Methods to Investigate Signal Transduction Pathways in Trypanosoma cruzi: Cyclic Nucleotide Phosphodiesterases Assay Protocols.

Methods Mol Biol. 2020;2116:523-534

Authors: Schoijet AC, Sternlieb T, Alonso GD

Abstract
Intracellular levels of cyclic nucleotide second messengers are regulated predominantly by a large superfamily of phosphodiesterases (PDEs). Most of the different PDE variants play specific physiological functions; in fact, PDEs can associate with other proteins allowing them to be strategically anchored throughout the cell. In this regard, precise cellular expression and compartmentalization of these enzymes produce the specific control of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) gradients in cells and enable their integration with other signaling pathways.In trypanosomatids, some PDEs are essential for their survival and play fundamental roles in the adaptation of these parasites to different environmental stresses, as well as in the differentiation between their different life cycle forms. Given that these enzymes not only are similar to human PDEs but also have differential biochemical properties, and due to the great knowledge of drugs that target human PDEs, trypanosomatid PDEs could be postulated as important therapeutic targets through the repositioning of drugs.In this chapter, we describe a simple and sensitive radioisotope-based method to measure cyclic 3',5'-nucleotide phosphodiesterase using [3H]cAMP.

PMID: 32221940 [PubMed - as supplied by publisher]

Drug repositioning by prediction of drug's anatomical therapeutic chemical code via network-based inference approaches.

Brief Bioinform. 2020 Mar 28;:

Authors: Peng Y, Wang M, Xu Y, Wu Z, Wang J, Zhang C, Liu G, Li W, Li J, Tang Y

Abstract
Drug discovery and development is a time-consuming and costly process. Therefore, drug repositioning has become an effective approach to address the issues by identifying new therapeutic or pharmacological actions for existing drugs. The drug's anatomical therapeutic chemical (ATC) code is a hierarchical classification system categorized as five levels according to the organs or systems that drugs act and the pharmacology, therapeutic and chemical properties of drugs. The 2nd-, 3rd- and 4th-level ATC codes reserved the therapeutic and pharmacological information of drugs. With the hypothesis that drugs with similar structures or targets would possess similar ATC codes, we exploited a network-based approach to predict the 2nd-, 3rd- and 4th-level ATC codes by constructing substructure drug-ATC (SD-ATC), target drug-ATC (TD-ATC) and Substructure&Target drug-ATC (STD-ATC) networks. After 10-fold cross validation and two external validations, the STD-ATC models outperformed the SD-ATC and TD-ATC ones. Furthermore, with KR as fingerprint, the STD-ATC model was identified as the optimal model with AUC values at 0.899 ± 0.015, 0.916 and 0.893 for 10-fold cross validation, external validation set 1 and external validation set 2, respectively. To illustrate the predictive capability of the STD-ATC model with KR fingerprint, as a case study, we predicted 25 FDA-approved drugs (22 drugs were actually purchased) to have potential activities on heart failure using that model. Experiments in vitro confirmed that 8 of the 22 old drugs have shown mild to potent cardioprotective activities on both hypoxia model and oxygen-glucose deprivation model, which demonstrated that our STD-ATC prediction model would be an effective tool for drug repositioning.

PMID: 32221552 [PubMed - as supplied by publisher]

Investigation of auranofin and gold-containing analogues antibacterial activity against multidrug-resistant Neisseria gonorrhoeae.

Sci Rep. 2020 Mar 27;10(1):5602

Authors: Elkashif A, Seleem MN

Abstract
Neisseria gonorrhoeae represents an urgent public health threat due to the rapid emergence of resistance to current antibiotics and the limited number of anti-gonococcal agents currently in clinical trials. This study utilized a drug repositioning strategy to investigate FDA-approved gold-containing drugs against N. gonorrhoeae. Auranofin, sodium aurothiomalate and aurothioglucose inhibited 48 clinical isolates of N. gonorrhoeae including multidrug-resistant strains at a concentration as low as 0.03 µg/mL. A time-kill assay revealed that auranofin exhibited rapid bactericidal activity against N. gonorrhoeae. Moreover, both sodium aurothiomalate and aurothioglucose did not inhibit growth of vaginal protective commensal lactobacilli. Auranofin, in combination with azithromycin, ceftriaxone, cefixime or tetracycline showed an additive effect against four N. gonorrhoeae strains, suggesting the possibility of using auranofin in dual therapy. Moreover, auranofin reduced the burden of intracellular N. gonorrhoeae by over 99% outperforming the drug of choice ceftriaxone. Auranofin was found superior to ceftriaxone in reducing the secretion of the pro-inflammatory cytokine IL-8 by endocervical cells infected with N. gonorrhoeae. Furthermore, auranofin exhibited a prolonged post-antibiotic effect over 10 h, as well as inability to generate resistant mutants. Overall, the current study suggests that repurposing gold-containing drugs, like auranofin, for treatment of gonorrhea warrants further investigation.

PMID: 32221472 [PubMed - as supplied by publisher]

Repurposing Clinical Drugs as AdoMetDC Inhibitors Using the SCAR Strategy.

Front Pharmacol. 2020;11:248

Authors: Zhang Y, Zheng Q, Zhou Y, Liu S

Abstract
With the escalating costs in drug development, discovering new uses of approved drugs, i.e., drug repurposing, has attracted increasing interest. Spermidine and spermine are important polyamines for most cells and their biosynthesis are strictly regulated by the polyamine metabolic network. In cancerous cells and tumor environments, the concentrations of polyamines are much higher than in normal cells. During the synthesis of spermidine and spermine, an amino-propyl group is provided by decarboxylated S-adenosylmethionine, and the latter is generated from S-adenosylmethionine by AdoMetDC (AdoMet decarboxylase). Therefore, as a rate-limiting enzyme in the biosynthesis of spermidine and spermine, AdoMetDC has been an attractive drug target in cancer studies. In the last decades, many AdoMetDC inhibitors have been discovered, and several AdoMetDC inhibitors are under clinical trials, but unfortunately, none of them have been approved yet. To overcome the high costs in time and money for discovering de novo inhibitors, we set out to repurpose clinic drugs as AdoMetDC inhibitors. We used steric-clashes alleviating receptors (SCAR), a computer-aided drug discovery strategy developed by us recently for in silico screening. By combining computational screening and experimental validation, we successfully identified two approved drugs that have inhibitory potency on AdoMetDC's enzymatic activity. SCAR was previously shown to be suitable for the discovery of both covalent and non-covalent inhibitors, and this work further demonstrated the value of the SCAR strategy in drug repurposing.

PMID: 32218733 [PubMed - as supplied by publisher]

Drug repurposing and rediscovery: Design, synthesis and preliminary biological evaluation of 1-arylamino-3-aryloxypropan-2-ols as anti-melanoma agents.

Bioorg Med Chem. 2020 Mar 03;:115404

Authors: Chang Q, Long J, Hu L, Chen Z, Li Q, Hu G

Abstract
Malignant melanoma (MM) presents as the highest morbidity and mortality type in skin cancer. Herein, inspired by the previously reported anti-melanoma effect of propranolol, a widely applied β adrenergic receptor antagonist as cardiovascular drug, we set out to exploit its potential as anti-melanoma therapy based on the drug repurposing strategy. Structural optimization of propranolol yielded 5m, which exhibits dramatically improved potency on human melanoma cell growth (1.98-3.70 μM), compared to propranolol (59.5-75.8 μM). Further investigation demonstrated that 5m could inhibit colony formation of melanoma cell line (completely abolished at 2 μM for 5m, partially inhibited at 50 μM for propranolol), induce cell apoptosis and cell cycle arrest in the G2/M phase (both observed at 1 μM). Preliminary mechanism study indicated that 5m could disrupt the cellular microtubule network, which suggested tubulin as a potential target. Docking study provided a structural insight into the interaction between 5m and tubulin. In summary, our study presents a drug repurposing case that redirects a cardiovascular agent to an anti-melanoma agent.

PMID: 32216987 [PubMed - as supplied by publisher]

Everolimus Rescues the Phenotype of Elastin Insufficiency in Patient Induced Pluripotent Stem Cell-Derived Vascular Smooth Muscle Cells.

Arterioscler Thromb Vasc Biol. 2020 Mar 26;:ATVBAHA119313936

Authors: Kinnear C, Agrawal R, Loo C, Pahnke A, Rodrigues DC, Thompson T, Akinrinade O, Ahadian S, Keeley F, Radisic M, Mital S, Ellis J

Abstract
OBJECTIVE: Elastin gene deletion or mutation leads to arterial stenoses due to vascular smooth muscle cell (SMC) proliferation. Human induced pluripotent stem cells-derived SMCs can model the elastin insufficiency phenotype in vitro but show only partial rescue with rapamycin. Our objective was to identify drug candidates with superior efficacy in rescuing the SMC phenotype in elastin insufficiency patients. Approach and Results: SMCs generated from induced pluripotent stem cells from 5 elastin insufficiency patients with severe recurrent vascular stenoses (3 Williams syndrome and 2 elastin mutations) were phenotypically immature, hyperproliferative, poorly responsive to endothelin, and exerted reduced tension in 3-dimensional smooth muscle biowires. Elastin mRNA and protein were reduced in SMCs from patients compared to healthy control SMCs. Fourteen drug candidates were tested on patient SMCs. Of the mammalian target of rapamycin inhibitors studied, everolimus restored differentiation, rescued proliferation, and improved endothelin-induced calcium flux in all patient SMCs except 3 Williams syndrome. Of the calcium channel blockers, verapamil increased SMC differentiation and reduced proliferation in Williams syndrome patient cells but not in elastin mutation patients and had no effect on endothelin response. Combination treatment with everolimus and verapamil was not superior to everolimus alone. Other drug candidates had limited efficacy.
CONCLUSIONS: Everolimus caused the most consistent improvement in SMC differentiation, proliferation and in SMC function in patients with both syndromic and nonsyndromic elastin insufficiency, and offers the best candidate for drug repurposing for treatment of elastin insufficiency associated vasculopathy.

PMID: 32212852 [PubMed - as supplied by publisher]

Clinical and Immunological Outcomes in High-Risk Resected Melanoma Patients Receiving Peptide-Based Vaccination and Interferon Alpha, With or Without Dacarbazine Preconditioning: A Phase II Study.

Front Oncol. 2020;10:202

Authors: Urbani F, Ferraresi V, Capone I, Macchia I, Palermo B, Nuzzo C, Torsello A, Pezzotti P, Giannarelli D, Pozzi AF, Santaquilani M, Roazzi P, Bastucci S, Catricalà C, La Malfa A, Vercillo G, Gualtieri N, Buccione C, Castiello L, Cognetti F, Nisticò P, Belardelli F, Moschella F, Proietti E

Abstract
Clinical studies based on novel rationales and mechanisms of action of chemotherapy agents and cytokines can contribute to the development of new concepts and strategies of antitumor combination therapies. In previous studies, we investigated the paradoxical immunostimulating effects of some chemotherapeutics and the immunoadjuvant activity of interferon alpha (IFN-α) in preclinical and clinical models, thus unraveling novel rationales and mechanisms of action of chemotherapy agents and cytokines for cancer immunotherapy. Here, we carried out a randomized, phase II clinical trial, in which we analyzed the relapse-free (RFS) and overall survival (OS) of 34 completely resected stage III-IV melanoma patients, treated with peptide-based vaccination (Melan-A/MART-1 and NY-ESO-1) in combination with IFN-α2b, with (arm 2) or without (arm 1) dacarbazine preconditioning. All patients were included in the intention-to-treat analysis. At a median follow-up of 4.5 years (interquartile range, 15.4-81.0 months), the rates of RFS were 52.9 and 35.3% in arms 1 and 2, respectively. The 4.5-year OS rates were 68.8% in arm 1 and 62.7% in arm 2. No significant differences were observed between the two arms for both RFS and OS. Interestingly, the RFS and OS curves remained stable starting from 18 and 42 months, respectively. Grade 3 adverse events occurred in 5.9% of patients, whereas grade 4 events were not observed. Both treatments induced a significant expansion of vaccine-specific CD8+ T cells, with no correlation with the clinical outcome. However, treatment-induced increase of polyfunctionality and of interleukin 2 production by Melan-A-specific CD8+ T cells and expansion/activation of natural killer cells correlated with RFS, being observed only in nonrelapsing patients. Despite the recent availability of different therapeutic options, low-cost, low-toxic therapies with long-lasting clinical effects are still needed in patients with high-risk resected stage III/IV melanoma. The combination of peptide vaccination with IFN-α2b showed a minimal toxicity profile and resulted in encouraging RFS and OS rates, justifying further evaluation in clinical trials, which may include the use of checkpoint inhibitors to further expand the antitumor immune response and the clinical outcome. Clinical Trial Registration: https://www.clinicaltrialsregister.eu/ctr-search/search, identifier: 2008-008211-26.

PMID: 32211314 [PubMed]

Construction of Glycometabolism- and Hormone-Related lncRNA-Mediated Feedforward Loop Networks Reveals Global Patterns of lncRNAs and Drug Repurposing in Gestational Diabetes.

Front Endocrinol (Lausanne). 2020;11:93

Authors: Fu X, Cong H, Zhao S, Li Y, Liu T, Sun Y, Lv N

Abstract
Gestational diabetes mellitus (GDM) is a condition associated with the onset of abnormal glucose tolerance during pregnancy. Long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and genes can form lncRNA-mediated feedforward loops (lnc-FFLs), which are functional network motifs that regulate a wide range of biological processes and diseases. However, lnc-FFL network motifs have not been systematically investigated in GDM, and their role in the disease remains largely unknown. In the present study, a global lnc-FFL network was constructed and analyzed. Glycometabolism- and hormone-related lnc-FFL networks were extracted from the global network. An integrated algorithm was designed to identify dysregulated glycometabolism- and hormone-related lnc-FFLs in GDM. The patterns of dysregulated lnc-FFLs in GDM were complex. Moreover, there were strong associations between dysregulated glycometabolism- and hormone-related lnc-FFLs in GDM. Core modules were extracted from the dysregulated lnc-FFL networks in GDM and showed specific and essential functions. In addition, dysregulated lnc-FFLs could combine with ceRNAs and form more complex modules, which could play novel roles in GDM. Notably, we discovered that the dysregulated lnc-FFLs were enriched in the thyroid hormone signaling pathway. Some drug-repurposing candidates, such as hormonal drugs, could be identified based on lnc-FFLs in GDM. In summary, the present study highlighted the effect of dysregulated glycometabolism- and hormone-related lnc-FFLs in GDM and revealed their potential for the discovery of novel biomarkers and therapeutic targets for GDM.

PMID: 32210913 [PubMed]

Identification of the Antidepressant Vilazodone as an Inhibitor of Inositol Polyphosphate Multikinase by Structure-Based Drug Repositioning.

Mol Cells. 2020 Mar 31;43(3):222-227

Authors: Lee B, Park SJ, Lee S, Park SE, Lee E, Song JJ, Byun Y, Kim S

Abstract
Inositol polyphosphate multikinase (IPMK) is required for the biosynthesis of inositol phosphates (IPs) through the phosphorylation of multiple IP metabolites such as IP3 and IP4. The biological significance of IPMK's catalytic actions to regulate cellular signaling events such as growth and metabolism has been studied extensively. However, pharmacological reagents that inhibit IPMK have not yet been identified. We employed a structure-based virtual screening of publicly available U.S. Food and Drug Administration-approved drugs and chemicals that identified the antidepressant, vilazodone, as an IPMK inhibitor. Docking simulations and pharmacophore analyses showed that vilazodone has a higher affinity for the ATP-binding catalytic region of IPMK than ATP and we validated that vilazodone inhibits IPMK's IP kinase activities in vitro . The incubation of vilazodone with NIH3T3-L1 fibroblasts reduced cellular levels of IP5 and other highly phosphorylated IPs without influencing IP4 levels. We further found decreased Akt phosphorylation in vilazodone-treated HCT116 cancer cells. These data clearly indicate selective cellular actions of vilazodone against IPMK-dependent catalytic steps in IP metabolism and Akt activation. Collectively, our data demonstrate vilazodone as a method to inhibit cellular IPMK, providing a valuable pharmacological agent to study and target the biological and pathological processes governed by IPMK.

PMID: 32209735 [PubMed - in process]

Identification of the Antidepressant Vilazodone asan Inhibitor of Inositol Polyphosphate Multikinaseby Structure-Based Drug Repositioning.

Mol Cells. 2020 Mar 31;43(3):222-227

Authors: Lee B, Park SJ, Lee S, Park SE, Lee E, Song JJ, Byun Y, Kim S

Abstract
Inositol polyphosphate multikinase (IPMK) is required for the biosynthesis of inositol phosphates (IPs) through the phosphorylation of multiple IP metabolites such as IP3 and IP4. The biological significance of IPMK's catalytic actions to regulate cellular signaling events such as growth and metabolism has been studied extensively. However, pharmacological reagents that inhibit IPMK have not yet been identified. We employed a structure-based virtual screening of publicly available U.S. Food and Drug Administration-approved drugs and chemicals that identified the antidepressant, vilazodone, as an IPMK inhibitor. Docking simulations and pharmacophore analyses showed that vilazodone has a higher affinity for the ATP-binding catalytic region of IPMK than ATP and we validated that vilazodone inhibits IPMK's IP kinase activities in vitro . The incubation of vilazodone with NIH3T3-L1 fibroblasts reduced cellular levels of IP5 and other highly phosphorylated IPs without influencing IP4 levels. We further found decreased Akt phosphorylation in vilazodone-treated HCT116 cancer cells. These data clearly indicate selective cellular actions of vilazodone against IPMK-dependent catalytic steps in IP metabolism and Akt activation. Collectively, our data demonstrate vilazodone as a method to inhibit cellular IPMK, providing a valuable pharmacological agent to study and target the biological and pathological processes governed by IPMK.

PMID: 32209734 [PubMed - in process]

Anti-HCV, nucleotide inhibitors, repurposing against COVID-19.

Life Sci. 2020 May 01;248:117477

Authors: Elfiky AA

Abstract
AIMS: A newly emerged Human Coronavirus (HCoV) is reported two months ago in Wuhan, China (COVID-19). Until today >2700 deaths from the 80,000 confirmed cases reported mainly in China and 40 other countries. Human to human transmission is confirmed for COVID-19 by China a month ago. Based on the World Health Organization (WHO) reports, SARS HCoV is responsible for >8000 cases with confirmed 774 deaths. Additionally, MERS HCoV is responsible for 858 deaths out of about 2500 reported cases. The current study aims to test anti-HCV drugs against COVID-19 RNA dependent RNA polymerase (RdRp).
MATERIALS AND METHODS: In this study, sequence analysis, modeling, and docking are used to build a model for Wuhan COVID-19 RdRp. Additionally, the newly emerged Wuhan HCoV RdRp model is targeted by anti-polymerase drugs, including the approved drugs Sofosbuvir and Ribavirin.
KEY FINDINGS: The results suggest the effectiveness of Sofosbuvir, IDX-184, Ribavirin, and Remidisvir as potent drugs against the newly emerged HCoV disease.
SIGNIFICANCE: The present study presents a perfect model for COVID-19 RdRp enabling its testing in silico against anti-polymerase drugs. Besides, the study presents some drugs that previously proved its efficiency against the newly emerged viral infection.

PMID: 32119961 [PubMed - indexed for MEDLINE]

Understanding of Zaire ebolavirus-human protein interaction for drug repurposing.

Virusdisease. 2020 Mar;31(1):28-37

Authors: Muthaiyan M, Pushan SS, Naorem LD, Venkatesan A

Abstract
The Ebola virus is a human aggressive pathogen causes Ebola virus disease that threatens public health, for which there is no Food Drug Administration approved medication. Drug repurposing is an alternative method to find the novel indications of known drugs to treat the disease effectively at low cost. The present work focused on understanding the host-virus interaction as well as host virus drug interaction to identify the disease pathways and host-directed drug targets. Thus, existing direct physical Ebola-human protein-protein interaction (PPI) was collected from various publicly available databases and also literature through manual curation. Further, the functional and pathway enrichment analysis for the proteins were performed using database for annotation, visualization, and integrated discovery and the enriched gene ontology biological process terms includes chromatin assembly or disassembly, nucleosome organization, nucleosome assembly. Also, the enriched Kyoto Encyclopedia of Genes and Genome pathway terms includes systemic lupus erythematosus, alcoholism, and viral carcinogenesis. From the PPI network, important large histone clusters and tubulin were observed. Further, the host-virus and host-virus-drug interaction network has been generated and found that 182 drugs are associated with 45 host genes. The obtained drugs and their interacting targets could be considered for Ebola treatment.

PMID: 32206696 [PubMed]

Coronavirus puts drug repurposing on the fast track.

Nat Biotechnol. 2020 Feb 27;:

Authors: Harrison C

PMID: 32205870 [PubMed - as supplied by publisher]

Carvedilol serves as a novel CYP1B1 inhibitor, a systematic drug repurposing approach through structure-based virtual screening and experimental verification.

Eur J Med Chem. 2020 Mar 16;193:112235

Authors: Wang Y, He X, Li C, Ma Y, Xue W, Hu B, Wang J, Zhang T, Zhang F

Abstract
Cytochrome P450 1B1 (CYP1B1) is a promising target for prevention and therapy of cancer, particularly those with drug resistance, stimulating cancer cell survival, and promoting cancer resistance. In view of the extreme complexity and high risk in drug discovery and development, a drug repurposing strategy was applied in the present study to find potential CYP1B1 inhibitors through structure-based virtual screening in the FDA database. Intriguingly, after a thorough assessment of docking scores, binding affinities, as well as binding modes, six compounds were highlighted for further verification. In fact, both carvedilol and indacaterol showed inhibitory activity towards human CYP1B1 with the IC50 of 1.11 μM and 59.52 μM, respectively, according to EROD assay; however, neither docking score nor the detailed binding mode of carvedilol in the hit pose dictated to be a superior CYP1B1 inhibitor to indacaterol, which called for the necessity to re-access the binding mode of carvedilol. Thus, the top two representative docking poses of carvedilol were re-assessed. Indeed, compared to the one hit in the virtual screening (due to a false positive Glide gscore), the other docking pose exhibited ideal performance in both molecular dynamics (MD) simulation, binding free energy, and density functional theory (DFT) calculation evaluations. This identification of the exact binding pose of carvedilol is not only essential for a better understanding of the mechanism underlying its activity, but also contributes to uncovering the structure-activity relationship of CYP1B1 inhibitors. Of note, carvedilol exhibited direct cytotoxicity against both human lung adenocarcinoma epithelial cell line A459 and its Taxol-resistant subline (A549/Taxol). In particular, it showed superior toxicity towards A549/Taxol cells that overexpressed CYP1B1, which further supported its potential to be an effective CYP1B1 inhibitor.

PMID: 32203789 [PubMed - as supplied by publisher]

Association of sleep among 30 antidepressants: a population-wide adverse drug reaction study, 2004-2019.

PeerJ. 2020;8:e8748

Authors: Eugene AR

Abstract
Background: Sleep is one of the most essential processes required to maintain a healthy human life, and patients experiencing psychiatric illness often experience an inability to sleep. The aim of this study is to test the hypothesis that antidepressant compounds with strong binding affinities for the serotonin 5-HT2C receptor, histamine H1 receptors, or norepinephrine transporter (NET) will be associated with the highest odds of somnolence.
Methods: Post-marketing cases of patient adverse drug reactions were obtained from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) during the reporting window of January 2004 to September 2019. Disproportionality analyses of antidepressants reporting somnolence were calculated using the case/non-case method. The reporting odds-ratios (ROR) and corresponding 95% confidence interval (95% CI) were computed and all computations and graphing conducted in R.
Results: There were a total of 69,196 reported cases of somnolence out of a total of 7,366,864 cases reported from January 2004 to September 2019. Among the 30 antidepressants assessed, amoxapine (n = 16) reporting odds-ratio (ROR) = 7.1 (95% confidence interval [CI] [4.3-11.7]), atomoxetine (n = 1,079) ROR = 6.6 (95% CI [6.2-7.1]), a compound generally approved for attention deficit hyperactivity disorder (ADHD), and maprotiline (n = 18) ROR = 6.3 (95% CI, 3.9-10.1) were the top three compounds ranked with the highest reporting odds of somnolence. In contrast, vortioxetine (n = 52) ROR = 1.3 (95% CI [1.0-1.8]), milnacipran (n = 58) ROR = 2.1 (95% CI [1.7-2.8]), and bupropion (n = 1,048) ROR = 2.2 (95% CI [2.1-2.4]) are least significantly associated with somnolence. Moreover, levomilnacipran (n = 1) ROR = 0.4 (95% CI [0.1-2.9]) was not associated with somnolence.
Conclusion: Among the thirty tested antidepressants, consistent with the original hypothesis, amoxepine has strongest 5-HT2C receptor binding affinity and has the highest reporting odds of somnolence. Atomoxetine, ranked second in reporting odds of somnolence overall, binds to the NET with with the strongest binding affinity among the thirty compounds. Mirtazapine, a tetracyclic antidepressant, was ranked 11th in reporting odds of somnolence and had the strongest H1 receptor binding affinity. This study provides an informative ranking of somnolence among thirty antidepressant compounds with an already wide array of clinical indications as well as provides insight into potential drug repurposing in psychopharmacology.

PMID: 32201646 [PubMed]

High throughput in vivo phenotypic screening for drug repurposing: Discovery of MLR-1023 a novel insulin sensitizer and novel Lyn kinase activator with clinical proof of concept.

Bioorg Med Chem. 2020 Mar 16;:115425

Authors: Lipinski CA, Reaume AG

Abstract
Drug discovery requires the combination of medicinal chemistry and biology. In this article Chris Lipinski, the medicinal chemist, describes the chemical origins at Pfizer of Tolimidone1 the starting point for the repurposed MLR-1023 (Ochman et al., 2012). Andrew Reaume, the biologist, describes his motivation to develop a high quality (i.e. in vivo model) phenotypic screening platform as an ideal drug repositioning platform.

PMID: 32201192 [PubMed - as supplied by publisher]

Therapeutic options for the 2019 novel coronavirus (2019-nCoV).

Nat Rev Drug Discov. 2020 03;19(3):149-150

Authors: Li G, De Clercq E

PMID: 32127666 [PubMed - indexed for MEDLINE]

Skin Delivery and Irritation Potential of Phenmetrazine as a Candidate Transdermal Formulation for Repurposed Indications.

AAPS J. 2019 05 31;21(4):70

Authors: Jiang Y, Murnane KS, Bhattaccharjee SA, Blough BE, Banga AK

Abstract
Phenmetrazine, a selective dopamine and norepinephrine releaser, previously available as an oral anorectic, is prone to be abused. This study aimed to assess the feasibility of delivering phenmetrazine via the transdermal route for a new indication, while also minimizing its abuse potential. The passive permeation of phenmetrazine through dermatomed human cadaver skin was evaluated using static Franz diffusion cells at 10 mg/mL for the fumarate salt, and at 20, 40, and 80 mg/mL for the free base in propylene glycol for 24 h. Further, oleic acid (5% w/w), oleyl alcohol (5% and 10% w/w), and lauric acid (10% w/w) were investigated as chemical permeation enhancers to enhance the delivery. Skin irritation potential was assessed using EpiDerm™ in vitro reconstructed human epidermal model. The free base showed superior 24-h delivery (8.13 ± 4.07%, 10.6 ± 2.5%, and 10.4 ± 1.4% for groups with 20, 40, and 80 mg/mL of the free base, respectively) to phenmetrazine fumarate salt (undetectable). The successful screening of effective chemical enhancers, oleyl alcohol (5% and 10% w/w), oleic acid (5% w/w), and lauric acid (10% w/w) resulted in significant enhancement of delivery. The calculated therapeutic relevant flux for the potential indication, attention deficit hyperactivity disorder, 20 μg/cm2/h was met, where a 24-mg daily dose from a 50-cm2 patch was projected to be delivered to a 60-kg individual. Irritation study results suggest that formulations with therapeutically relevant delivery are likely to be non-irritant. In conclusion, it is feasible to deliver therapeutically relevant amounts of phenmetrazine via the transdermal route.

PMID: 31152318 [PubMed - indexed for MEDLINE]

Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2.

Cell Discov. 2020;6:14

Authors: Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F

Abstract
Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead global epidemics with high morbidity and mortality. However, there are currently no effective drugs targeting 2019-nCoV/SARS-CoV-2. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV-host interactome and drug targets in the human protein-protein interaction network. Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV/SARS-CoV-2 shares the highest nucleotide sequence identity with SARS-CoV (79.7%). Specifically, the envelope and nucleocapsid proteins of 2019-nCoV/SARS-CoV-2 are two evolutionarily conserved regions, having the sequence identities of 96% and 89.6%, respectively, compared to SARS-CoV. Using network proximity analyses of drug targets and HCoV-host interactions in the human interactome, we prioritize 16 potential anti-HCoV repurposable drugs (e.g., melatonin, mercaptopurine, and sirolimus) that are further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. We further identify three potential drug combinations (e.g., sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) captured by the "Complementary Exposure" pattern: the targets of the drugs both hit the HCoV-host subnetwork, but target separate neighborhoods in the human interactome network. In summary, this study offers powerful network-based methodologies for rapid identification of candidate repurposable drugs and potential drug combinations targeting 2019-nCoV/SARS-CoV-2.

PMID: 32194980 [PubMed]

Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates.

F1000Res. 2020;9:129

Authors: Chen YW, Yiu CB, Wong KY

Abstract
We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL pro) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart.  With the 3CL pro molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache.  The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.

PMID: 32194944 [PubMed - in process]