prodrug strategy can be leveraged to efficiently address associated drug developability issues without making enormous derivatives. Prodrug strategy has been demonstrated to be very successful and fruitful in drug development, with around 20% of approved drugs from 2008 through 2020 being clarified as prodrugs [4]. In recent years, prodrug strategy has also been leveraged to address the delivery issues associated with gasotransmitters, including NO, H2S, CO as well as SO2 [5-8]. In this thematic issue, six excellent reviews were included, focusing on varied prodrug strategies in addressing different drug developability issues associated with anticancer drugs, central nervous system (CNS) drugs, and gasotransmitters....

scholarly journals In Vitro Immune Organs-on-Chip for Drug Development: A Review

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 278 ◽  
Author(s):  
Aya Shanti ◽  
Jeremy Teo ◽  
Cesare Stefanini
Keyword(s):  
Immune System ◽  
Drug Development ◽  
Attrition Rate ◽  
Human Immune System ◽  
Drug Candidates ◽  
Immune Organs ◽  
On Chip ◽  
High Attrition Rate

The current drug development practice lacks reliable and sensitive techniques to evaluate the immunotoxicity of drug candidates, i.e., their effect on the human immune system. This, in part, has resulted in a high attrition rate for novel drugs candidates. Organ-on-chip devices have emerged as key tools that permit the study of human physiology in controlled in vivo simulating environments. Furthermore, there has been a growing interest in developing the so called “body-on-chip” devices to better predict the systemic effects of drug candidates. This review describes existing biomimetic immune organs-on-chip, highlights their physiological relevance to drug development and discovery and emphasizes the need for developing comprehensive immune system-on-chip models. Such immune models can enhance the performance of novel drug candidates during clinical trials and contribute to reducing the high attrition rate as well as the high cost associated with drug development.

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