Repurposed quinacrine synergizes with cisplatin, reducing the effective dose required for treatment of head and neck squamous cell carcinoma.

Oncotarget. 2019 Aug 27;10(50):5229-5244

Authors: Bryant J, Batis N, Franke AC, Clancey G, Hartley M, Ryan G, Brooks J, Southam AD, Barnes N, Parish J, Roberts S, Khanim F, Spruce R, Mehanna H

Abstract
Despite highly toxic treatments, head and neck squamous cell carcinoma (HNSCC) have poor outcomes. There is an unmet need for more effective, less toxic therapies. Repurposing of clinically-approved drugs, with known safety profiles, may provide a time- and cost-effective approach to address this need. We have developed the AcceleraTED platform to repurpose drugs for HNSCC treatment; using in vitro assays (cell viability, clonogenic survival, apoptosis) and in vivo models (xenograft tumors in NOD/SCID/gamma mice). Screening a library of clinically-approved drugs identified the anti-malarial agent quinacrine as a candidate, which significantly reduced viability in a concentration dependent manner in five HNSCC cell lines (IC50 0.63-1.85 μM) and in six primary HNSCC samples (IC50 ~2 μM). Decreased clonogenic survival, increased apoptosis and accumulation of LC3-II (indicating altered autophagy) were also observed. Effects were additional to those resulting from standard treatments (cisplatin +/- irradiation) alone. In vivo, daily treatment with 100 mg/kg oral quinacrine plus cisplatin significantly inhibited tumor outgrowth, extending median time to reach maximum tumor volume from 20 to 32 days (p < 0.0001) versus control, and from 28 to 32 days versus 2 mg/kg cisplatin alone. Importantly, combination therapy enabled the dose of cisplatin to be halved to 1 mg/kg, whilst maintaining the same impairment of tumor growth. Treatment was well tolerated; murine plasma levels reached a steady concentration of 0.5 μg/mL, comparable to levels achievable and tolerated in humans. Consequently, due to its favorable toxicity profile and proven safety, quinacrine may be particularly useful in reducing cisplatin dose, especially in frail and older patients; warranting a clinical trial.

PMID: 31497252 [PubMed]

Identification of Anti-staphylococcal and Anti-biofilm Compounds by Repurposing the Medicines for Malaria Venture Pathogen Box.

Front Cell Infect Microbiol. 2018;8:365

Authors: Bhandari V, Chakraborty S, Brahma U, Sharma P

Abstract
There has been an alarming increase in infections caused by antimicrobial-resistant pathogens. These infections are responsible for more than half a million deaths globally each year. Staphylococcus aureus is one of the deadliest bacterial pathogen responsible for nosocomial and community acquired infections. The open-access Pathogen Box (PBox) provides a potential platform to identify new treatment options against antibiotic-resistant bacteria by repurposing it. In this study, we have screened the PBox library comprised of ~400 compounds to identify novel anti-staphylococcal compounds. in vitro antimicrobial screening using S. aureus isolates, ATCC 29213 (methicillin-sensitive) and ATCC 700699 (methicillin-resistant) revealed 13 compounds which showed highly potent antibacterial activity against both planktonic and biofilm state. The 13 compounds were not found cytotoxic to mouse macrophage cell line, RAW264.7. Out of the 13 compounds, only MMV687251 and MMV676477 revealed structural similarity with vancomycin by comparing their atomic pair fingerprints using Tanimoto coefficient method. The structural similarities may indicate similar mode of action like vancomycin for the two compounds. Our result showed that PBox compounds offer a promising lead for the development of new anti-staphylococcal treatment options.

PMID: 30406042 [PubMed - indexed for MEDLINE]

Drug repurposing for Alzheimer's disease based on transcriptional profiling of human iPSC-derived cortical neurons.

Transl Psychiatry. 2019 Sep 06;9(1):220

Authors: Williams G, Gatt A, Clarke E, Corcoran J, Doherty P, Chambers D, Ballard C

Abstract
Alzheimer's disease is a complex disorder encompassing multiple pathological features with associated genetic and molecular culprits. However, target-based therapeutic strategies have so far proved ineffective. The aim of this study is to develop a methodology harnessing the transcriptional changes associated with Alzheimer's disease to develop a high content quantitative disease phenotype that can be used to repurpose existing drugs. Firstly, the Alzheimer's disease gene expression landscape covering severe disease stage, early pathology progression, cognitive decline and animal models of the disease has been defined and used to select a set of 153 drugs tending to oppose disease-associated changes in the context of immortalised human cancer cell lines. The selected compounds have then been assayed in the more biologically relevant setting of iPSC-derived cortical neuron cultures. It is shown that 51 of the drugs drive expression changes consistently opposite to those seen in Alzheimer's disease. It is hoped that the iPSC profiles will serve as a useful resource for drug repositioning within the context of neurodegenerative disease and potentially aid in generating novel multi-targeted therapeutic strategies.

PMID: 31492831 [PubMed - in process]

Molecular Docking: Shifting Paradigms in Drug Discovery.

Int J Mol Sci. 2019 Sep 04;20(18):

Authors: Pinzi L, Rastelli G

Abstract
Molecular docking is an established in silico structure-based method widely used in drug discovery. Docking enables the identification of novel compounds of therapeutic interest, predicting ligand-target interactions at a molecular level, or delineating structure-activity relationships (SAR), without knowing a priori the chemical structure of other target modulators. Although it was originally developed to help understanding the mechanisms of molecular recognition between small and large molecules, uses and applications of docking in drug discovery have heavily changed over the last years. In this review, we describe how molecular docking was firstly applied to assist in drug discovery tasks. Then, we illustrate newer and emergent uses and applications of docking, including prediction of adverse effects, polypharmacology, drug repurposing, and target fishing and profiling, discussing also future applications and further potential of this technique when combined with emergent techniques, such as artificial intelligence.

PMID: 31487867 [PubMed - in process]

Disulfiram repurposing combined with nutritional copper supplement as add-on to chemotherapy in recurrent glioblastoma (DIRECT): Study protocol for a randomized controlled trial.

F1000Res. 2018;7:1797

Authors: Jakola AS, Werlenius K, Mudaisi M, Hylin S, Kinhult S, Bartek J, Salvesen Ø, Carlsen SM, Strandéus M, Lindskog M, Löfgren D, Rydenhag B, Carstam L, Gulati S, Solheim O, Bartek J, Solheim T

Abstract
Background: Disulfiram (DSF) is a well-tolerated, inexpensive, generic drug that has been in use to treat alcoholism since the 1950s. There is now independent preclinical data that supports DSF as an anticancer agent, and experimental data suggest that copper may increase its anti-neoplastic properties. There is also some clinical evidence that DSF is a promising anticancer agent in extracranial cancers. In glioblastoma, DSF induced O 6-methylguanine methyltransferase (MGMT) inhibition may increase response to alkylating chemotherapy. A recent phase I study demonstrated the safety of DSF in glioblastoma patients when DSF was administered at doses below 500 mg/day together with chemotherapy. We plan to assess the effects of DSF combined with nutritional copper supplement (DSF-Cu) as an adjuvant to alkylating chemotherapy in glioblastoma treatment. Methods: In an academic, industry independent, multicenter, open label randomized controlled phase II/III trial with parallel group design (1:1) we will assess the efficacy and safety of DSF-Cu in glioblastoma treatment. The study will include 142 patients at the time of first recurrence of glioblastoma where salvage therapy with alkylating chemotherapy is planned. Patients will be randomized to treatment with or without DSF-Cu. Primary end-point is survival at 6 months. Secondary end-points are overall survival, progression free survival, quality of life, contrast enhancing tumor volume and safety. Discussion: There is a need to improve the treatment of recurrent glioblastoma. Results from this randomized controlled trial with DSF-Cu in glioblastoma will serve as preliminary evidence of the future role of DSF-Cu in glioblastoma treatment and a basis for design and power estimations of future studies. In this publication we provide rationale for our choices and discuss methodological issues. Trial registration: The study underwent registration in EudraCT 2016-000167-16 (Date: 30.03.2016,) and Clinicaltrials.gov NCT02678975 (Date: 31.01.2016) before initiating the study.

PMID: 30647912 [PubMed - indexed for MEDLINE]

A new scope for orlistat: Effect of approved anti-obesity drug against experimental microsporidiosis.

Med Mycol. 2019 Feb 01;57(2):181-195

Authors: Abou-El-Naga IF, Said DE, Gaafar MR, Ahmed SM, El-Deeb SA

Abstract
As the current therapies for intestinal microsporidiosis are either inconsistent in their efficacies or hampered by several adverse effects, alternative antimicrosporidial agents are being sought. The present study is the first that was designed to evaluate the potency of orlistat, an approved anti-obesity drug, against intestinal microsporidiosis caused by both Enterocytozoon bieneusi and Encephalitozoon intestinalis. Results were assessed through studying fecal and intestinal spore load, intestinal histopathological changes, viability, and infectivity of spores from treated animals. Results showed that orlistat has promising antimicrosporidia potential, with better results in E. intestinalis than E. bieneusi. The animals that received orlistat showed statistically significant decrease in the fecal and intestinal spore load, when compared to the corresponding control infected nontreated mice. The results were insignificant compared to fumagillin and albendazole. Light microscopic examination of stained intestinal sections revealed amelioration of the pathological changes and decreased inflammatory cells detected in the control infected nontreated mice. Spores encountered from stool of orlistat-treated E. bieneusi and E. intestinalis mice showed low viability and significant reduction of infectivity versus their control. Thus, considering the results of the present work, orlistat proved its effectiveness against the intestinal microsporidial infection.

PMID: 29529254 [PubMed - indexed for MEDLINE]

In silico drug repositioning: from large-scale transcriptome data to therapeutics.

Arch Pharm Res. 2019 Sep 03;:

Authors: Kwon OS, Kim W, Cha HJ, Lee H

Abstract
Drug repositioning is an attractive alternative to conventional drug development when new beneficial effects of old drugs are clinically validated because pharmacokinetic and safety profiles are generally already available. Since ~ 30% of drugs newly approved by the US food and drug administration (FDA) are developed through drug repositioning, identifying novel usage for existing drugs is an emerging strategy for developing disease treatments. With advances in next-generation sequencing technologies, available transcriptome data related to diseases have expanded rapidly. Harnessing these resources enables a better understanding of disease mechanisms and drug mode of action (MOA), and moves toward personalized pharmacotherapy. In this review, we briefly outline publicly available large-scale transcriptome databases and tools for drug repositioning. We also highlight recent approaches leading to the discovery of novel drug targets, drug response biomarkers, drug indications, and drug MOA.

PMID: 31482491 [PubMed - as supplied by publisher]

A review of drug repositioning based chemical-induced cell line expression data.

Curr Med Chem. 2019 Sep 03;:

Authors: Wang F, Lei X, Wu FX

Abstract
Drug repositioning is an important area of biomedical research. The drug repositioning studies have shifted to computational approaches. Large-scale perturbation databases, such as the Connectivity Map and the Library of Integrated Network-Based Cellular Signatures, contain a number of chemical-induced gene expression profiles and provide great opportunities for computational biology and drug repositioning. One reason is that the profiles provided by the Connectivity Map and the Library of Integrated Network-Based Cellular Signatures databases show an overall view of biological mechanism in drugs, diseases and genes. In this article, we provide a review of the two databases and their recent applications in drug repositioning.

PMID: 31480994 [PubMed - as supplied by publisher]

Computational Drug Repurposing Algorithm Targeting TRPA1 Calcium Channel as a Potential Therapeutic Solution for Multiple Sclerosis.

Pharmaceutics. 2019 Sep 02;11(9):

Authors: Mihai DP, Nitulescu GM, Ion GND, Ciotu CI, Chirita C, Negres S

Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS) through neurodegeneration and demyelination, leading to physical/cognitive disability and neurological defects. A viable target for treating MS appears to be the Transient Receptor Potential Ankyrin 1 (TRPA1) calcium channel, whose inhibition has been shown to have beneficial effects on neuroglial cells and protect against demyelination. Using computational drug discovery and data mining methods, we performed an in silico screening study combining chemical graph mining, quantitative structure-activity relationship (QSAR) modeling, and molecular docking techniques in a global prediction model in order to identify repurposable drugs as potent TRPA1 antagonists that may serve as potential treatments for MS patients. After screening the DrugBank database with the combined generated algorithm, 903 repurposable structures were selected, with 97 displaying satisfactory inhibition probabilities and pharmacokinetics. Among the top 10 most probable inhibitors of TRPA1 with good blood brain barrier (BBB) permeability, desvenlafaxine, paliperidone, and febuxostat emerged as the most promising repurposable agents for treating MS. Molecular docking studies indicated that desvenlafaxine, paliperidone, and febuxostat are likely to induce allosteric TRPA1 channel inhibition. Future in vitro and in vivo studies are needed to confirm the biological activity of the selected hit molecules.

PMID: 31480671 [PubMed]

Mebendazole as a Candidate for Drug Repurposing in Oncology: An Extensive Review of Current Literature.

Cancers (Basel). 2019 Aug 31;11(9):

Authors: Guerini AE, Triggiani L, Maddalo M, Bonù ML, Frassine F, Baiguini A, Alghisi A, Tomasini D, Borghetti P, Pasinetti N, Bresciani R, Magrini SM, Buglione M

Abstract
Anticancer treatment efficacy is limited by the development of refractory tumor cells characterized by increased expression and activity of mechanisms promoting survival, proliferation, and metastatic spread. The present review summarizes the current literature regarding the use of the anthelmintic mebendazole (MBZ) as a repurposed drug in oncology with a focus on cells resistant to approved therapies, including so called "cancer stem cells". Mebendazole meets many of the characteristics desirable for a repurposed drug: good and proven toxicity profile, pharmacokinetics allowing to reach therapeutic concentrations at disease site, ease of administration and low price. Several in vitro studies suggest that MBZ inhibits a wide range of factors involved in tumor progression such as tubulin polymerization, angiogenesis, pro-survival pathways, matrix metalloproteinases, and multi-drug resistance protein transporters. Mebendazole not only exhibits direct cytotoxic activity, but also synergizes with ionizing radiations and different chemotherapeutic agents and stimulates antitumoral immune response. In vivo, MBZ treatment as a single agent or in combination with chemotherapy led to the reduction or complete arrest of tumor growth, marked decrease of metastatic spread, and improvement of survival. Further investigations are warranted to confirm the clinical anti-neoplastic activity of MBZ and its safety in combination with other drugs in a clinical setting.

PMID: 31480477 [PubMed]

Repurposing drugs to treat neurological diseases.

J Neurol. 2018 02;265(2):446-448

Authors: Massey TH, Robertson NP

PMID: 29322257 [PubMed - indexed for MEDLINE]

Efficacy of antiretroviral compounds against Toxoplasma gondii in vitro.

Int J Antimicrob Agents. 2019 Aug 31;:

Authors: Wang JL, Elsheikha HM, Li TT, He JJ, Bai MJ, Liang QL, Zhu XQ, Cong W

Abstract
The obligate intracellular parasite Toxoplasma gondii can infect nearly all warm-blooded animals including humans. Although infection with this parasite is generally benign, severe illness may occur in the infected individuals if their immunity becomes less competent, such as AIDS patients. In this study, we determined the inhibitory activity of 44 commonly used antiretroviral compounds against T. gondii in vitro. Fourteen of the 44 tested antiretroviral compounds showed potency against T. gondii at IC50 concentrations that ranged from 1.18 ± 2.21 µM (nelfinavir) to 18.89 ± 1.87 µM (trovirdine). Seven of the 14 potent antiretroviral compounds are HIV-1 protease inhibitors. We investigated whether co-administration of these 14 antiretroviral compounds interferes with the anti-T. gondii activity of the existing anti-T. gondii drugs, sulfadiazine or pyrimethamine. Results showed no significant interaction between any of the tested 14 antiretroviral compounds and pyrimethamine or sulfadiazine. These results warrant the investigation of whether the administration of the lead antiretroviral drugs with highly potent anti-T. gondii activity to AIDS patients may help in limiting the occurrence of toxoplasmic encephalitis.

PMID: 31479744 [PubMed - as supplied by publisher]

Repositioning Dopamine D2 Receptor Agonist Bromocriptine to Enhance Docetaxel Chemotherapy and Treat Bone Metastatic Prostate Cancer.

Mol Cancer Ther. 2018 09;17(9):1859-1870

Authors: Yang Y, Mamouni K, Li X, Chen Y, Kavuri S, Du Y, Fu H, Kucuk O, Wu D

Abstract
Docetaxel resistance remains a major obstacle in the treatment of prostate cancer bone metastasis. In this study, we demonstrate that the dopamine D2 receptor (DRD2) agonist bromocriptine effectively enhances docetaxel efficacy and suppresses skeletal growth of prostate cancer in preclinical models. DRD2 is ubiquitously expressed in prostate cancer cell lines and significantly reduced in prostate cancer tissues with high Gleason score. Bromocriptine has weak to moderate cytotoxicity in prostate cancer cells, but effectively induces cell-cycle arrest. At the molecular level, bromocriptine inhibits the expression of c-Myc, E2F-1, and survivin and increases the expression of p53, p21, and p27. Intriguingly, bromocriptine markedly reduces androgen receptor levels, partially through Hsp90-mediated protein degradation. The combination of bromocriptine and docetaxel demonstrates enhanced in vitro cytotoxicity in prostate cancer cells and significantly retards the skeletal growth of C4-2-Luc tumors in mice. Collectively, these results provide the first experimental evidence for repurposing bromocriptine as an effective adjunct therapy to enhance docetaxel efficacy in prostate cancer. Mol Cancer Ther; 17(9); 1859-70. ©2018 AACR.

PMID: 29907594 [PubMed - indexed for MEDLINE]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2019/09/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Salsalate, but not metformin or canagliflozin, slows kidney cyst growth in an adult-onset mouse model of polycystic kidney disease.

EBioMedicine. 2019 Aug 28;:

Authors: Leonhard WN, Song X, Kanhai AA, Iliuta IA, Bozovic A, Steinberg GR, Peters DJM, Pei Y

Abstract
BACKGROUND: Multiple preclinical studies have highlighted AMP-activated protein kinase (AMPK) as a potential therapeutic target for autosomal dominant polycystic kidney disease (ADPKD). Both metformin and canagliflozin indirectly activate AMPK by inhibiting mitochondrial function, while salsalate is a direct AMPK activator. Metformin, canagliflozin and salsalate (a prodrug dimer of salicylate) are approved for clinical use with excellent safety profile. Although metformin treatment had been shown to attenuate experimental cystic kidney disease, there are concerns that therapeutic AMPK activation in human kidney might require a higher oral metformin dose than can be achieved clinically.
METHODS: In this study, we tested metformin-based combination therapies for their additive (metformin plus canagliflozin) and synergistic (metformin plus salsalate) effects and each drug individually in an adult-onset conditional Pkd1 knock-out mouse model (n = 20 male/group) using dosages expected to yield clinically relevant drug levels.
FINDINGS: Compared to untreated mutant mice, treatment with salsalate or metformin plus salsalate improved kidney survival (i.e. blood urea nitrogen <20 mmol/L at the time of sacrifice) and reduced cystic kidney disease severity. However, the effects of metformin plus salsalate did not differ from salsalate alone; and neither metformin nor canagliflozin was effective. Protein expression and phosphorylation analyses indicated that salsalate treatment was associated with reduction in mTOR (mammalian target of rapamycin) activity and cellular proliferation in Pkd1 mutant mouse kidneys. Global gene expression analyses suggested that these effects were linked to restoration of mitochondrial function and suppression of inflammation and fibrosis.
INTERPRETATION: Salsalate is a highly promising candidate for drug repurposing and clinical testing in ADPKD.

PMID: 31473186 [PubMed - as supplied by publisher]

Perceptions of using lithium in fracture management: a survey of orthopaedic surgeons, fracture patients and the general public.

BMC Musculoskelet Disord. 2019 Aug 31;20(1):389

Authors: Vachhani K, Whyne CM, Schaffer A, Nam D

Abstract
BACKGROUND: Lithium, an established psychiatric medication, has recently been shown to enhance new bone formation in preclinical fracture models. Current research is focused on evaluating the efficacy of low-dose, short-term lithium treatment to improve long bone fracture healing through a Phase II randomized clinical trial (LiFT NCT02999022). In working towards future applications of lithium for fracture management, this study aimed to understand the current perceptions of lithium as a psychiatric drug and the potential barriers to its orthopaedic adoption.
METHODS: Three questionnaires, evaluating knowledge about lithium and willingness to embrace its use in fracture healing were disseminated among the general population, fracture patients eligible for the LiFT (Lithium for Fracture Treatment) trial and orthopaedic surgeons across Canada.
RESULTS: Of the 768 public respondents, 84% were willing to take a medication that would aid fracture healing but only 62.6% if the medication was lithium. Willingness dropped to 44.6% among the 168 respondents who knew about the psychiatric use of lithium. Lack of sufficient knowledge (n = 50) and concerns about side effects including effects on the brain (n = 74) were the main reasons cited by those who were unwilling to use lithium. Of the 29 fracture patients, only 20 patients had previously heard of lithium. Of these, 40% were willing to take lithium for fracture healing with an additional 10% if the dose was low or if the intake duration was short. Only 50% knew that lithium has side effects. Of the 43 orthopaedic surgeons, 38 surgeons knew about clinical use of lithium. Of these, 68% knew that lithium has side effects and 29% knew that it interacts with other drugs. While most agreed that new strategies are needed to improve fracture management, only 68% were willing to prescribe lithium for fractures with an additional 16% if there is scientific evidence and/or a standard dosing protocol.
CONCLUSIONS: This study identified a lack of knowledge about uses and side effects of lithium among all three cohorts. A robust educational framework for orthopaedic surgeons, their patients and the members of their clinical care teams will be essential to widespread repurposing of lithium for fracture care.

PMID: 31470828 [PubMed - in process]

PDE3 Inhibitors Repurposed as Treatments for Age-Related Cognitive Impairment.

Mol Neurobiol. 2019 Jun;56(6):4306-4316

Authors: Yanai S, Endo S

Abstract
As the population of older individuals grows worldwide, researchers have increasingly focused their attention on identifying key molecular targets of age-related cognitive impairments, with the aim of developing possible therapeutic interventions. Two such molecules are the intracellular cyclic nucleotides, cAMP and cGMP. These second messengers mediate fundamental aspects of brain function relevant to memory, learning, and cognitive function. Consequently, phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP, are promising targets for the development of cognition-enhancing drugs. Inhibitors that target PDEs work by elevating intracellular cAMP. In this review, we provide an overview of different PDE inhibitors, and then we focus on pharmacological and physiological effects of PDE3 inhibitors in the CNS and peripheral tissues. Finally, we discuss findings from experimental and preliminary clinical studies and the potential beneficial effects of the PDE3 inhibitor cilostazol on age-related cognitive impairments. In the innovation pipeline of pharmaceutical development, the antiplatelet agent cilostazol has come into the spotlight as a novel treatment for mild cognitive impairment. Overall, the repurposing of cilostazol may represent a potentially promising way to treat mild cognitive impairment, Alzheimer's disease, and vascular dementia. In this review, we present a brief summary of cAMP signaling and different PDE inhibitors, followed by a discussion of the pharmacological and physiological role of PDE3 inhibitors. In this context, we discuss the repurposing of a PDE3 inhibitor, cilostazol, as a potential treatment for age-related cognitive impairment based on recent research.

PMID: 30311144 [PubMed - indexed for MEDLINE]

Repurposing of Tranilast for Potential Neuropathic Pain Treatment by Inhibition of Sepiapterin Reductase in the BH4 Pathway.

ACS Omega. 2019 Jul 31;4(7):11960-11972

Authors: Moore BJR, Islam B, Ward S, Jackson O, Armitage R, Blackburn J, Haider S, McHugh PC

Abstract
Tetrahydrobiopterin (BH4) is a cofactor in the production of various signaling molecules including nitric oxide, dopamine, adrenaline, and noradrenaline. BH4 levels are critical for processes associated with cardiovascular function, inflammation, mood, pain, and neurotransmission. Increasing pieces of evidence suggest that BH4 is upregulated in chronic pain. Sepiapterin reductase (SPR) catalyzes both the reversible reduction of sepiapterin to dihydrobiopterin (BH2) and 6-pyruvoyl-tetrahydrobiopterin to BH4 within the BH4 pathway. Therefore, inhibition of SPR by small molecules can be used to control BH4 production and ultimately alleviate chronic pain. Here, we have used various in silico and in vitro experiments to show that tranilast, licensed for use in bronchial asthma, can inhibit sepiapterin reduction by SPR. Docking and molecular dynamics simulations suggest that tranilast can bind to human SPR (hSPR) at the same site as sepiapterin including S157, one of the catalytic triad residues of hSPR. Colorimetric assays revealed that tranilast was nearly twice as potent as the known hSPR inhibitor, N-acetyl serotonin. Tranilast was able to inhibit hSPR activity both intracellularly and extracellularly in live cells. Triple quad mass spectrophotometry of cell lysates showed a proportional decrease of BH4 in cells treated with tranilast. Our results suggest that tranilast can act as a potent hSPR inhibitor and therefore is a valid candidate for drug repurposing in the treatment of chronic pain.

PMID: 31460307 [PubMed]

Large-Scale Target Identification of Herbal Medicine Using a Reverse Docking Approach.

ACS Omega. 2019 Jun 30;4(6):9710-9719

Authors: Zhang H, Pan J, Wu X, Zuo AR, Wei Y, Ji ZL

Abstract
Herbal medicine has been used to countermine various diseases for centuries. However, most of the therapeutic targets underlying herbal therapy remain unclear, which largely slow down the novel drug discovery process from natural products. In this study, we developed a novel computational pipeline for assisting de novo identification of protein targets for herbal ingredients. The pipeline involves pharmacophore comparison and reverse ligand-protein docking simulation in a high throughput manner. We evaluated the pipeline using three traditional Chinese medicine ingredients such as acteoside, quercetin, and epigallocatechin gallate as examples. A majority of current known targets of these ingredients were successfully identified by the pipeline. Structural comparative analyses confirmed that the predicted ligand-target interactions used the same binding pockets and binding modes as those of known ligand-target interactions. Furthermore, we illustrated the mechanism of actions of the ingredients by constructing the pharmacological networks on the basis of the predicted target profiles. In summary, we proposed an efficient and economic option for large-scale target exploration in the herb study. This pipeline will be particularly valuable in aiding precise drug discovery and drug repurposing from natural products.

PMID: 31460061 [PubMed]

Repurposing of sodium valproate in colon cancer associated with diabetes mellitus: Role of HDAC inhibition.

Eur J Pharm Sci. 2018 08 30;121:188-199

Authors: Patel MM, Patel BM

Abstract
BACKGROUND AND PURPOSE: Diabetic patients are at greater risk for colon cancer. Histone deacetylases (HDACs) serve as common target for both. The key objective of the study was to evaluate the effect of sodium valproate in type 2 diabetes mellitus associated colon cancer.
EXPERIMENTAL APPROACH: High fat diet and streptozotocin were used to induce type 2 diabetes. Following this, after diabetes confirmation, colon cancer was induced using 1,2 dimethylhydrazine (25 mg/kg, s.c.) once weekly from 7th week to 20th weeks. Sodium valproate (200 mg/kg) treatment was given from 20th to 24th week. At the end of 24 weeks, several enzymatic and biochemical parameters, were estimated. MTT, clonogenic and scratch wound healing assay were carried out in HCT-15 cell line.
KEY RESULTS: Hyperglycemia, hyperinsulinemia, increase in cytokines (TNF-α and IL-1β) and carcinoembryonic antigen and presence of proliferating cells was seen in disease control animals which was prevented by sodium valproate treatment. Overexpression of relative HDAC2 mRNA levels was found in diseased control animals, which was reduced by sodium valproate treatment. IC50 of sodium valproate was found to be 3.40 mM and 3.73 mM at 48 h and 72 h respectively on HCT-15 cell line. Sodium valproate also dose dependently prevented colony formation and cell migration.
CONCLUSION AND IMPLICATIONS: Sodium valproate can be considered for repurposing in colon cancer associated with diabetes mellitus.

PMID: 29852291 [PubMed - indexed for MEDLINE]