Prediction of new drug indications based on clinical data and network modularity.

Sci Rep. 2016;6:32530

Authors: Yu L, Ma X, Zhang L, Zhang J, Gao L

Abstract
Drug repositioning is commonly done within the drug discovery process in order to adjust or expand the application line of an active molecule. Previous computational methods in this domain mainly focused on shared genes or correlations between genes to construct new drug-disease associations. We propose a method that can not only handle drugs or diseases with or without related genes but consider the network modularity. Our method firstly constructs a drug network and a disease network based on side effects and symptoms respectively. Because similar drugs imply similar diseases, we then cluster the two networks to identify drug and disease modules, and connect all possible drug-disease module pairs. Further, based on known drug-disease associations in CTD and using local connectivity of modules, we predict potential drug-disease associations. Our predictions are validated by testing their overlaps with drug indications reported in published literatures and CTD, and KEGG enrichment analysis are also made on their related genes. The experimental results demonstrate that our approach can complement the current computational approaches and its predictions can provide new clues for the candidate discovery of drug repositioning.

PMID: 27678071 [PubMed - as supplied by publisher]

In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state.

Aging (Albany NY). 2016 Sep 24;

Authors: Aliper A, Belikov AV, Garazha A, Jellen L, Artemov A, Suntsova M, Ivanova A, Venkova L, Borisov N, Buzdin A, Mamoshina P, Putin E, Swick AG, Moskalev A, Zhavoronkov A

Abstract
Populations in developed nations throughout the world are rapidly aging, and the search for geroprotectors, or anti-aging interventions, has never been more important. Yet while hundreds of geroprotectors have extended lifespan in animal models, none have yet been approved for widespread use in humans. GeroScope is a computational tool that can aid prediction of novel geroprotectors from existing human gene expression data. GeroScope maps expression differences between samples from young and old subjects to aging-related signaling pathways, then profiles pathway activation strength (PAS) for each condition. Known substances are then screened and ranked for those most likely to target differential pathways and mimic the young signalome. Here we used GeroScope and shortlisted ten substances, all of which have lifespan-extending effects in animal models, and tested 6 of them for geroprotective effects in senescent human fibroblast cultures. PD-98059, a highly selective MEK1 inhibitor, showed both life-prolonging and rejuvenating effects. Natural compounds like N-acetyl-L-cysteine, Myricetin and Epigallocatechin gallate also improved several senescence-associated properties and were further investigated with pathway analysis. This work not only highlights several potential geroprotectors for further study, but also serves as a proof-of-concept for GeroScope, Oncofinder and other PAS-based methods in streamlining drug prediction, repurposing and personalized medicine.

PMID: 27677171 [PubMed - as supplied by publisher]

Targeting PI4K for Radiosensitization: A Potential Model of Drug Repositioning.

Int J Radiat Oncol Biol Phys. 2016 Oct 1;96(2S):E558

Authors: Kim IA, Kwon J, Park YH, Kim DH, Park JM

PMID: 27675011 [PubMed - as supplied by publisher]

Polypharmacology in Precision Oncology: Current Applications and Future Prospects.

Curr Pharm Des. 2016 Sep 23;

Authors: Antolin AA, Workman P, Mestres J, Al-Lazikani B

Abstract
Over the past decade, a more comprehensive, large-scale approach to studying cancer genetics and biology has revealed the challenges of tumor heterogeneity, adaption, evolution and drug resistance, while systems-based pharmacology and chemical biology strategies have uncovered a much more complex interaction between drugs and the human proteome than was previously anticipated. In this mini-review we assess the progress and potential of drug polypharmacology in biomarker-driven precision oncology. Polypharmacology not only provides great opportunities for drug repurposing to exploit off-target effects in a new single-target indication but through simultaneous blockade of multiple targets or pathways offers exciting opportunities to slow, overcome or even prevent inherent or adaptive drug resistance. We highlight the many challenges associated with exploiting known or desired polypharmacology in drug design and development, and assess computational and experimental methods to uncover unknown polypharmacology. A comprehensive understanding of the intricate links between polypharmacology, efficacy and safety is urgently needed if we are to tackle the enduring challenge of cancer drug resistance and to fully exploit polypharmacology for the ultimate benefit of cancer patients.

PMID: 27669965 [PubMed - as supplied by publisher]

Busting the billion-dollar myth: how to slash the cost of drug development.

Nature. 2016 Aug 25;536(7617):388-90

Authors: Maxmen A

PMID: 27558048 [PubMed - indexed for MEDLINE]

Repurposed therapeutic agents targeting the Ebola virus: a protocol for a systematic review.

Syst Rev. 2015;4:171

Authors: Sweiti H, Ekwunife O, Jaschinski T, Lhachimi SK

Abstract
BACKGROUND: The recent Ebola epidemic in western Africa developed into an acute public health emergency of unprecedented level in modern times. The treatment provided in most cases has been limited to supportive care, as no approved therapies are available to date. Several established, licenced drugs have been suggested as potential repurposed therapeutic agents for Ebola. However, scientific data on their efficacy in treating Ebola is limited. The purpose of this review is to systematically assess scientific evidence on potential drugs targeting Ebola. In specific, we aim to (1) identify drug library screens involving therapeutic agents targeting the Ebola virus, (2) list potential approved drugs identified from drug screens and review their mechanism of action against the Ebola virus and (3) summarise the outcome of preclinical and clinical trials investigating approved drugs targeting the Ebola virus.
METHODS/DESIGN: We will develop comprehensive systematic search strategies and will perform a systematic literature search in MEDLINE, Embase and Cochrane Central Register of Controlled Trials (CENTRAL). Two authors will independently screen the titles, abstracts and the references of all selected articles on the basis of inclusion criteria. These include any available drug screening, preclinical studies and clinical studies examining the efficacy of approved therapeutic agents targeting the Ebola virus. There will be no restrictions on the type of participants, the type of comparator, time or setting. Data extraction and quality assessment will be undertaken by two review authors working independently.
DISCUSSION: This systematic review will provide systematic knowledge on potential repurposed therapeutic agents targeting Ebola. It aims to help guide future investigations on repurposed drugs and avoid repetitive studies.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015024349.

PMID: 26607658 [PubMed - indexed for MEDLINE]

Modeling of Plasmodium falciparum Telomerase Reverse Transcriptase Ternary Complex: Repurposing of Nucleoside Analog Inhibitors.

Assay Drug Dev Technol. 2015 Dec;13(10):628-37

Authors: Mohanty P, Gupta A, Bhatnagar S

Abstract
The Plasmodium falciparum telomerase reverse transcriptase (PfTERT) is a ribonucleoprotein that assists the maintenance of the telomeric ends of chromosomes by reverse transcription of its own RNA subunit. It represents an attractive therapeutic target for eradication of the plasmodial parasite at the asexual liver stage. Automated modeling using MUSTER and knowledge-based techniques were used to obtain a three-dimensional model of the active site of reverse transcriptase domain of PfTERT, which is responsible for catalyzing the addition of incoming dNTPs to the growing DNA strand in presence of divalent magnesium ions. Further, the ternary complex of the active site of PfTERT bound to a DNA-RNA duplex was also modeled using Haddock server and represents the functional form of the enzyme. Initially, established nucleoside analog inhibitors of PfTERT, AZTTP, and ddGTP were docked in the modeled binding site of the PfTERT ternary complex using AutoDock v4.2. Subsequently, docking studies were carried out with 14 approved nucleoside analog inhibitors. Docking studies predicted that floxuridine, gemcitabine, stavudine, and vidarabine have high affinity for the PfTERT ternary complex. Further analysis on the basis of known side effects led us to propose repositioning of vidarabine as a suitable drug candidate for inhibition of PfTERT.

PMID: 26690766 [PubMed - indexed for MEDLINE]

Interview with Raúl Insa, MD, PhD.

Assay Drug Dev Technol. 2015 Dec;13(10):603-5

Authors: Insa R, Mucke H

PMID: 26690763 [PubMed - indexed for MEDLINE]

Regulatory exclusivities for medicinal products for human use in the EU.

Pharm Pat Anal. 2016;5(1):5-8

Authors: Schoonderbeek C, Jong B

PMID: 26674744 [PubMed - indexed for MEDLINE]

New Indications and a Sense of (Re)purpose.

EBioMedicine. 2015 Oct;2(10):1257-8

Authors:

PMID: 26629497 [PubMed - indexed for MEDLINE]

Repurposing Kinase Inhibitors as Antiviral Agents to Control Influenza A Virus Replication.

Assay Drug Dev Technol. 2015 Dec;13(10):638-49

Authors: Perwitasari O, Yan X, O'Donnell J, Johnson S, Tripp RA

Abstract
Influenza A virus (IAV) infection causes seasonal epidemics of contagious respiratory illness that causes substantial morbidity and some mortality. Regular vaccination is the principal strategy for controlling influenza virus, although vaccine efficacy is variable. IAV antiviral drugs are available; however, substantial drug resistance has developed to two of the four currently FDA-approved antiviral drugs. Thus, new therapeutic approaches are being sought to reduce the burden of influenza-related disease. A high-throughput screen using a human kinase inhibitor library was performed targeting an emerging IAV strain (H7N9) in A549 cells. The inhibitor library contained 273 structurally diverse, active cell permeable kinase inhibitors with known bioactivity and safety profiles, many of which are at advanced stages of clinical development. The current study shows that treatment of human A549 cells with kinase inhibitors dinaciclib, flavopiridol, or PIK-75 exhibits potent antiviral activity against H7N9 IAV as well as other IAV strains. Thus, targeting host kinases can provide a broad-spectrum therapeutic approach against IAV. These findings provide a path forward for repurposing existing kinase inhibitors safely as potential antivirals, particularly those that can be tested in vivo and ultimately for clinical use.

PMID: 26192013 [PubMed - indexed for MEDLINE]

Radiation Protective Effects of Baclofen Predicted by a Computational Drug Repurposing Strategy.

Pharmacol Res. 2016 Sep 21;

Authors: Ren L, Xie D, Li P, Qu X, Zhang X, Xing Y, Zhou P, Bo X, Zhou Z, Wang S

Abstract
Exposure to ionizing radiation causes damage to living tissues; however, only a small number of agents have been approved for use in radiation injuries. Radioprotector is the primary countermeasure to radiation injury and none radioprotector has indeed reached the drug development stage. Repurposing the long list of approved, non-radioprotective drugs is an attractive strategy to find new radioprotective agents. Here, we applied a computational approach to discover new radioprotectors in silico by comparing publicly available gene expression data of ionizing radiation-treated samples from the Gene Expression Omnibus (GEO) database with gene expression signatures of more than 1,309 small-molecule compounds from the Connectivity Map (cmap) dataset. Among the best compounds predicted to be therapeutic for ionizing radiation damage by this approach were some previously reported radioprotectors and baclofen (P<0.01), a chemical that was not previously used as radioprotector. Validation using a cell-based model and a rodent in vivo model demonstrated that treatment with baclofen reduced radiation-induced cytotoxicity in vitro (P<0.01), attenuated bone marrow damage and increased survival in vivo (P<0.05). These findings suggest that baclofen might serve as a radioprotector. The drug repurposing strategy by connecting the GEO data and cmap can be used to identify known drugs as potential radioprotective agents.

PMID: 27664700 [PubMed - as supplied by publisher]

In Silico Prediction and In Vitro and In Vivo Validation of Acaricide Fluazuron as a Potential Inhibitor of FGFR3 and a Candidate Anticancer Drug for Bladder Carcinoma.

Chem Biol Drug Des. 2016 Sep 24;

Authors: Ke K, Li H, Yao H, Shi XN, Dong C, Zhu Y, Liu X, Li L, Leung KS, Wong MH, Liu XD, Kung HF, Lin MC

Abstract
Bladder carcinoma (BC) is the 9(th) most common cause of cancer worldwide. Surgical resection and conventional chemotherapy and radiotherapy will ultimately fail due to tumor recurrence and resistance. Thus, the development of novel treatment is urgently needed. Fibroblast growth factor receptor 3 (FGFR3) is an important and well-established target for BC treatment. In this study, we utilized the free and open-source protein-ligand docking software idock to prospectively identify potential inhibitors of FGFR3 from 3167 worldwide approved small-molecule drugs using a repositioning strategy. Six high-scoring compounds were purchased and tested in vitro. Among them, the acaricide drug fluazuron exhibited the highest anti-proliferative effect in human BC cell lines RT112 and RT4. We further demonstrated that fluazuron treatment significantly increased the percentage of apoptosis cells, decreased the phosphorylation level of FGFR3 and its downstream proteins FRS2-α, AKT and ERK. We also investigated the anticancer effect of fluazuron in vivo in BALB/C nude mice subcutaneously xenografted with RT112 cells. Our results showed that oral treatment with fluazuron (80mg/kg) significantly inhibited tumor growth. These results suggested for the first time that fluazuron is a potential inhibitor of FGFR3 and a candidate anticancer drug for the treatment of BC. This article is protected by copyright. All rights reserved.

PMID: 27664399 [PubMed - as supplied by publisher]

Poly(ADP-ribose)polymerase is not involved in the neuroprotection exerted by azithromycin against ischemic stroke in mice.

Eur J Pharmacol. 2016 Sep 20;

Authors: Petrelli F, Muzzi M, Chiarugi A, Bagetta G, Amantea D

Abstract
Repurposing azithromycin has recently emerged as a promising strategy for the acute treatment of ischemic stroke. The mechanism of neuroprotection depends on the ability of this macrolide to promote polarization of microglia/macrophages towards beneficial M2 phenotypes. The immunomodulatory and anti-inflammatory effects of azithromycin, well documented in chronic inflammatory airway diseases, have been ascribed to the inhibition of the transcription factors nuclear factor (NF)-κB and activator protein (AP)-1. Since these inflammatory transcription factors are positively regulated by poly(ADP-ribose)polymerase (PARP)-1, an enzyme actively involved in ischemic brain injury, we have investigated whether the neuroprotective properties of azithromycin in ischemic stroke involve upstream modulation of PARP-1. Administration of a single dose of this macrolide antibiotic upon reperfusion reduced, to a similar extent in wild type and PARP-1 knockout mice, infarct brain damage produced by transient occlusion of the middle cerebral artery. Moreover, we demonstrated the lack of effects of azithromycin on PARP-dependent death of HeLa cells, as well as on activity of purified PARP-1 and PARP-2. Thus, azithromycin protects mice against ischemic stroke injury through a mechanism independent of PARP activation.

PMID: 27663279 [PubMed - as supplied by publisher]

Repurposing of nitroxoline as a potential anticancer agent against human prostate cancer: a crucial role on AMPK/mTOR signaling pathway and the interplay with Chk2 activation.

Oncotarget. 2015 Nov 24;6(37):39806-20

Authors: Chang WL, Hsu LC, Leu WJ, Chen CS, Guh JH

Abstract
Nitroxoline is an antibiotic by chelating Zn2+ and Fe2+ from biofilm matrix. In this study, nitroxoline induced G1 arrest of cell cycle and subsequent apoptosis in prostate cancer cells through ion chelating-independent pathway. It decreased protein levels of cyclin D1, Cdc25A and phosphorylated Rb, but activated AMP-activated protein kinase (AMPK), a cellular energy sensor and signal transducer, leading to inhibition of downstream mTOR-p70S6K signaling. Knockdown of AMPKα significantly rescued nitroxoline-induced inhibition of cyclin D1-Rb-Cdc25A axis indicating AMPK-dependent mechanism. However, cytoprotective autophagy was simultaneously evoked by nitroxoline. Comet assay and Western blot analysis demonstrated DNA damaging effect and activation of Chk2 other than Chk1 to nitroxoline action. Instead of serving as a DNA repair transducer, nitroxoline-mediated Chk2 activation was identified to function as a pro-apoptotic inducer. In conclusion, the data suggest that nitroxoline induces anticancer activity through AMPK-dependent inhibition of mTOR-p70S6K signaling pathway and cyclin D1-Rb-Cdc25A axis, leading to G1 arrest of cell cycle and apoptosis. AMPK-dependent activation of Chk2, at least partly, contributes to apoptosis. The data suggest the potential role of nitroxoline for therapeutic development against prostate cancers.

PMID: 26447757 [PubMed - indexed for MEDLINE]

In silico prediction of chemical mechanism-of-action via an improved network-based inference method.

Br J Pharmacol. 2016 Sep 20;

Authors: Wu Z, Lu W, Wu D, Luo A, Bian H, Li J, Li W, Liu G, Huang J, Cheng F, Tang Y

Abstract
BACKGROUND AND PURPOSE: Deciphering chemical mechanism-of-action (MoA) enables the development of novel therapeutics (e.g. drug repositioning) and evaluation of drug side effects. Development of novel computational methods for chemical MoA assessment under systems pharmacology framework would accelerate drug discovery and development with high efficiency and low cost.
EXPERIMENTAL APPROACH: In this study, we proposed an improved network-based inference method, namely balanced substructure-drug-target network-based inference (bSDTNBI), to predict MoA for old drugs, clinical failed drugs, and new chemical entities. Specifically, three parameters were introduced into network-based resource diffusion processes to adjust the initial resource allocation of different node types, the weighted values of different edge types, and the influence of hub nodes, respectively. The performance of the method was systematically validated by benchmark datasets and bioassays.
KEY RESULTS: High performance was yielded for bSDTNBI in both 10-fold and leave-one-out cross validations. A global drug-target network was built to explore MoA of anticancer drugs and repurpose old drugs for 15 cancer types/subtypes. In a case study, 27 predicted candidates among 56 commercially available compounds were experimentally validated to have binding affinities on estrogen receptor α with IC50 or EC50 values ≤ 10 μM. Furthermore, two dual ligands with both agonistic and antagonistic activities ≤ 1 μM would provide potential lead compounds for the development of novel targeted therapy in breast cancer or osteoporosis.
CONCLUSION AND IMPLICATIONS: In summary, bSDTNBI would provide a powerful tool for the MoA assessment on both old drugs and novel compounds in drug discovery and development.

PMID: 27646592 [PubMed - as supplied by publisher]

Repurposing of approved cardiovascular drugs.

J Transl Med. 2016;14(1):269

Authors: Ishida J, Konishi M, Ebner N, Springer J

Abstract
Research and development of new drugs requires both long time and high costs, whereas safety and tolerability profiles make the success rate of approval very low. Drug repurposing, applying known drugs and compounds to new indications, has been noted recently as a cost-effective and time-unconsuming way in developing new drugs, because they have already been proven safe in humans. In this review, we discuss drug repurposing of approved cardiovascular drugs, such as aspirin, beta-blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, cardiac glycosides and statins. Regarding anti-tumor activities of these agents, a number of experimental studies have demonstrated promising pleiotropic properties, whereas all clinical trials have not shown expected results. In pathological conditions other than cancer, repurposing of cardiovascular drugs is also expanding. Numerous experimental studies have reported possibilities of drug repurposing in this field and some of them have been tried for new indications ('bench to bedside'), while unexpected results of clinical studies have given hints for drug repurposing and some unknown mechanisms of action have been demonstrated by experimental studies ('bedside to bench'). The future perspective of experimental and clinical studies using cardiovascular drugs are also discussed.

PMID: 27646033 [PubMed - as supplied by publisher]

Neuroprotective and immunomodulatory effects of raloxifene in the myenteric plexus of a mouse model of Parkinson's disease.

Neurobiol Aging. 2016 Aug 16;48:61-71

Authors: Poirier AA, Côté M, Bourque M, Morissette M, Di Paolo T, Soulet D

Abstract
Motor symptoms in Parkinson's disease (PD) are often preceded by nonmotor symptoms related to dysfunctions of the autonomic nervous system such as constipation, defecatory problems, and delayed gastric emptying. These gastrointestinal impairments are associated with the alteration of dopaminergic (DAergic) neurons in the myenteric plexus of the gut. Recently, we demonstrated the anti-inflammatory properties of estrogens to treat intestinal neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The present study aimed to investigate the neuroprotective and anti-inflammatory roles of raloxifene, a selective estrogen receptor modulator (SERM) already commercialized for osteoporosis treatment. In MPTP-treated mice, we found that raloxifene decreased the loss of DAergic neurons and prevented the increase in proinflammatory macrophage density in the myenteric plexus. Interestingly, raloxifene activity was prevented by the G protein-coupled estrogen receptor 1 (GPER1) antagonist G15, suggesting that raloxifene effects were mainly mediated by GPER1. Moreover, monocytic cell proinflammatory polarization, nuclear factor-kappa B (NF-κB) response, nitric oxide (NO), and proinflammatory cytokines production following 1-methyl-4-phenylpyridinium (MPP(+)) treatment were also prevented by raloxifene in vitro. Overall, the present results suggest that raloxifene may help preventing the loss of DAergic neurons in the myenteric plexus in an MPTP mouse model of PD, at least in part through its anti-inflammatory effects. This suggests that drug repurposing of raloxifene might represent a promising therapeutic avenue to prevent systemic inflammation and peripheral neuronal dysfunction at early PD stages.

PMID: 27644075 [PubMed - as supplied by publisher]

Preclinical development of moxidectin as a novel therapeutic for alcohol use disorder.

Neuropharmacology. 2016 Sep 15;

Authors: Huynh N, Arabian N, Naito A, Louie S, Jakowec MW, Asatryan L, Davies DL

Abstract
Current pharmacotherapies for alcohol used disorder (AUD) are few and relatively ineffective illustrating the need for the development of new, effective medications. Using a translational approach, our laboratory reported that ivermectin, an FDA-approved, human and animal anti-parasitic agent, can significantly reduce ethanol intake in male and female mice across different drinking paradigms. Extending this line of investigation, the current paper investigated the utility of moxidectin (MOX), an analogue of ivermectin, to reduce ethanol intake. Notably, MOX is widely held to have lower neurotoxicity potential and improved margin of safety compared to ivermectin. Using a 24-h-two-bottle choice paradigm, MOX significantly reduced ethanol intake in a dose dependent manner in both male and female C57BL/6J mice, respectively (1.25-7.5 mg/kg) and (1.25-10 mg/kg). Further, multi-day administration of MOX (2.5 mg/kg; intraperitoneal injection) for 5 consecutive days significantly reduced ethanol intake in both the 24-h-two-bottle choice and Drinking-in-the-Dark paradigms in female mice. No overt signs of behavioral toxicity were observed. Notably in both male and female mice, MOX significantly reduced ethanol intake starting approximately 4 h post-injection. Using a Xenopus oocyte expression system, we found that MOX significantly potentiated P2X4 receptors (P2X4R) function and antagonized the inhibitory effects of ethanol on ATP-gated currents in P2X4Rs. This latter finding represents the first report of MOX having activity on P2X4Rs. In addition, MOX potentiated GABAA receptors, but to a lesser degree as compared to ivermectin supporting the hypothesis that MOX would be advantageous (compared to ivermectin) with respect to reducing contraindications. Overall, the results illustrate the potential for development of MOX as a novel pharmacotherapy for the treatment of AUD.

PMID: 27641072 [PubMed - as supplied by publisher]

In silico drug re-purposing against African sleeping sickness using GlcNAc-PI de-N-acetylase as an experimental target.

Comput Biol Chem. 2015 Dec;59 Pt A:87-94

Authors: Rashmi M, Swati D

Abstract
Trypanosoma brucei is a protozoan that causes African sleeping sickness in humans. Many glycoconjugate compounds are present on the entire cell surface of Trypanosoma brucei to control the infectivity and survival of this pathogen. These gycoconjugates are anchored to the plasma membrane with the help of glycosyl phosphatidyl inositol (GPI) anchors. This type of anchor is much more common in protozoans than in other eukaryotes. The second step of glycosyl phosphatidyl inositol (GPI) anchor biosynthesis is catalyzed by an enzyme, which is GlcNAc-PI de-N-acetylase. GlcNAc-PI de-N-acetylase has a conserved GPI domain, which is responsible for the functionality of this enzyme. In this study, the three-dimensional structure of the target is modelled by I-TASSER and the ligand is modelled by PRODRG server. It is found that the predicted active site residues of the GPI domain are ultra-conserved for the Trypanosomatidae family. The predicted active site residues are His41, Pro42, Asp43, Asp44, Met47, Phe48, Ser74, Arg80, His103, Val144, Ser145, His147 and His150. Two hydrogen bond acceptors and four hydrogen bond donors are found in the modelled pharmacophore. All compounds of the Drugbank database and twenty three known inhibitors have been considered for structure based virtual screening. This work is focused on approved drugs because they are already tested for safety and effectiveness in humans. After the structure-based virtual screening, seventeen approved drugs and two inhibitors are found, which interact with the ligand on the basis of the designed pharmacophore. The docking has been performed for the resultant seventeen approved drugs and two known inhibitors. Two approved drugs have negative binding energy and their pKa values are similar to the selected known inhibitors. The result of this study suggests that the approved drugs Ethambutol (DB00330) and Metaraminol (DB00610) may prove useful in the treatment of African sleeping sickness.

PMID: 26476127 [PubMed - indexed for MEDLINE]