Exploring anti-malarial potential of FDA approved drugs: an in silico approach.

Malar J. 2017 Jul 18;16(1):290

Authors: Ramakrishnan G, Chandra N, Srinivasan N

Abstract
BACKGROUND: The critically important issue on emergence of drug-resistant malarial parasites is compounded by cross resistance, where resistance to one drug confers resistance to other chemically similar drugs or those that share mode of action. This aspect requires discovery of new anti-malarial compounds or formulation of new combination therapy. The current study attempts to contribute towards accelerating anti-malarial drug development efforts, by exploring the potential of existing FDA-approved drugs to target proteins of Plasmodium falciparum.
METHODS: Using comparative sequence and structure analyses, FDA-approved drugs, originally developed against other pathogens, were identified as potential repurpose-able candidates against P. falciparum. The rationale behind the undertaken approach is the likeliness of small molecules to bind to homologous targets. Such a study of evolutionary relationships between established targets and P. falciparum proteins aided in identification of approved drug candidates that can be explored for their anti-malarial potential.
RESULTS: Seventy-one FDA-approved drugs were identified that could be repurposed against P. falciparum. A total of 89 potential targets were recognized, of which about 70 are known to participate in parasite housekeeping machinery, protein biosynthesis, metabolic pathways and cell growth and differentiation, which can be prioritized for chemotherapeutic interventions. An additional aspect of prioritization of predicted repurpose-able drugs has been explored on the basis of ability of the drugs to permeate cell membranes, i.e., lipophilicity, since the parasite resides within a parasitophorous vacuole, within the erythrocyte, during the blood stages of infection. Based on this consideration, 46 of 71 FDA-approved drugs have been identified as feasible repurpose-able candidates against P. falciparum, and form a first-line for laboratory investigations. At least five of the drugs identified in the current analysis correspond to existing antibacterial agents already under use as repurposed anti-malarial agents.
CONCLUSIONS: The drug-target associations predicted, primarily by taking advantage of evolutionary information, provide a valuable resource of attractive and feasible candidate drugs that can be readily taken through further stages of anti-malarial drug development pipeline.

PMID: 28720135 [PubMed - in process]

Identification of driver copy number alterations in diverse cancer types and application in drug repositioning.

Mol Oncol. 2017 Jul 18;:

Authors: Zhou W, Zhao Z, Wang R, Han Y, Wang C, Yang F, Han Y, Liang H, Qi L, Wang C, Guo Z, Gu Y

Abstract
Results from numerous studies suggest an important role for somatic copy number alterations (SCNAs) in cancer progression. Our work aimed to identify the drivers (oncogenes or tumor suppressor genes) that reside in recurrently aberrant genomic regions, including a large number of genes or non-coding genes, which remain a challenge for decoding the SCNAs involved in carcinogenesis. Here, we propose a new approach to comprehensively identify drivers, using 8740 cancer samples involving 18 cancer types from The Cancer Genome Atlas (TCGA). On average, 84 drivers were revealed for each cancer type, including protein-coding genes, long non-coding RNAs (lncRNA) and microRNAs (miRNAs). We demonstrated that the drivers showed significant attributes of cancer genes, and significantly overlapped with known cancer genes, including MYC, CCND1, and ERBB2 in breast cancer, and the lncRNA PVT1 in multiple cancer types. Pan-cancer analyses of drivers revealed specificity and commonality across cancer types, and the non-coding drivers showed a higher cancer-type specificity than that of coding drivers. Some cancer types from different tissue origins were found to converge to high similarity because of the significant overlap of drivers, such as head and neck squamous cell carcinoma (HNSC) and lung squamous cell carcinoma (LUSC). The lncRNA SOX2-OT, a common driver of HNSC and LUSC, showed significant expression correlation with the oncogene SOX2. In addition, because some drivers are common in multiple cancer types and have been targeted by known drugs, we revealed that some drugs could be successfully repositioned which was validated by the datasets of drug response assays in cell lines. Our work reported a new method to comprehensively identify drivers in SCNAs across diverse cancer types, providing a feasible strategy for cancer drug repositioning as well as novel findings regarding cancer-associated non-coding RNA discovery. This article is protected by copyright. All rights reserved.

PMID: 28719033 [PubMed - as supplied by publisher]

Drugs currently under investigation for the treatment of invasive candidiasis.

Expert Opin Investig Drugs. 2017 Jul;26(7):825-831

Authors: McCarthy MW, Walsh TJ

Abstract
INTRODUCTION: The widespread implementation of immunosuppressants, immunomodulators, hematopoietic stem cell transplantation and solid organ transplantation in clinical practice has led to an expanding population of patients who are at risk for invasive candidiasis, which is the most common form of fungal disease among hospitalized patients in the developed world. The emergence of drug-resistant Candida spp. has added to the morbidity associated with invasive candidiasis and novel therapeutic strategies are urgently needed. Areas covered: In this paper, we explore investigational agents for the treatment of invasive candidiasis, with particular attention paid to compounds that have recently entered phase I or phase II clinical trials. Expert opinion: The antifungal drug development pipeline has been severely limited due to regulatory hurdles and a systemic lack of investment in novel compounds. However, several promising drug development strategies have recently emerged, including chemical screens involving Pathogen Box compounds, combination antifungal therapy, and repurposing of existing agents that were initially developed to treat other conditions, all of which have the potential to redefine the treatment of invasive candidiasis.

PMID: 28617137 [PubMed - indexed for MEDLINE]

Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease.

Gut. 2017 Jan;66(1):180-190

Authors: Rotman Y, Sanyal AJ

Abstract
Given the high prevalence and rising incidence of non-alcoholic fatty liver disease (NAFLD), the absence of approved therapies is striking. Although the mainstay of treatment of NAFLD is weight loss, it is hard to maintain, prompting the need for pharmacotherapy as well. A greater understanding of disease pathogenesis in recent years was followed by development of new classes of medications, as well as potential repurposing of currently available agents. NAFLD therapies target four main pathways. The dominant approach is targeting hepatic fat accumulation and the resultant metabolic stress. Medications in this group include peroxisome proliferator-activator receptor agonists (eg, pioglitazone, elafibranor, saroglitazar), medications targeting the bile acid-farnesoid X receptor axis (obeticholic acid), inhibitors of de novo lipogenesis (aramchol, NDI-010976), incretins (liraglutide) and fibroblast growth factor (FGF)-21 or FGF-19 analogues. A second approach is targeting the oxidative stress, inflammation and injury that follow the metabolic stress. Medications from this group include antioxidants (vitamin E), medications with a target in the tumour necrosis factor α pathway (emricasan, pentoxifylline) and immune modulators (amlexanox, cenicriviroc). A third group has a target in the gut, including antiobesity agents such as orlistat or gut microbiome modulators (IMM-124e, faecal microbial transplant, solithromycin). Finally, as the ongoing injury leads to fibrosis, the harbinger of liver-related morbidity and mortality, antifibrotics (simtuzumab and GR-MD-02) will be an important element of therapy. It is very likely that in the next few years several medications will be available to clinicians treating patients with NAFLD across the entire spectrum of disease.

PMID: 27646933 [PubMed - indexed for MEDLINE]

Cell specificity dictates similarities in gene expression in multiple sclerosis, Parkinson's disease, and Alzheimer's disease.

PLoS One. 2017;12(7):e0181349

Authors: Itoh Y, Voskuhl RR

Abstract
Drug repurposing is an efficient approach in new treatment development since it leverages previous work from one disease to another. While multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD) are all neurodegenerative diseases of the central nervous system (CNS) and differ in many clinical and pathological aspects, it is possible that they may share some mechanistic features. We hypothesized that focusing on gene expression in a CNS cell type specific manner might uncover similarities between diseases that could be missed using whole tissue gene expression analyses. We found similarities and differences in gene expression in these three distinct diseases, depending upon cell type. Microglia genes were increased in all three diseases, and gene expression levels were correlated strongly among these three neurodegenerative diseases. In astrocytes and endothelia, upregulation and correlations were observed only between MS and PD, but not AD. Neuronal genes were down-regulated in all three diseases, but correlations of changes of individual genes between diseases were not strong. Oligodendrocyte showed gene expression changes that were not shared among the three diseases. Together these data suggest that treatments targeting microglia are most amenable to drug repurposing in MS, PD, and AD, while treatments targeting other CNS cells must be tailored to each disease.

PMID: 28715462 [PubMed - in process]

Editorial: Computational and Experimental Approaches in Multi-target Pharmacology.

Front Pharmacol. 2017;8:443

Authors: Anastasio TJ

PMID: 28713280 [PubMed]

Drug repurposing in cancer.

Pharmacol Res. 2017 Jul 13;:

Authors: Sleire L, Førde HE, Netland IA, Leiss L, Enger PØ

Abstract
Cancer is a major health issue worldwide, and the global burden of cancer is expected to increase in the coming years. Whereas the limited success with current therapies has driven huge investments into drug development, the average number of FDA approvals per year has declined since the 1990s. This unmet need for more effective anti-cancer drugs has sparked a growing interest for drug repurposing, i.e. using drugs already approved for other indications to treat cancer. As such, data both from pre-clinical experiments, clinical trials and observational studies have demonstrated anti-tumor efficacy for compounds within a wide range of drug classes other than cancer. Whereas some of them induce cancer cell death or suppress various aspects of cancer cell behavior in established tumors, others may prevent cancer development. Here, we provide an overview of promising candidates for drug repurposing in cancer, as well as studies describing the biological mechanisms underlying their anti-neoplastic effects.

PMID: 28712971 [PubMed - as supplied by publisher]

Future Directions of Genomics Research in Rheumatic Diseases.

Rheum Dis Clin North Am. 2017 Aug;43(3):481-487

Authors: Okada Y, Kishikawa T, Sakaue S, Hirata J

Abstract
Recent developments in human genome genotyping and sequencing technologies, such as genome-wide association studies and whole-genome sequencing analyses, have successfully identified several risk genes of rheumatic diseases. Fine-mapping studies using the HLA imputation method revealed that classical and non-classical HLA genes contribute to the risk of rheumatic diseases. Integration of human disease genomics with biological, medical, and clinical databases should contribute to the elucidation of disease pathogenicity and novel drug discovery. Disease risk genes identified by large-scale genetic studies are considered to be promising resources for novel drug discovery, including drug repositioning and biomarker microRNA screening for rheumatoid arthritis.

PMID: 28711147 [PubMed - in process]

Drug Repositioning Strategies for the Identification of Novel Therapies for Rheumatic Autoimmune Inflammatory Diseases.

Rheum Dis Clin North Am. 2017 Aug;43(3):467-480

Authors: Grammer AC, Lipsky PE

Abstract
Rheumatic Autoimmune Inflammatory Diseases such as Sjögren's and lupus lack modern treatments. Less than 5% of drugs approved by the FDA from 2014 to mid-2016 had a RAID indication. Many RAID standard-of-care drugs were repurposed based on serendipitous observations, similarity-of-disease categorization, and/or off-target effects. Recently, drug repurposing has become more intentional, relying on an evolving awareness of molecular underpinnings, as well as a better understanding of drug-target interactions by computational modeling. Understanding mechanisms of disease pathogenesis can be synergistic in identifying new drug candidates and target pathways using unbiased Big-Data repositioning approaches as genomics, PheWAS (disease mechanism-of-action), GWAS and/or epigenetic-profiling.

PMID: 28711146 [PubMed - in process]

Repurposing of Potent Drug Candidates for Multiparasite Targeting.

Trends Parasitol. 2017 Mar;33(3):158-161

Authors: Jain V, Sharma A

Abstract
Parasite-directed drug discovery efforts require sustained and substantial scientific resources. Many eukaryotic parasites share similarities in metabolic pathways and housekeeping genes, as evident from their underlying protein sequences. Their subsequent structural congruence within enzyme active sites can thus be leveraged for multiparasite targeting using similar or identical drug probes. This bodes well for delivering new anti-infectives.

PMID: 28081985 [PubMed - indexed for MEDLINE]

Database of Optimized Proteomic Quantitative Methods for Human Drug Disposition-Related Proteins for Applications in Physiologically Based Pharmacokinetic Modeling.

CPT Pharmacometrics Syst Pharmacol. 2017 Apr;6(4):267-276

Authors: Vrana M, Whittington D, Nautiyal V, Prasad B

Abstract
The purpose of this study was to create an open access repository of validated liquid chromatography tandem mass spectrometry (LC-MS/MS) multiple reaction monitoring (MRM) methods for quantifying 284 important proteins associated with drug absorption, distribution, metabolism, and excretion (ADME). Various in silico and experimental approaches were used to select surrogate peptides and optimize instrument parameters for LC-MS/MS quantification of the selected proteins. The final methods were uploaded to an online public database (QPrOmics; www.qpromics.uw.edu/qpromics/assay/), which provides essential information for facile method development in triple quadrupole mass spectrometry (MS) instruments. To validate the utility of the methods, the differential tissue expression of 107 key ADME proteins was characterized in the tryptic digests of the pooled subcellular fractions of human liver, kidneys, intestines, and lungs. These methods and the data are critical for development of physiologically based pharmacokinetic (PBPK) models to predict xenobiotic disposition.

PMID: 28074615 [PubMed - indexed for MEDLINE]

Antidepressants in the Treatment of Functional Dyspepsia: A Systematic Review and Meta-Analysis.

PLoS One. 2016;11(6):e0157798

Authors: Lu Y, Chen M, Huang Z, Tang C

Abstract
BACKGROUND: Antidepressants have been empirically used in the treatment of functional dyspepsia (FD). However, results from recent clinical trials investigating their efficacy are conflicting. The aim of this study is to evaluate the efficacy of antidepressants in the management of FD in adults.
METHODS: Databases of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and BIOSIS Previews were searched for all randomized controlled trials (RCT) investigating efficacy of antidepressants in the management of FD in adult patients. Data of overall symptom unimproved and adverse events were compared between the antidepressants and placebo group.
RESULTS: The search strategy identified 432 citations. Of those, eight RCTs met the inclusion criteria and were included in the meta-analysis. The pooled relative risk (RR) of symptom unimproved with tricyclic antidepressants (TCAs) versus placebo was 0.76 (95% CI: 0.62 to 0.94, P = 0.01; I2 = 0%, P = 0.39). By contrast, selective serotonin reuptake inhibitors (SSRIs) did not show a benefit over placebo (RR = 1.00, 95% CI: 0.86 to 1.17, P = 0.95; I2 = 0%, P = 0.82). Adverse events were significantly more frequent among patients receiving antidepressants than those receiving placebos (RR = 1.64, 95% CI: 1.14 to 2.35, P = 0.007).
CONCLUSION: TCAs but not SSRIs, are effective in the treatment of FD, but antidepressants were also associated with more adverse events compared with placebo.

PMID: 27310135 [PubMed - indexed for MEDLINE]

Vinblastine as a second rescue for the treatment of canine multicentric lymphoma in 39 cases (2005 to 2014).

J Small Anim Pract. 2016 Aug;57(8):429-34

Authors: Lenz JA, Robat CS, Stein TJ

Abstract
OBJECTIVES: The objective of this study was to retrospectively evaluate response and outcome of dogs with multicentric lymphoma treated with single-agent vinblastine as a second rescue.
METHODS: Medical records from 39 client-owned dogs receiving vinblastine rescue treatment (having relapsed on or following completion of UW-Madison and CCNU/L-asparaginase protocols), between 2005 and 2014, were reviewed for information regarding clinical presentation, diagnostic testing, drug dosage, number of treatments, side effects, response and outcome.
RESULTS: The median starting dose of vinblastine was 2·6 mg/m(2) (1·7 to 2·8 mg/m(2) ), administered weekly until disease progression. Of the 39 dogs treated, 3 dogs (7·7%) achieved a complete remission, 7 dogs (17·9%) achieved a partial response, 18 dogs (46·2%) maintained stable disease and 11 (28·2%) had progressive disease. Ten dogs (25·6%) developed a grade III or IV neutropenia, and 4 dogs (10·3%) developed grade III or IV thrombocytopenia (one dog in both categories). After starting vinblastine, the median progression-free survival was 29·5 days (0 to 77 days) and overall median survival time was 46 days (4 to 250 days). Duration of first remission was identified as a positive predictor of outcome.
CLINICAL SIGNIFICANCE: Single-agent vinblastine is well tolerated in dogs with relapsed or refractory lymphoma. Responses were incomplete and short-lasting.

PMID: 27251593 [PubMed - indexed for MEDLINE]

Generating Gene Ontology-Disease Inferences to Explore Mechanisms of Human Disease at the Comparative Toxicogenomics Database.

PLoS One. 2016;11(5):e0155530

Authors: Davis AP, Wiegers TC, King BL, Wiegers J, Grondin CJ, Sciaky D, Johnson RJ, Mattingly CJ

Abstract
Strategies for discovering common molecular events among disparate diseases hold promise for improving understanding of disease etiology and expanding treatment options. One technique is to leverage curated datasets found in the public domain. The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) manually curates chemical-gene, chemical-disease, and gene-disease interactions from the scientific literature. The use of official gene symbols in CTD interactions enables this information to be combined with the Gene Ontology (GO) file from NCBI Gene. By integrating these GO-gene annotations with CTD's gene-disease dataset, we produce 753,000 inferences between 15,700 GO terms and 4,200 diseases, providing opportunities to explore presumptive molecular underpinnings of diseases and identify biological similarities. Through a variety of applications, we demonstrate the utility of this novel resource. As a proof-of-concept, we first analyze known repositioned drugs (e.g., raloxifene and sildenafil) and see that their target diseases have a greater degree of similarity when comparing GO terms vs. genes. Next, a computational analysis predicts seemingly non-intuitive diseases (e.g., stomach ulcers and atherosclerosis) as being similar to bipolar disorder, and these are validated in the literature as reported co-diseases. Additionally, we leverage other CTD content to develop testable hypotheses about thalidomide-gene networks to treat seemingly disparate diseases. Finally, we illustrate how CTD tools can rank a series of drugs as potential candidates for repositioning against B-cell chronic lymphocytic leukemia and predict cisplatin and the small molecule inhibitor JQ1 as lead compounds. The CTD dataset is freely available for users to navigate pathologies within the context of extensive biological processes, molecular functions, and cellular components conferred by GO. This inference set should aid researchers, bioinformaticists, and pharmaceutical drug makers in finding commonalities in disease mechanisms, which in turn could help identify new therapeutics, new indications for existing pharmaceuticals, potential disease comorbidities, and alerts for side effects.

PMID: 27171405 [PubMed - indexed for MEDLINE]

Repurposing ivacaftor for treatment of staphylococcus aureus infections.

Int J Antimicrob Agents. 2017 Jul 07;:

Authors: Thakare R, Singh AK, Das S, Vasudevan N, Jachak GR, Reddy DS, Dasgupta A, Chopra S

Abstract
Drug repurposing of non-antimicrobials is a novel method to augment a seriously depleted drug pipeline for targeting drug-resistant pathogens. This article highlights the potent antimicrobial activity of Ivacaftor against Staphylococcus aureus, including vancomycin- and other multidrug-resistant strains. The potent activity of Ivacaftor in vivo is also demonstrated in a murine neutropenic thigh infection model. Taken together, these results support the potential of Ivacaftor as an antimicrobial agent for the treatment of staphylococcal infections.

PMID: 28694231 [PubMed - as supplied by publisher]

A Framework for the Targeted Selection of Herbs with Similar Efficacy by Exploiting Drug Repositioning Technique and Curated Biomedical Knowledge.

J Ethnopharmacol. 2017 Jul 04;:

Authors: Yea SJ, Kim BY, Kim C, Yi MY

Abstract
ETHNO PHARMACOLOGICAL RELEVANCE: Plants have been the most important natural resources for traditional medicine and for the modern pharmaceutical industry. They have been in demand in regards to finding alternative medicinal herbs with similar efficacy. Due to the very low probability of discovering useful compounds by random screening, researchers have advocated for using targeted selection approaches. Furthermore, because drug repositioning can speed up the process of drug development, an integrated technique that exploits chemical, genetic, and disease information has been recently developed. Building upon these findings, in this paper, we propose a novel framework for the targeted selection of herbs with similar efficacy by exploiting drug repositioning technique and curated modern scientific biomedical knowledge, with the goal of improving the possibility of inferring the traditional empirical ethno-pharmacological knowledge.
MATERIALS AND METHODS: To rank candidate herbs on the basis of similarities against target herb, we proposed and evaluated a framework that is comprised of the following four layers: links, extract, similarity, and model. In the framework, multiple databases are linked to build an herb-compound-protein-disease network which was composed of one tripartite network and two bipartite networks allowing comprehensive and detailed information to be extracted. Further, various similarity scores between herbs are calculated, and then prediction models are trained and tested on the basis of theses similarity features.
RESULTS: The proposed framework has been found to be feasible in terms of link loss. Out of the 50 similarities, the best one enhanced the performance of ranking herbs with similar efficacy by about 120-320% compared with our previous study. Also, the prediction model showed improved performance by about 180-480%. While building the prediction model, we identified the compound information as being the most important knowledge source and structural similarity as the most useful measure.
CONCLUSIONS: In the proposed framework, we took the knowledge of herbal medicine, chemistry, biology, and medicine into consideration to rank herbs with similar efficacy in candidates. The experimental results demonstrated that the performances of framework outperformed the baselines and identified the important knowledge source and useful similarity measure.

PMID: 28687508 [PubMed - as supplied by publisher]

Drug repurposing screens and synergistic drug-combinations for infectious diseases.

Br J Pharmacol. 2017 Jul 07;:

Authors: Zheng W, Sun W, Simeonov A

Abstract
Infectious diseases account for nearly one fifth of the worldwide death toll every year. Continuous increase of drug-resistant pathogens is a big challenge for treatment of infectious diseases. In addition, emerging outbreaks of infections and new pathogens are potential threats to public health. Lack of effective treatments for drug-resistant bacteria and recent outbreaks of Ebola and Zika viral infections have become a global public health concern. The number of newly approved antibiotics has decreased significantly in the last two decades compared to previous decades. Inversely paralleled with this, is an increase in the number of trend of drug-resistant bacteria. To counter these threats and challenges, new strategies and technology platforms are critically needed. Drug repurposing has emerged as an alternative approach for rapid identification of effective therapeutics to treat the infectious diseases. For treatment of severe infections, synergistic drug combination using approved drugs identified from drug repurposing screens is a useful option which may overcome the problem of weak activity of individual drugs. Collaborative efforts including government, academic researchers and private drug industry can facilitate the translational research to produce more effective new therapeutics such as narrow spectrum antibiotics against drug-resistant bacteria for these global challenges.

PMID: 28685814 [PubMed - as supplied by publisher]

DeCAF-Discrimination, Comparison, Alignment Tool for 2D PHarmacophores.

Molecules. 2017 Jul 06;22(7):

Authors: Stepniewska-Dziubinska MM, Zielenkiewicz P, Siedlecki P

Abstract
Comparison of small molecules is a common component of many cheminformatics workflows, including the design of new compounds and libraries as well as side-effect predictions and drug repurposing. Currently, large-scale comparison methods rely mostly on simple fingerprint representation of molecules, which take into account the structural similarities of compounds. Methods that utilize 3D information depend on multiple conformer generation steps, which are computationally expensive and can greatly influence their results. The aim of this study was to augment molecule representation with spatial and physicochemical properties while simultaneously avoiding conformer generation. To achieve this goal, we describe a molecule as an undirected graph in which the nodes correspond to atoms with pharmacophoric properties and the edges of the graph represent the distances between features. This approach combines the benefits of a conformation-free representation of a molecule with additional spatial information. We implemented our approach as an open-source Python module called DeCAF (Discrimination, Comparison, Alignment tool for 2D PHarmacophores), freely available at http://bitbucket.org/marta-sd/decaf. We show DeCAF's strengths and weaknesses with usage examples and thorough statistical evaluation. Additionally, we show that our method can be manually tweaked to further improve the results for specific tasks. The full dataset on which DeCAF was evaluated and all scripts used to calculate and analyze the results are also provided.

PMID: 28684712 [PubMed - in process]

More Treatments on Deck for Alcohol Use Disorder.

JAMA. 2017 Jun 13;317(22):2267-2269

Authors: Lyon J

PMID: 28538998 [PubMed - indexed for MEDLINE]

Molecular docking studies on thirteen fluoroquinolines with human topoisomerase II a and b.

In Silico Pharmacol. 2016 Dec;5(1):4

Authors: Jadhav AK, Karuppayil SM

Abstract
DNA relaxation is an important step in DNA replication. DNA topoisomerases play a major role in DNA relaxation. Hence these enzymes are important targets for cancer drugs. DNA topoisomerase inhibitors bind to the transient enzyme-DNA complex and inhibit DNA replication. Various inhibitors of topoisomerase I and II are prescribed as drugs. Topoisomerase II is considered as an important target for the development of anticancer drugs. In this study we have demonstrated molecular docking of thirteen fluoroquinolines with human DNA topoisomerase II alpha (a) and beta (b). Fluoroquinolines are broad spectrum antibacterial antibiotics and it is highly effective against various bacterial infections. Some of the fluoroquinolines like moxifloxacin exert antifungal as well as anti-cancer activity. It forms complexes with topoisomerase II a and are responsible for stoppage DNA replication. Molecular docking studies showed that fluoroquinolines has shown formation of hydrogen bond and good binding affinity with human Topo2a and Topo2b. Hence FQs may inhibit the activity of enzyme topoisomerase by binding at its active site. Ofloxacin, sparafloxacin, ciprofloxacin and moxifloxacin are predicted to be the most potent inhibitors among the thirteen FQs docked. GLN773, ASN770, LYS723 and TRP931 amino acid residues of Topo2a are involved in binding with FQs while ASP479, SER480, ARG820, ARG503, LYS456 and GLN778 amino acid residues of Topo2b are involved in binding with FQs. Our in silico study suggests that fluoroquinolines could be repositioned as DNA topoisomerase II inhibitors hence can be used as anticancer drugs. In vitro and in vivo experiments need to be done to confirm their efficacy.

PMID: 28667488 [PubMed - in process]