Iran J Biotechnol. 2022 Jul 1;20(3):e2968. doi: 10.30498/ijb.2022.269817.2968. eCollection 2022 Jul.

ABSTRACT

BACKGROUND: As the most prevalent form of liver cancer, hepatocellular carcinoma (HCC) ranks the fifth highest cause of cancer-related death worldwide. Despite recent advancements in diagnostic and therapeutic techniques, the prognosis for HCC is still unknown.

OBJECTIVES: This study aimed to identify potential genes contributing to HCC pathogenicity.

MATERIALS AND METHODS: To this end, we examined the GSE39791 microarray dataset, which included 72 HCC samples and 72 normal samples. An investigation of co-expression networks using WGCNA found a highly conserved blue module with 665 genes that were strongly linked to HCC.

RESULTS: APOF, NAT2, LCAT, TTC36, IGFALS, ASPDH, and VIPR1 were the blue module's top 7 hub genes. According to the results of hub gene enrichment, the most related issues in the biological process and KEGG were peroxisome organization and metabolic pathways, respectively. In addition, using the drug-target network, we discovered 19 FDA-approved medication candidates for different reasons that might potentially be employed to treat HCC patients through the modulation of 3 hub genes of the co-expression network (LCAT, NAT2, and VIPR1). Our findings also demonstrated that the 3 scientifically validated miRNAs regulated the co-expression network by the VIPR1 hub gene.

CONCLUSION: We found co-expressed gene modules and hub genes linked with HCC advancement, offering insights into the mechanisms underlying HCC progression as well as some potential HCC treatments.

PMID:36381283 | PMC:PMC9618018 | DOI:10.30498/ijb.2022.269817.2968

OMICS. 2022 Nov 15. doi: 10.1089/omi.2022.0138. Online ahead of print.

ABSTRACT

The mechanisms of systemic autoimmune diseases (ADs) are still not clearly understood. Understanding the etiology of systemic ADs and identifying new therapeutic targets require a systems science approach. Using publicly available transcriptome data and bioinformatic analysis, we investigated the differential gene expression profiles of patients with scleroderma, systemic lupus erythematosus, and Sjogren's syndrome. Of these common differentially expressed gene signatures, 208 were regulated in the same direction (either upregulated or downregulated in all datasets) and used for drug repositioning. Six small molecule drug candidates (KU-0063794, YM-155 [sepantronium bromide], MST-312 [telomerase inhibitor IX], PLX-4720, ZM 336372, and 528116.cdx [PIK-75]) were discovered by drug repositioning as potential therapeutics for systemic ADs. The Search Tool for Chemical Interactions was used to find the anticipated target genes of the repositioned molecules. The PI3K/AKT pathway topped the list of common enriched pathways with the most anticipated target genes of the six repositioned small molecules. We also report here the molecular docking findings on the binding affinity between the repositioned drug candidates and genes from the protein-protein interaction network modules of anticipated target genes. Taken together, this study provides new insights and opens up new possibilities on both pathogenesis and treatment of systemic ADs through drug repositioning.

PMID:36378860 | DOI:10.1089/omi.2022.0138

Kidney Int. 2022 Oct 29:S0085-2538(22)00911-5. doi: 10.1016/j.kint.2022.09.029. Online ahead of print.

ABSTRACT

Blood pressure is regulated by a complex neurohumoral system including the renin-angiotensin-aldosterone system, natriuretic peptides, endothelial pathways, the sympathetic nervous system, and the immune system. This review charts the evolution of our understanding of the genomic basis of hypertension at increasing resolution over the last 5 decades from monogenic causes to polygenic associations, spanning ∼30 monogenic rare variants and >1500 single nucleotide variants. Unexpected early wins from blood pressure genomics include deepening of our understanding of the complex causation of hypertension; refinement of causal estimates bidirectionally between blood pressure, risk factors, and outcomes through Mendelian randomization; risk stratification using polygenic risk scores; and opportunities for precision medicine and drug repurposing.

PMID:36377113 | DOI:10.1016/j.kint.2022.09.029

Mol Divers. 2022 Nov 14. doi: 10.1007/s11030-022-10561-y. Online ahead of print.

ABSTRACT

Breast cancer is recognized globally as one of the leading causes of malignant morbidity. It is a heterogeneous disease that accounts for 30 percent of all women diagnosed with cancer. To bring an anti-cancer drug from the bench to the bedside is an expensive and time-consuming process. The drug repurposing approach targets new enemies (new diseases) with old weapons (known drugs). The present study identified an FDA-approved drug targeting the γ-secretase complex involved in the Notch signaling pathway in breast cancer stem cells (BCSCs). A literature survey and in-silico study identified Venetoclax as a γ-secretase inhibitor (GSI) from 1615 FDA-approved drug compounds. In-silico docking potential of Venetoclax was better than the standard γ-secretase inhibitor RO4929097. Also, the molecular dynamics simulations of 200 ns confirmed the stability of the Venetoclax-γ-secretase complex. These findings suggest that the use of Venetoclax represents a potential γ-secretase inhibitor in breast cancer stem cells. Eventually, the in vitro and clinical evaluation will be needed to confirm the potential chemopreventive and treatment effects of Venetoclax against breast cancer and breast cancer stem cells. Venetoclax appeared as the most promising drug of the 1615 FDA-approved drugs. Our in-silico findings suggest that Venetoclax may act as a γ-secretase inhibitor against the Notch signaling pathway in breast cancer stem cells.

PMID:36376717 | DOI:10.1007/s11030-022-10561-y

Int J Pharm. 2022 Nov 9:122379. doi: 10.1016/j.ijpharm.2022.122379. Online ahead of print.

ABSTRACT

Anthracyclines such as doxorubicin (Dox) are the preferred chemotherapeutics for several cancers. However, Dox-induced cardiotoxicity limits its therapeutic potential. Liposomal encapsulation of Dox has been used for patients with risk to develop Dox induced cardiotoxicity but does not surpass the efficacy of the unencapsulated drug. Statins are widely used as cholesterol lowering drugs and have also demonstrated cardioprotective activity in cancer patients undergoing Dox therapy. We developed a liposome loaded with Dox and simvastatin (Sim) and investigated their effect on cardiomyocytes and zebrafish larvae. Furthermore, we investigated if the doses required for cardioprotection compromised the cytotoxicity of Dox in mammary and prostate cancer cells. Combination of Sim and Dox reduced ROS generation in cardiomyocytes, both given as free drugs, or co-encapsulated in liposomes. In contrast, Sim potentiated ROS-generation and cytotoxic activity of Dox towards cancer cells also when co-encapsulated in liposomes. In zebrafish larvae, Sim treatment reduced Dox-induced cardiac affection, and the liposomes did not induce any sign of Dox-induced cardiotoxicity. Our results show that liposomal co-encapsulation of Sim and Dox can be an efficient way of further reducing the risk of cardiotoxic events of liposomal Dox, while retaining, or even potentiating the anti-cancer effect of Dox.

PMID:36370997 | DOI:10.1016/j.ijpharm.2022.122379

Biomed Pharmacother. 2022 Nov 9;157:113904. doi: 10.1016/j.biopha.2022.113904. Online ahead of print.

ABSTRACT

Neurodegenerative diseases have been a weighty problem in elder people who might be stricken with motor or/and cognition defects with lower life quality urging for effective treatment. Drugs are costly from development to market, so that drug repurposing, exploration of existing drugs for novel therapeutic purposes, becomes a wise and popular strategy to raise new treatment options. Clemastine fumarate, different from anti-allergic effect as H1 histamine antagonist, was screened and identified as promising drug for remyelination and autophagy enhancement. Surprisingly, fumarate salt also has similar effect. Hence, whether clemastine fumarate would make a protective impact on neurodegenerative diseases and what contribution fumarate probably makes are intriguing to us. In this review, we summarize the potential mechanism surrounding clemastine fumarate in current literature, and try to distinguish independent or synergistic effect between clemastine and fumarate, aiming to find worthwhile research direction for neurodegeneration diseases.

PMID:36370521 | DOI:10.1016/j.biopha.2022.113904

Alzheimers Res Ther. 2022 Nov 11;14(1):169. doi: 10.1186/s13195-022-01103-7.

ABSTRACT

Drug repositioning and repurposing has proved useful in identifying new treatments for many diseases, which can then rapidly be brought into clinical practice. Currently, there are few effective pharmacological treatments for Lewy body dementia (which includes both dementia with Lewy bodies and Parkinson's disease dementia) apart from cholinesterase inhibitors. We reviewed several promising compounds that might potentially be disease-modifying agents for Lewy body dementia and then undertook an International Delphi consensus study to prioritise compounds. We identified ambroxol as the top ranked agent for repurposing and identified a further six agents from the classes of tyrosine kinase inhibitors, GLP-1 receptor agonists, and angiotensin receptor blockers that were rated by the majority of our expert panel as justifying a clinical trial. It would now be timely to take forward all these compounds to Phase II or III clinical trials in Lewy body dementia.

PMID:36369100 | DOI:10.1186/s13195-022-01103-7

Neuropharmacology. 2022 Nov 8:109327. doi: 10.1016/j.neuropharm.2022.109327. Online ahead of print.

ABSTRACT

BACKGROUND: The prevalences of Alzheimer's disease (AD) and type 2 diabetes (T2D) continuously increase with the aging of world population. Clinical and epidemiological studies indicate that T2D is an important risk factor for AD. However, the mechanisms underlying the linkage of the two disorders are still not fully elucidated. The aim of this study is to explore the molecular mechanisms of their comorbidity and potential drug targets for AD treatment.

METHODS: We first compiled comprehensive lists of genes associated with AD and T2D, respectively. Then, we investigated the signatures of the shared genes and screened for interactions between the hub genes. Subsequently, we used Autodock Vina to perform molecular docking to predict new drug candidates. Lastly, structure and dynamics of docking results were examined by molecular dynamics simulation to verify drug reliability.

RESULTS: We obtained 917 AD-associated genes, 631 T2D-associated genes and 175 shared genes between the two disorders for subsequent analyses. Functional analysis revealed that metabolic process, lipid and atherosclerosis, AMPK signaling pathway, insulin resistance, chemokines and cytokines were enriched in the shared genes. In addition, 50 central hub genes were identified, including IL6, TNF, INS, IL1B, AKT1, VEGFA, IL10, TP53, PTGS2, TLR4, and others. Finally, we predicted new drug candidates (verdoheme and stannsoporfin) that could be potentially used for AD treatment.

CONCLUSIONS: Our study confirmed that there are important shared genes and pathways between AD and T2D, which may provide clues to reveal the molecular mechanism underlying the pathophysiology of the two diseases and help us to discover novel drug candidates for the treatment of AD. The results may also provide clues into identification of new targets and strategies for prevention and therapy of T2D that predisposes to AD.

PMID:36368623 | DOI:10.1016/j.neuropharm.2022.109327

PLoS One. 2022 Nov 11;17(11):e0277355. doi: 10.1371/journal.pone.0277355. eCollection 2022.

ABSTRACT

BACKGROUND: Patient interest in the use of cannabis-based medicines (CBMs) has increased in Australia. While recent policy and legislative changes have enabled health practitioners to prescribe CBMs for their patients, many patients still struggle to access CBMs. This paper employed a thematic analysis to submissions made to a 2019 Australian government inquiry into current barriers of patient access to medical cannabis.

METHODS: We identified 121 submissions from patients or family members (n = 63), government bodies (n = 5), non-government organisations (i.e., professional health bodies, charities, consumer organisations or advocacy groups; n = 25), medical cannabis and pharmaceutical industry (n = 16), and individual health professionals, academics, or research centres (n = 12). Data were coded using NVivo 12 software and thematically analysed. The findings were presented narratively using a modified Levesque's patient-centred access to care framework which includes: i) appropriateness; ii) availability and geographic accessibility; iii) acceptability; and iv) affordability.

RESULTS: Submissions from government agencies and professional health bodies consistently supported maintaining the current regulatory frameworks and access pathways, whereas an overwhelming majority of patients, advocacy groups and the medical cannabis industry described the current regulatory and access models as 'not fit for purpose'. These differing views seem to arise from divergent persepctives on (i) what and how much evidence is needed for policy and practice, and (ii) how patients should be given access to medical cannabis products amidst empirical uncertainty. Notwithstanding these differences, there were commonalities among some stakeholders regarding the various supply, regulatory, legislative, financial, and dispensing challenges that hindered timely access to CBMs.

CONCLUSIONS: Progress in addressing the fundamental barriers that determine if and how a patient accesses and uses CBMs needs i) a 'system-level' reform that gives due consideration to the geographic disparity in access to prescribers and medical cannabis, and ii) reframing societal and health professional's views of CBMs by decoupling recreational vs medical cannabis.

PMID:36367871 | DOI:10.1371/journal.pone.0277355

Chem Biol Drug Des. 2022 Nov 11. doi: 10.1111/cbdd.14179. Online ahead of print.

ABSTRACT

The coronavirus pandemic known as COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), threatens public health worldwide. Approval of COVID-19 vaccines and antiviral drugs have greatly reduced the severe cases and mortality rate. However, the continues mutations of viruses are challenging the efficacies of vaccines and antiviral drugs. Drug repurposing campaign has identified two JAK1/2 inhibitors ruxolitinib and baricitinib as potential antiviral drugs. Ruxolitinib and baricitinib exerts dual antiviral effect by modulation of inflammatory response via JAK1/2 and inhibition of viral entry via AAK1 and GAK. Inspired by this, in an effort to diversify chemical space, three analogues ((R)-8, (S)-8 and 9) of ruxolitinib and baricitinb were made using scaffold hopping strategy. Compound 9 displayed potent and comparable potencies against AAK1, JAK1 and JAK2 compared to Baricitinib. Notably, compound 9 showed better selectivity for AAK1, JAK1 and JAK2 over GAK. Besides, compound 9 displayed good druglikeness according to Lipinski's and Veber's rule. We thereby identified a potential lead compound 9, which might be used for the further development of anti-coronaviral therapy.

PMID:36366971 | DOI:10.1111/cbdd.14179

Viruses. 2022 Oct 31;14(11):2417. doi: 10.3390/v14112417.

ABSTRACT

The repurposing of licenced drugs for use against COVID-19 is one of the most rapid ways to develop new and alternative therapeutic options to manage the ongoing pandemic. Given circa 7817 licenced compounds available from Compounds Australia that can be screened, this paper demonstrates the utility of commercially available ex vivo/3D airway and alveolar tissue models. These models are a closer representation of in vivo studies than in vitro models, but retain the benefits of rapid in vitro screening for drug efficacy. We demonstrate that several existing drugs appear to show anti-SARS-CoV-2 activity against both SARS-CoV-2 Delta and Omicron Variants of Concern in the airway model. In particular, fluvoxamine, as well as aprepitant, everolimus, and sirolimus, has virus reduction efficacy comparable to the current standard of care (remdesivir, molnupiravir, nirmatrelvir). Whilst these results are encouraging, further testing and efficacy studies are required before clinical use can be considered.

PMID:36366514 | DOI:10.3390/v14112417

Pathogens. 2022 Nov 3;11(11):1291. doi: 10.3390/pathogens11111291.

ABSTRACT

Tuberculosis (TB) is one of the leading causes of death worldwide, consistently threatening public health. Conventional tuberculosis treatment requires a long-term treatment regimen and is associated with side effects. The efficacy of antitubercular drugs has decreased with the emergence of drug-resistant TB; therefore, the development of new TB treatment strategies is urgently needed. In this context, we present host-directed therapy (HDT) as an alternative to current tuberculosis therapy. Unlike antitubercular drugs that directly target Mycobacterium tuberculosis (Mtb), the causative agent of TB, HDT is an approach for treating TB that appropriately modulates host immune responses. HDT primarily aims to enhance the antimicrobial activity of the host in order to control Mtb infection and attenuate excessive inflammation in order to minimize tissue damage. Recently, research based on the repositioning of drugs for use in HDT has been in progress. Based on the overall immune responses against Mtb infection and the immune-evasion mechanisms of Mtb, this review examines the repositioned drugs available for HDT and their mechanisms of action.

PMID:36365041 | DOI:10.3390/pathogens11111291

Molecules. 2022 Nov 4;27(21):7553. doi: 10.3390/molecules27217553.

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV), belonging to the betacoronavirus genus can cause severe respiratory illnesses, accompanied by pneumonia, multiorgan failure, and ultimately death. CoVs have the ability to transgress species barriers and spread swiftly into new host species, with human-to-human transmission causing epidemic diseases. Despite the severe public health threat of MERS-CoV, there are currently no vaccines or drugs available for its treatment. MERS-CoV papain-like protease (PLpro) is a key enzyme that plays an important role in its replication. In the present study, we evaluated the inhibitory activities of doxorubicin (DOX) against the recombinant MERS-CoV PLpro by employing protease inhibition assays. Hydrolysis of fluorogenic peptide from the Z-RLRGG-AMC-peptide bond in the presence of DOX showed an IC50 value of 1.67 μM at 30 min. Subsequently, we confirmed the interaction between DOX and MERS-CoV PLpro by thermal shift assay (TSA), and DOX increased ΔTm by ~20 °C, clearly indicating a coherent interaction between the MERS-CoV PL protease and DOX. The binding site of DOX on MERS-CoV PLpro was assessed using docking techniques and molecular dynamic (MD) simulations. DOX bound to the thumb region of the catalytic domain of the MERS-CoV PLpro. MD simulation results showed flexible BL2 loops, as well as other potential residues, such as R231, R233, and G276 of MERS-CoV PLpro. Development of drug repurposing is a remarkable opportunity to quickly examine the efficacy of different aspects of treating various diseases. Protease inhibitors have been found to be effective against MERS-CoV to date, and numerous candidates are currently undergoing clinical trials to prove this. Our effort follows a in similar direction.

PMID:36364379 | DOI:10.3390/molecules27217553

Molecules. 2022 Nov 3;27(21):7522. doi: 10.3390/molecules27217522.

ABSTRACT

The SARS-CoV-2 non-structural protein 13 (nsp13) helicase is an essential enzyme for viral replication and has been identified as an attractive target for the development of new antiviral drugs. In detail, the helicase catalyzes the unwinding of double-stranded DNA or RNA in a 5' to 3' direction and acts in concert with the replication-transcription complex (nsp7/nsp8/nsp12). In this work, bioinformatics and computational tools allowed us to perform a detailed conservation analysis of the SARS-CoV-2 helicase genome and to further predict the druggable enzyme's binding pockets. Thus, a structure-based virtual screening was used to identify valuable compounds that are capable of recognizing multiple nsp13 pockets. Starting from a database of around 4000 drugs already approved by the Food and Drug Administration (FDA), we chose 14 shared compounds capable of recognizing three out of four sites. Finally, by means of visual inspection analysis and based on their commercial availability, five promising compounds were submitted to in vitro assays. Among them, PF-03715455 was able to block both the unwinding and NTPase activities of nsp13 in a micromolar range.

PMID:36364347 | DOI:10.3390/molecules27217522

Int J Mol Sci. 2022 Oct 26;23(21):12975. doi: 10.3390/ijms232112975.

ABSTRACT

Noise is a basic ingredient in data, since observed data are always contaminated by unwanted deviations, i.e., noise, which, in the case of overdetermined systems (with more data than model parameters), cause the corresponding linear system of equations to have an imperfect solution. In addition, in the case of highly underdetermined parameterization, noise can be absorbed by the model, generating spurious solutions. This is a very undesirable situation that might lead to incorrect conclusions. We presented mathematical formalism based on the inverse problem theory combined with artificial intelligence methodologies to perform an enhanced sampling of noisy biomedical data to improve the finding of meaningful solutions. Random sampling methods fail for high-dimensional biomedical problems. Sampling methods such as smart model parameterizations, forward surrogates, and parallel computing are better suited for such problems. We applied these methods to several important biomedical problems, such as phenotype prediction and a problem related to predicting the effects of protein mutations, i.e., if a given single residue mutation is neutral or deleterious, causing a disease. We also applied these methods to de novo drug discovery and drug repositioning (repurposing) through the enhanced exploration of huge chemical space. The purpose of these novel methods that address the problem of noise and uncertainty in biomedical data is to find new therapeutic solutions, perform drug repurposing, and accelerate and optimize drug discovery, thus reestablishing homeostasis. Finding the right target, the right compound, and the right patient are the three bottlenecks to running successful clinical trials from the correct analysis of preclinical models. Artificial intelligence can provide a solution to these problems, considering that the character of the data restricts the quality of the prediction, as in any modeling procedure in data analysis. The use of simple and plain methodologies is crucial to tackling these important and challenging problems, particularly drug repositioning/repurposing in rare diseases.

PMID:36361765 | DOI:10.3390/ijms232112975

Cells. 2022 Nov 3;11(21):3482. doi: 10.3390/cells11213482.

ABSTRACT

Pancreatic cancer is a leading cause of cancer mortality and is projected to become the second-most common cause of cancer mortality in the next decade. While gene-wide association studies and next generation sequencing analyses have identified molecular patterns and transcriptome profiles with prognostic relevance, therapeutic opportunities remain limited. Among the genes that are upregulated in pancreatic ductal adenocarcinomas (PDAC), the leukaemia inhibitory factor (LIF), a cytokine belonging to IL-6 family, has emerged as potential therapeutic candidate. LIF is aberrantly secreted by tumour cells and promotes tumour progression in pancreatic and other solid tumours through aberrant activation of the LIF receptor (LIFR) and downstream signalling that involves the JAK1/STAT3 pathway. Since there are no LIFR antagonists available for clinical use, we developed an in silico strategy to identify potential LIFR antagonists and drug repositioning with regard to LIFR antagonists. The results of these studies allowed the identification of mifepristone, a progesterone/glucocorticoid antagonist, clinically used in medical abortion, as a potent LIFR antagonist. Computational studies revealed that mifepristone binding partially overlapped the LIFR binding site. LIF and LIFR are expressed by human PDAC tissues and PDAC cell lines, including MIA-PaCa-2 and PANC-1 cells. Exposure of these cell lines to mifepristone reverses cell proliferation, migration and epithelial mesenchymal transition induced by LIF in a concentration-dependent manner. Mifepristone inhibits LIFR signalling and reverses STAT3 phosphorylation induced by LIF. Together, these data support the repositioning of mifepristone as a potential therapeutic agent in the treatment of PDAC.

PMID:36359879 | DOI:10.3390/cells11213482

Biomolecules. 2022 Nov 10;12(11):1666. doi: 10.3390/biom12111666.

ABSTRACT

Drug repositioning, an important method of drug development, is utilized to discover investigational drugs beyond the originally approved indications, expand the application scope of drugs, and reduce the cost of drug development. With the emergence of increasingly drug-disease-related biological networks, the challenge still remains to effectively fuse biological entity data and accurately achieve drug-disease repositioning. This paper proposes a new drug repositioning method named EMPHCN based on enhanced message passing and hypergraph convolutional networks (HGCN). It firstly constructs the homogeneous multi-view information with multiple drug similarity features and then extracts the intra-domain embedding of drugs through the combination of HGCN and channel attention mechanism. Secondly, inter-domain information of known drug-disease associations is extracted by graph convolutional networks combining node and edge embedding (NEEGCN), and a heterogeneous network composed of drugs, proteins and diseases is built as an important auxiliary to enhance the inter-domain message passing of drugs and diseases. Besides, the intra-domain embedding of diseases is also extracted through HGCN. Ultimately, intra-domain and inter-domain embeddings of drugs and diseases are integrated as the final embedding for calculating the drug-disease correlation matrix. Through 10-fold cross-validation on some benchmark datasets, we find that the AUPR of EMPHCN reaches 0.593 (T1) and 0.526 (T2), respectively, and the AUC achieves 0.887 (T1) and 0.961 (T2) respectively, which shows that EMPHCN has an advantage over other state-of-the-art prediction methods. Concerning the new disease association prediction, the AUC of EMPHCN through the five-fold cross-validation reaches 0.806 (T1) and 0.845 (T2), which are 4.3% (T1) and 4.0% (T2) higher than the second best existing methods, respectively. In the case study, EMPHCN also achieves satisfactory results in real drug repositioning for breast carcinoma and Parkinson's disease.

PMID:36359016 | DOI:10.3390/biom12111666

Biomolecules. 2022 Nov 5;12(11):1641. doi: 10.3390/biom12111641.

ABSTRACT

Corticosteroids, oral or transtympanic, remain the mainstay for inner ear diseases characterized by hearing fluctuation or sudden changes in hearing, including sudden sensorineural hearing loss (SSNHL), Meniere's disease (MD), and autoimmune inner ear disease (AIED). Despite their use across these diseases, the rate of complete recovery remains low, and results across the literature demonstrates significant heterogeneity with respect to the effect of corticosteroids, suggesting a need to identify more efficacious treatment options. Previously, our group has cross-referenced steroid-responsive genes in the cochlea with published single-cell and single-nucleus transcriptome datasets to demonstrate that steroid-responsive differentially regulated genes are expressed in spiral ganglion neurons (SGN) and stria vascularis (SV) cell types. These differentially regulated genes represent potential druggable gene targets. We utilized multiple gene target databases (DrugBank, Pharos, and LINCS) to identify orally administered, FDA approved medications that potentially target these genes. We identified 42 candidate drugs that have been shown to interact with these genes, with an emphasis on safety profile, and tolerability. This study utilizes multiple databases to identify drugs that can target a number of druggable genes in otologic disorders that are commonly treated with steroids, providing a basis for establishing novel repurposing treatment trials.

PMID:36358991 | DOI:10.3390/biom12111641

Biomolecules. 2022 Oct 26;12(11):1559. doi: 10.3390/biom12111559.

ABSTRACT

We present the Pharmacorank search tool as an objective means to obtain prioritized protein drug targets and their associated medications according to user-selected diseases. This tool could be used to obtain prioritized protein targets for the creation of novel medications or to predict novel indications for medications that already exist. To prioritize the proteins associated with each disease, a gene similarity profiling method based on protein functions is implemented. The priority scores of the proteins are found to correlate well with the likelihoods that the associated medications are clinically relevant in the disease's treatment. When the protein priority scores are plotted against the percentage of protein targets that are known to bind medications currently indicated to treat the disease, which we termed the pertinency score, a strong correlation was observed. The correlation coefficient was found to be 0.9978 when using a weighted second-order polynomial fit. As the highly predictive fit was made using a broad range of diseases, we were able to identify a general threshold for the pertinency score as a starting point for considering drug repositioning candidates. Several repositioning candidates are described for proteins that have high predicated pertinency scores, and these provide illustrative examples of the applications of the tool. We also describe focused reviews of repositioning candidates for Alzheimer's disease. Via the tool's URL, https://protein.som.geisinger.edu/Pharmacorank/, an open online interface is provided for interactive use; and there is a site for programmatic access.

PMID:36358909 | DOI:10.3390/biom12111559

Mol Biotechnol. 2022 Nov 10. doi: 10.1007/s12033-022-00595-w. Online ahead of print.

ABSTRACT

Monkeypox Virus (MPXV), the causative agent of Monkeypox (MPX) disease, is an emerging zoonotic pathogen spreading in different endemic and non-endemic nations and creating outbreaks. MPX treatment mainly includes Cidofovir and Tecovirimat but they have several side effects and solely depending on these drugs may promote the emergence of drug-resistant variants. Hence, new drugs are required to control the spread of the disease. In this study, we explored the MPXV proteome to suggest repurposable drugs. DrugBank screening revealed drugs such as Brinzolamide, Dorzolamide, Methazolamide, Zidovudine, Gemcitabine, Hydroxyurea, Fludarabine, and Tecovirimat as controls. Structural analogs of these compounds were extracted from ChEMBL Database. After Molecular docking and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET)-based screening, we identified Zidovudine (binding affinity-5.9 kcal/mol) and a Harmala alkaloid (2S,4R)-4-(9H-Pyrido[3,4-b]indol-1-yl)-1,2,4-butanetriol (binding affinity - 6.6 kcal/mol) against L2R receptor (Thymidine Kinase). Moreover, Fludarabine (binding affinity - 6.4 kcal/mol) and 5'-Dehydroadenosine (binding affinity - 6.4 kcal/mol) can strongly interact with the I4L receptor (Ribonucleotide reductase large subunit R1). Molecular Dynamics (MD) simulations suggest all of these compounds can change the C-alpha backbone, residue mobility, compactness, and solvent accessible surface area of L2R and I4L. Our results strongly suggest that these drug repurposing small molecules are worth exploring in vivo and in vitro for clinical applications.

PMID:36357534 | DOI:10.1007/s12033-022-00595-w