Cancers (Basel). 2021 Nov 29;13(23):5993. doi: 10.3390/cancers13235993.

ABSTRACT

High-grade serous ovarian cancer (HGSOC) is the most common ovarian cancer subtype, and the overall survival rate has not improved in the last three decades. Currently, most patients develop recurrent disease within 3 years and succumb to the disease within 5 years. This is an important area of research, as the major obstacle to the treatment of HGSOC is the development of resistance to platinum chemotherapy. The cause of chemoresistance is still largely unknown and may be due to epigenetics modifications that are driving HGSOC metastasis and treatment resistance. The identification of epigenetic changes in chemoresistant HGSOC enables the development of epigenetic modulating drugs that may be used to improve outcomes. Several epigenetic modulating drugs have displayed promise as drug targets for HGSOC, such as demethylating agents azacitidine and decitabine. Others, such as histone deacetylase inhibitors and miRNA-targeting therapies, demonstrated promising preclinical results but resulted in off-target side effects in clinical trials. This article reviews the epigenetic modifications identified in chemoresistant HGSOC and clinical trials utilizing epigenetic therapies in HGSOC.

PMID:34885103 | DOI:10.3390/cancers13235993

Int J Mol Sci. 2021 Dec 5;22(23):13155. doi: 10.3390/ijms222313155.

ABSTRACT

Molecular mechanisms underlying the beneficial effect of sitagliptin repurposed for hepatic ischemia-reperfusion injury (IRI) are poorly understood. We aimed to evaluate the impact of IRI and sitagliptin on the hepatic profile of eicosanoids (LC-MS/MS) and expression/concentration (RTqPCR/ELISA) of GLP-1/GLP-1R, SDF-1α/CXCR4 and VIP/VPAC1, VPAC2, and PAC1 in 36 rats. Animals were divided into four groups and subjected to ischemia (60 min) and reperfusion (24 h) with or without pretreatment with sitagliptin (5 mg/kg) (IR and SIR) or sham-operated with or without sitagliptin pretreatment (controls and sitagliptin). PGI2, PGE2, and 13,14-dihydro-PGE1 were significantly upregulated in IR but not SIR, while sitagliptin upregulated PGD2 and 15-deoxy-12,14-PGJ2. IR and sitagliptin non-significantly upregulated GLP-1 while Glp1r expression was borderline detectable. VIP concentration and Vpac2 expression were downregulated in IR but not SIR, while Vpac1 was significantly downregulated solely in SIR. IRI upregulated both CXCR4 expression and concentration, and sitagliptin pretreatment abrogated receptor overexpression and downregulated Sdf1. In conclusion, hepatic IRI is accompanied by an elevation in proinflammatory prostanoids and overexpression of CXCR4, combined with downregulation of VIP/VPAC2. Beneficial effects of sitagliptin during hepatic IRI might be mediated by drug-induced normalization of proinflammatory prostanoids and upregulation of PGD2 and by concomitant downregulation of SDF-1α/CXCR4 and reinstating VIP/VCAP2 signaling.

PMID:34884960 | DOI:10.3390/ijms222313155

Int J Mol Sci. 2021 Nov 27;22(23):12829. doi: 10.3390/ijms222312829.

ABSTRACT

Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.

PMID:34884638 | DOI:10.3390/ijms222312829

J Mycol Med. 2021 Dec 1;32(1):101232. doi: 10.1016/j.mycmed.2021.101232. Online ahead of print.

ABSTRACT

Candida auris emerges as an important causative agent of fungal infections, with worrisome mortality rates, mainly in immunocompromised individuals. This scenario is worsened by the limited availability of antifungal drugs and the increasing development of resistance to them. Due to the relevance of C. auris infections to public health, several studies aimed to discover new antifungal compounds capable of overcoming this fungus. Nonetheless, these information are decentralized, precluding the understandment of the current status of the search for new anti-C. auris compounds. Thus, this integrative review aimed to summarize information regarding anti-C. auris compounds reported in literature. After using predefined selection criteria, 71 articles were included in this review, and data from a total of 101 substances were extracted. Most of the studies tested synthetic substances, including several azoles. Moreover, drug repurposing emerges as a suitable strategy to discover new anti-C. auris agents. Few studies, however, assessed the mechanism of action and the in vivo antifungal activity of the compounds. Therefore, more studies must be performed to evaluate the usefulness of these substances as anti-C. auris therapies.

PMID:34883404 | DOI:10.1016/j.mycmed.2021.101232

Emerg Top Life Sci. 2021 Dec 9:ETLS20210223. doi: 10.1042/ETLS20210223. Online ahead of print.

ABSTRACT

Drug repositioning aims to reuse existing drugs, shelved drugs, or drug candidates that failed clinical trials for other medical indications. Its attraction is sprung from the reduction in risk associated with safety testing of new medications and the time to get a known drug into the clinics. Artificial Intelligence (AI) has been recently pursued to speed up drug repositioning and discovery. The essence of AI in drug repositioning is to unify the knowledge and actions, i.e. incorporating real-world and experimental data to map out the best way forward to identify effective therapeutics against a disease. In this review, we share positive expectations for the evolution of AI and drug repositioning and summarize the role of AI in several methods of drug repositioning.

PMID:34881780 | DOI:10.1042/ETLS20210223

Emerg Top Life Sci. 2021 Dec 9:ETLS20210249. doi: 10.1042/ETLS20210249. Online ahead of print.

ABSTRACT

Alzheimer's disease (AD) remains a devastating neurodegenerative disease with few preventive or curative treatments available. Modern technology developments of high-throughput omics platforms and imaging equipment provide unprecedented opportunities to study the etiology and progression of this disease. Meanwhile, the vast amount of data from various modalities, such as genetics, proteomics, transcriptomics, and imaging, as well as clinical features impose great challenges in data integration and analysis. Machine learning (ML) methods offer novel techniques to address high dimensional data, integrate data from different sources, model the etiological and clinical heterogeneity, and discover new biomarkers. These directions have the potential to help us better manage the disease progression and develop novel treatment strategies. This mini-review paper summarizes different ML methods that have been applied to study AD using single-platform or multi-modal data. We review the current state of ML applications for five key directions of AD research: disease classification, drug repurposing, subtyping, progression prediction, and biomarker discovery. This summary provides insights about the current research status of ML-based AD research and highlights potential directions for future research.

PMID:34881778 | DOI:10.1042/ETLS20210249

Clin Cancer Res. 2021 Dec 8:clincanres.3471.2021. doi: 10.1158/1078-0432.CCR-21-3471. Online ahead of print.

ABSTRACT

While metastatic osteosarcoma is rare in humans, it is the most common bone tumor found in any breed of dog. Given the genetic similarities between canine and human osteosarcomas, canine clinical trials allow for rapid testing and drug repurposing at a speed that cannot be achieved using osteosarcoma patients.

PMID:34880110 | DOI:10.1158/1078-0432.CCR-21-3471

ACS Infect Dis. 2021 Dec 8. doi: 10.1021/acsinfecdis.1c00367. Online ahead of print.

ABSTRACT

Glycopeptides, a class of cell wall biosynthesis inhibitors, have been the antibiotics of choice against drug-resistant Gram-positive bacterial infections. Their unique mechanism of action involving binding to the substrate of cell wall biosynthesis and substantial longevity in clinics makes this class of antibiotics an attractive choice for drug repurposing and reprofiling. However, resistance to glycopeptides has been observed due to alterations in the substrate, cell wall thickening, or both. The emergence of glycopeptide resistance has resulted in the development of synthetic and semisynthetic glycopeptide analogues to target acquired resistance. Recent findings demonstrate that these derivatives, along with some of the FDA approved glycopeptides have been shown to have antimicrobial activity against Gram-negative bacteria, Mycobacteria, and viruses thus expanding their spectrum of activity across the microbial kingdom. Additional mechanisms of action and identification of novel targets have proven to be critical in broadening the spectrum of activity of glycopeptides. This review focuses on the applications of glycopeptides beyond their traditional target group of Gram-positive bacteria. This will aid in making the scientific community aware about the nontraditional activity profiles of glycopeptides, identify the existing loopholes, and further explore this antibiotic class as a potential broad-spectrum antimicrobial agent.

PMID:34878254 | DOI:10.1021/acsinfecdis.1c00367

J Biomol Struct Dyn. 2021 Dec 8:1-13. doi: 10.1080/07391102.2021.2010601. Online ahead of print.

ABSTRACT

COVID-19 is a worldwide health crisis seriously endangering the arsenal of antiviral and antibiotic drugs. It is urgent to find an effective antiviral drug against pandemic caused by the severe acute respiratory syndrome (Sars-Cov-2), which increases global health concerns. As it can be expensive and time-consuming to develop specific antiviral drugs, reuse of FDA-approved drugs that provide an opportunity to rapidly distribute effective therapeutics can allow to provide treatments with known preclinical, pharmacokinetic, pharmacodynamic and toxicity profiles that can quickly enter in clinical trials. In this study, using the structural information of molecules and proteins, a list of repurposed drug candidates was prepared again with the graph neural network-based GEFA model. The data set from the public databases DrugBank and PubChem were used for analysis. Using the Tanimoto/jaccard similarity analysis, a list of similar drugs was prepared by comparing the drugs used in the treatment of COVID-19 with the drugs used in the treatment of other diseases. The resultant drugs were compared with the drugs used in lung cancer and repurposed drugs were obtained again by calculating the binding strength between a drug and a target. The kinase inhibitors (erlotinib, lapatinib, vandetanib, pazopanib, cediranib, dasatinib, linifanib and tozasertib) obtained from the study can be used as an alternative for the treatment of COVID-19, as a combination of blocking agents (gefitinib, osimertinib, fedratinib, baricitinib, imatinib, sunitinib and ponatinib) such as ABL2, ABL1, EGFR, AAK1, FLT3 and JAK1, or antiviral therapies (ribavirin, ritonavir-lopinavir and remdesivir).Communicated by Ramaswamy H. Sarma.

PMID:34877907 | DOI:10.1080/07391102.2021.2010601

CPT Pharmacometrics Syst Pharmacol. 2021 Dec 8. doi: 10.1002/psp4.12751. Online ahead of print.

ABSTRACT

Cystic fibrosis is a lethal autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The common ΔF508-CFTR mutation results in protein misfolding and proteasomal degradation. If ΔF508-CFTR trafficks to the cell surface, its anion channel function may be partially restored. Several in vitro strategies can partially correct ΔF508-CFTR trafficking and function, including low-temperature, small molecules, overexpression of miR-138, or knockdown of SIN3A. The challenge remains to translate such interventions into therapies and to understand their mechanisms. One approach for connecting such interventions to small molecule therapies that has previously succeeded for cystic fibrosis and other diseases is via mRNA expression profiling and iterative searches of small molecules with similar expression signatures. Here, we query the Library of Integrated Network-based Cellular Signatures (LINCS) using transcriptomic signatures from previously generated CF expression data, including RNAi- and low temperature-based rescue signatures. This LINCS in silico screen prioritized 135 small molecules that mimicked our rescue interventions based on their genome-wide transcriptional perturbations. Functional screens of these small molecules identified eight compounds that partially restored ΔF508-CFTR function, as assessed by cAMP-activated chloride conductance. Of these, XL147 rescued ΔF508-CFTR function in primary CF airway epithelia, while also showing cooperativity when administered with C18. Improved CF corrector therapies are greatly needed and this integrative drug prioritization approach offers a novel method to both identify small molecules that may rescue ΔF508-CFTR function and identify gene networks underlying such rescue.

PMID:34877817 | DOI:10.1002/psp4.12751

World J Gastroenterol. 2021 Nov 14;27(42):7210-7232. doi: 10.3748/wjg.v27.i42.7210.

ABSTRACT

Clostridioides difficile (C. difficile) is a gram-positive, anaerobic spore-forming bacterium and a major cause of antibiotic-associated diarrhea. Humans are naturally resistant to C. difficile infection (CDI) owing to the protection provided by healthy gut microbiota. When the gut microbiota is disturbed, C. difficile can colonize, produce toxins, and manifest clinical symptoms, ranging from asymptomatic diarrhea and colitis to death. Despite the steady-if not rising-prevalence of CDI, it will certainly become more problematic in a world of antibiotic overuse and the post-antibiotic era. C. difficile is naturally resistant to most of the currently used antibiotics as it uses multiple resistance mechanisms. Therefore, current CDI treatment regimens are extremely limited to only a few antibiotics, which include vancomycin, fidaxomicin, and metronidazole. Therefore, one of the main challenges experienced by the scientific community is the development of alternative approaches to control and treat CDI. In this Frontier article, we collectively summarize recent advances in alternative treatment approaches for CDI. Over the past few years, several studies have reported on natural product-derived compounds, drug repurposing, high-throughput library screening, phage therapy, and fecal microbiota transplantation. We also include an update on vaccine development, pre- and pro-biotics for CDI, and toxin antidote approaches. These measures tackle CDI at every stage of disease pathology via multiple mechanisms. We also discuss the gaps and concerns in these developments. The next epidemic of CDI is not a matter of if but a matter of when. Therefore, being well-equipped with a collection of alternative therapeutics is necessary and should be prioritized.

PMID:34876784 | PMC:PMC8611198 | DOI:10.3748/wjg.v27.i42.7210

Pharmacopsychiatry. 2021 Dec 7. doi: 10.1055/a-1686-9620. Online ahead of print.

ABSTRACT

Serotonin reuptake inhibitors (SRIs) are safe and widely used for a variety of indications including depressive disorders, anxiety, and chronic pain. Besides inhibiting the serotonin transporter, these medications have broad-spectrum properties in many systems. Their roles have been studied in cancer, Alzheimer's disease, and infectious processes. The COVID-19 pandemic highlighted the importance of drug repurposing of medications already in use. We conducted a narrative review of current evidence and ongoing research on drug repurposing of SRIs, with a focus on immunomodulatory, antiproliferative, and neuroprotective activity. SRIs may have clinical use as repurposed agents for a wide variety of conditions including but not limited to COVID-19, Alzheimer's disease, and neoplastic processes. Further research, particularly randomized controlled trials, will be necessary to confirm the utility of SRIs for new indications.

PMID:34875696 | DOI:10.1055/a-1686-9620

Int J Parasitol Drugs Drug Resist. 2021 Nov 25;17:204-212. doi: 10.1016/j.ijpddr.2021.10.003. Online ahead of print.

ABSTRACT

Naegleria fowleri is both a pathogenic and a free-living microbial eukaryote, responsible for the development of primary amoebic meningoencephalitis (PAM) in humans. PAM is a rapid, severe and fatal underestimated infectious disease, which has been reported in countries with warmer climates. The major drawbacks with PAM are the lack of effective therapies and delay in diagnosis. The current frontline treatment presents a low rate of recovery (5%) and severe adverse effects. For example, many drug candidates lack efficacy, since they do not effectively cross the blood-brain-barrier. Consequently, more effective drugs are urgently needed. Herein, we report a new in vitro method suitable for medium- and high-throughput drug discovery assays, using the closely related Naegleria gruberi as a model. We have subsequently used this method to screen a library of 1175 Food and Drug Administration-approved drugs. As a result, we present three drugs (camptothecin, pyrimethamine, and terbinafine) that can be repurposed, and are anticipated to readily cross the blood-brain-barrier with activity against Naegleria species in therapeutically achievable concentrations. Successively, we integrated several in vitro assays that resulted in identifying fast-acting and high amoebicidal drugs. In conclusion, we present a new approach for the identification of anti-Naegleria drugs along with three potential drug candidates for further development for the treatment of PAM.

PMID:34875573 | DOI:10.1016/j.ijpddr.2021.10.003

Bioorg Med Chem. 2021 Nov 22;53:116523. doi: 10.1016/j.bmc.2021.116523. Online ahead of print.

ABSTRACT

Since the end of 2019, the outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic. There is an urgent need for effective and low-toxic antiviral drugs to remedy Remdesivir's limitation. Hydroxychloroquine, a broad spectrum anti-viral drug, showed inhibitory activity against SARS-CoV-2 in some studies. Thus, we adopted a drug repurposing strategy, and further investigated hydroxychloroquine. We obtained different configurations of hydroxychloroquine side chains by using chiral resolution technique, and successfully furnished R-/S-hydroxychloroquine sulfate through chemical synthesis. The R configuration of hydroxychloroquine was found to exhibit higher antiviral activity (EC50 = 3.05 μM) and lower toxicity in vivo. Therefore, R-HCQ is a promising lead compound against SARS-CoV-2. Our research provides new strategy for the subsequent research on small molecule inhibitors against SARS-CoV-2.

PMID:34875467 | DOI:10.1016/j.bmc.2021.116523

J Ethnopharmacol. 2021 Dec 4:114893. doi: 10.1016/j.jep.2021.114893. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: A mixture (SH003) of Astragalus membranaceus (Fisch.) Bunge, Angelica gigas Nakai, and Trichosanthes Kirilowii (Maxim.) has beneficial effects against several carcinomas. There have been few reports on an immune-enhancing activity of SH003 and its active constituent nodakenin.

AIM OF THE STUDY: This study aimed at identifying the immune-enhancing effect of SH003 and nodakenin.

MATERIALS AND METHODS: The immune-enhancing effect was evaluated using RAW264.7 macrophages, mouse primary splenocytes, and a cyclophosphamide (CP)-induced immunosuppression murine model.

RESULTS: The results show that SH003 or nodakenin stimulated the production levels of granulocyte colony-stimulating factor, IL-12, IL-2, IL-6, TNF-α, and nitric oxide (NO) and the expression levels of iNOS in RAW264.7 macrophages. SH003 or nodakenin also enhanced NF-κB p65 activation in RAW264.7 macrophages. SH003 or nodakenin stimulated the production levels of IFN-γ, IL-12, IL-2, TNF-α, and NO and the expression levels of iNOS in splenocytes. SH003 or nodakenin increased the splenic lymphocyte proliferation and splenic NK cell activity. In addition, SH003 or nodakenin increased the levels of IFN-γ, IL-12, IL-2, IL-6, and TNF-α in the serum and spleen of CP-treated mice, alleviating CP-induced immunosuppression.

CONCLUSION: Taken together, the results of this study show that SH003 improved immunosuppression through the activation of macrophages, splenocytes, and NK cells. These findings suggest that SH003 could be applied as a potential immunostimulatory agent for a variety of diseases caused or exacerbated by immunodeficiency.

PMID:34875347 | DOI:10.1016/j.jep.2021.114893

Bioinformatics. 2021 Dec 7:btab826. doi: 10.1093/bioinformatics/btab826. Online ahead of print.

ABSTRACT

MOTIVATION: Drug repurposing is a potential alternative to the traditional drug discovery process. Drug repurposing can be formulated as a recommender system that recommends novel indications for available drugs based on known drug-disease associations. This paper presents a method based on non-negative matrix factorization (NMF-DR) to predict the drug-related candidate disease indications. This work proposes a recommender system-based method for drug repurposing to predict novel drug indications by integrating drug and diseases related data sources. For this purpose, this framework first integrates two types of disease similarities, the associations between drugs and diseases, and the various similarities between drugs from different views to make a heterogeneous drug-disease interaction network. Then, an improved non-negative matrix factorization-based method is proposed to complete the drug-disease adjacency matrix with predicted scores for unknown drug-disease pairs.

RESULTS: The comprehensive experimental results show that NMF-DR achieves superior prediction performance when compared with several existing methods for drug-disease association prediction.

AVAILABILITY: The program is available at https://github.com/sshaghayeghs/NMF-DR.

PMID:34875000 | DOI:10.1093/bioinformatics/btab826

Curr Res Pharmacol Drug Discov. 2021;2:100042. doi: 10.1016/j.crphar.2021.100042. Epub 2021 Jul 28.

ABSTRACT

It has been said that COVID-19 is a generational challenge in many ways. But, at the same time, it becomes a catalyst for collective action, innovation, and discovery. Realizing the full potential of artificial intelligence (AI) for structure determination of unknown proteins and drug discovery are some of these innovations. Potential applications of AI include predicting the structure of the infectious proteins, identifying drugs that may be effective in targeting these proteins, and proposing new chemical compounds for further testing as potential drugs. AI and machine learning (ML) allow for rapid drug development including repurposing existing drugs. Algorithms were used to search for novel or approved antiviral drugs capable of inhibiting SARS-CoV-2. This paper presents a survey of AI and ML methods being used in various biochemistry of SARS-CoV-2, from structure to drug development, in the fight against the deadly COVID-19 pandemic. It is envisioned that this study will provide AI/ML researchers and the wider community an overview of the current status of AI applications particularly in structural biology, drug repurposing, and development, and motivate researchers in harnessing AI potentials in the fight against COVID-19.

PMID:34870150 | PMC:PMC8317454 | DOI:10.1016/j.crphar.2021.100042

Curr Res Pharmacol Drug Discov. 2021;2:100011. doi: 10.1016/j.crphar.2020.100011. Epub 2020 Dec 11.

ABSTRACT

There are currently no emergency treatments for pandemics, yet drug repositioning has emerged as the foremost treatment development strategy for COVID-19, with an aim to identify successful antiviral therapeutics from safe, non-antiviral candidates. These therapeutics include antibiotics such as azithromycin and the antiparasitic nitazoxanide, both of which exhibit antiviral activity. Broad-spectrum therapeutics (BSTs) are a class of antimicrobials active against multiple pathogen types. Establishment of a developmental framework for BSTs will markedly improve global preparedness for future health emergencies.

PMID:34870144 | PMC:PMC8035643 | DOI:10.1016/j.crphar.2020.100011

Front Microbiol. 2021 Nov 18;12:759817. doi: 10.3389/fmicb.2021.759817. eCollection 2021.

ABSTRACT

The apicomplexan parasite, Theileria annulata, is the most prevalent hemoprotozoan in livestock, causing significant economic losses worldwide. It is essential to develop new and improved therapeutics, as current control measures are compromised by the development of resistance against the only available antitheilerial drug, buparvaquone (BPQ). Histone deacetylase inhibitors (HDACi) were shown to treat cancer effectively and revealed in vitro antiparasitic activity against apicomplexan parasites such as Plasmodium and Toxoplasma. In this study, we investigated the antitheilerial activity of the four anti-cancer HDACi (vorinostat, romidepsin, belinostat, and panobinostat) against the schizont stage of T. annulata parasites. All four HDACi showed potent activity and increased hyperacetylation of the histone-4 protein. However, based on the low host cell cytotoxicity and IC50 values, vorinostat (0.103 μM) and belinostat (0.069 μM) were the most effective showing antiparasitic activity. The parasite-specific activities of the HDACi (vorinostat and belinostat) were evaluated by western blotting using parasite-specific antibodies and in silico analysis. Both vorinostat and belinostat reduced the Theileria infected cell viability by downregulating anti-apoptotic proteins and mitochondrial dysfunction, leading to caspase-dependent cell apoptosis. The HDACi caused irreversible and antiproliferative effects on the Theileria infected cell lines. Our results collectively showed that vorinostat and belinostat could be used as an alternative therapy for treating Theileria parasites.

PMID:34867888 | PMC:PMC8640587 | DOI:10.3389/fmicb.2021.759817

Front Endocrinol (Lausanne). 2021 Nov 18;12:711906. doi: 10.3389/fendo.2021.711906. eCollection 2021.

ABSTRACT

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two neuropeptides that contribute to the regulation of intestinal motility and secretion, exocrine and endocrine secretions, and homeostasis of the immune system. Their biological effects are mediated by three receptors named VPAC1, VPAC2 and PAC1 that belong to class B GPCRs. VIP and PACAP receptors have been identified as potential therapeutic targets for the treatment of chronic inflammation, neurodegenerative diseases and cancer. However, pharmacological use of endogenous ligands for these receptors is limited by their lack of specificity (PACAP binds with high affinity to VPAC1, VPAC2 and PAC1 receptors while VIP recognizes both VPAC1 and VPAC2 receptors), their poor oral bioavailability (VIP and PACAP are 27- to 38-amino acid peptides) and their short half-life. Therefore, the development of non-peptidic small molecules or specific stabilized peptidic ligands is of high interest. Structural similarities between VIP and PACAP receptors are major causes of difficulties in the design of efficient and selective compounds that could be used as therapeutics. In this study we performed structure-based virtual screening against the subset of the ZINC15 drug library. This drug repositioning screen provided new applications for a known drug: ticagrelor, a P2Y12 purinergic receptor antagonist. Ticagrelor inhibits both VPAC1 and VPAC2 receptors which was confirmed in VIP-binding and calcium mobilization assays. A following analysis of detailed ticagrelor binding modes to all three VIP and PACAP receptors with molecular dynamics revealed its allosteric mechanism of action. Using a validated homology model of inactive VPAC1 and a recently released cryo-EM structure of active VPAC1 we described how ticagrelor could block conformational changes in the region of 'tyrosine toggle switch' required for the receptor activation. We also discuss possible modifications of ticagrelor comparing other P2Y12 antagonist - cangrelor, closely related to ticagrelor but not active for VPAC1/VPAC2. This comparison with inactive cangrelor could lead to further improvement of the ticagrelor activity and selectivity for VIP and PACAP receptor sub-types.

PMID:34867774 | PMC:PMC8637020 | DOI:10.3389/fendo.2021.711906