Proteomics Clin Appl. 2023 May 31:e2300016. doi: 10.1002/prca.202300016. Online ahead of print.

ABSTRACT

Breast cancer, a multi-networking heterogeneous disease, has emerged as a serious impediment to progress in clinical oncology. Although technological advancements and emerging cancer research studies have mitigated breast cancer lethality, a precision cancer-oriented solution has not been achieved. Thus, this review will persuade the acquiescence of proteomics-based diagnostic and therapeutic options in breast cancer management. Recently, the evidence of breast cancer health surveillance through imaging proteomics, single-cell proteomics, interactomics, and post-translational modification (PTM) tracking, to construct proteome maps and proteotyping for stage-specific and sample-specific cancer subtyping have outperformed conventional ways of dealing with breast cancer by increasing diagnostic efficiency, prognostic value, and predictive response. Additionally, the paradigm shift in applied proteomics for designing a chemotherapy regimen to identify novel drug targets with minor adverse effects has been elaborated. Finally, the potential of proteomics in alleviating the occurrence of chemoresistance and enhancing reprofiled drugs' effectiveness to combat therapeutic obstacles has been discussed. Owing to the enormous potential of proteomics techniques, the clinical recognition of proteomics in breast cancer management can be achievable and therapeutic intricacies can be surmountable.

PMID:37259687 | DOI:10.1002/prca.202300016

Pharmaceuticals (Basel). 2023 Feb 14;16(2):296. doi: 10.3390/ph16020296.

ABSTRACT

Recently the E protein of SARS-CoV-2 has become a very important target in the potential treatment of COVID-19 since it is known to regulate different stages of the viral cycle. There is biochemical evidence that E protein exists in two forms, as monomer and homopentamer. An in silico screening analysis was carried out employing 5852 ligands (from Zinc databases), and performing an ADMET analysis, remaining a set of 2155 compounds. Furthermore, docking analysis was performed on specific sites and different forms of the E protein. From this study we could identify that the following ligands showed the highest binding affinity: nilotinib, dutasteride, irinotecan, saquinavir and alectinib. We carried out some molecular dynamics simulations and free energy MM-PBSA calculations of the protein-ligand complexes (with the mentioned ligands). Of worthy interest is that saquinavir, nilotinib and alectinib are also considered as a promising multitarget ligand because it seems to inhibit three targets, which play an important role in the viral cycle. On the other side, saquinavir was shown to be able to bind to E protein both in its monomeric as well as pentameric forms. Finally, further experimental assays are needed to probe our hypothesis derived from in silico studies.

PMID:37259437 | DOI:10.3390/ph16020296

Pharmaceuticals (Basel). 2023 Jan 19;16(2):151. doi: 10.3390/ph16020151.

ABSTRACT

Dementia, most often associated with neurodegenerative diseases, affects millions of people worldwide, predominantly the elderly. Unfortunately, no treatment is still available. Therefore, there is an urgent need to address this situation. This review presents the state of the art of drug discovery and developments in targeting dementia. Several approaches are discussed, such as drug repurposing, the use of small molecules, and phosphodiesterase inhibitors. Furthermore, the review also provides insights into clinical trials of these molecules. Emphasis has been placed on small molecules and multi-target-directed ligands, as well as disease-modifying therapies. Finally, attention is drawn to the possibilities of applications of nanotechnology in managing dementia.

PMID:37259302 | DOI:10.3390/ph16020151

J Vet Med Sci. 2023 May 31. doi: 10.1292/jvms.23-0154. Online ahead of print.

ABSTRACT

In recent years, strategies targeting β-cell protection via autoimmune regulation have been suggested as novel and potent immunotherapeutic interventions against type 1 diabetes mellitus (T1D). Here, we investigated the potential of toceranib (TOC), a receptor-type tyrosine kinase (RTK) inhibitor used in veterinary practice, to ameliorate T1D. TOC reversed streptozotocin-induced T1D and improved the abnormalities in muscle and bone metabolism characteristic of T1D. Histopathological examination revealed that TOC significantly suppressed β-cell depletion and improved glycemic control with restoration of serum insulin levels. However, the effect of TOC on blood glucose levels and insulin secretion capacity is attenuated in chronic T1D, a more β-cell depleted state. These findings suggest that TOC improves glycemic control by ameliorating the streptozotocin-induced decrease in insulin secretory capacity. Finally, we examined the role of platelet-derived growth factor receptor (PDGFR) inhibition, a target of TOC, and found that inhibition of PDGFR reverses established T1D in mice. Our results show that TOC reverses T1D by preserving islet function via inhibition of RTK. The previously unrecognized pharmacological properties of TOC have been revealed, and these properties could lead to its application in the treatment of T1D in the veterinary field.

PMID:37258127 | DOI:10.1292/jvms.23-0154

Curr Microbiol. 2023 May 31;80(7):230. doi: 10.1007/s00284-023-03332-x.

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) poses a great threat to human health, and the formation of biofilm and persister cells make the situation even worse. Drug repurposing is an effective way to solve this problem by shortening the drug development times and reducing the research costs. In this study, CD5789 (trifarotene), a fourth-generation retinoid to be approved by the FDA in 2019 for the topical acne vulgaris regimens, was exhibited antimicrobial activity against MRSA type strains and its clinical isolates with the minimal concentration (MIC) of 2-4 μg/mL and 4-16 μg/mL, respectively, in a dose-dependent manner. By crystal violet staining, we found that CD5789 could inhibit the biofilm formation by MRSA and could further eradicate the pre-formed biofilm at the concentration of 8 μg/mL. By checkerboard dilution assay, sub-MIC of CD5789 showed synergistic antimicrobial effects with sub-MIC of gentamycin against MRSA type strains as well as clinical isolates. In addition, CD5789 also exhibited effective bactericidal activity against MRSA persister cells at the concentration of 8 ~ 16 μg/mL. Extremely low cytotoxicity of CD5789 was observed by CCK-8 assay indicated the well tolerability to human body. In all, CD5789 has the potential to be an alternative for the treatment of refractory MRSA-related infections.

PMID:37256372 | DOI:10.1007/s00284-023-03332-x

J Diabetes Metab Disord. 2022 Dec 2;22(1):225-236. doi: 10.1007/s40200-022-01109-w. eCollection 2023 Jun.

ABSTRACT

BACKGROUND: There are evidences linking diabetes to the pathogenesis and progression of various cancers. Metformin is a well-known antidiabetic drug that reduces the levels of circulating glucose and insulin in patients with both insulin resistance and hyperinsulinemia. Aim of the present study was to evaluate the effect of metformin on the liver of rats bearing prostate cancer, diabetes and prostate cancer + diabetes via histopathological and biochemical methods.

METHODS: Male Copenhagen rats were divided into six groups. Control group, diabetic group, cancer group, diabetic + cancer group, diabetic + cancer + metformin group, cancer + metformin group. Diabetes was induced by injecting single dose of streptozotocin (65 mg/kg) to Copenhagen rats, cancer induced 2 × 104 Mat-LyLu cells. Metformin treatment was administered daily by gavage following inocculation of the Mat- Lylu cells to fifth and sixth group. The experiment was terminated on the 14th day following Mat-LyLu cell injection. At the end of the experimental period, the rats were sacrificed, and liver tissue was taken. Liver damage was scored. Biochemically, serum prostate-specific antigen level was determined by employing Enzyme Linked Immuno Sorbent Assay method. In addition, the activities of different enzyme and biochemical parameters were determined spectrophotometrically inform the hepatic tissue specimens.

RESULTS: The findings of this study reveal that histopathological and biochemical damage in cancer and diabetic + cancer groups decreased significantly in the metformin treated groups.

CONCLUSION: These highlights that the antidiabetic drug metformin can be repositioned for attenuating liver tissue damage associated with prostate cancer and diabetes.

PMID:37255805 | PMC:PMC10225428 | DOI:10.1007/s40200-022-01109-w

Clin Infect Dis. 2023 May 24;76(10):1735-1737. doi: 10.1093/cid/ciad086.

NO ABSTRACT

PMID:37253130 | DOI:10.1093/cid/ciad086

Bioinformatics. 2023 May 30:btad355. doi: 10.1093/bioinformatics/btad355. Online ahead of print.

ABSTRACT

MOTIVATION: Large-scale prediction of drug-target affinity (DTA) plays an important role in drug discovery. In recent years, machine learning algorithms have made great progress in DTA prediction by utilizing sequence or structural information of both drugs and proteins. However, sequence-based algorithms ignore the structural information of molecules and proteins, while graph-based algorithms are insufficient in feature extraction and information interaction.

RESULTS: In this paper, we propose NHGNN-DTA, a node-adaptive hybrid neural network for interpretable DTA prediction. It can adaptively acquire feature representations of drugs and proteins and allow information to interact at the graph level, effectively combining the advantages of both sequence-based and graph-based approaches. Experimental results have shown that NHGNN-DTA achieved new state-of-the-art performance. It achieved the mean squared error (MSE) of 0.196 on the Davis dataset (below 0.2 for the first time) and 0.124 on the KIBA dataset (3% improvement). Meanwhile, in the case of cold start scenario, NHGNN-DTA proved to be more robust and more effective with unseen inputs than baseline methods. Furthermore, the multi-head self-attention mechanism endows the model with interpretability, providing new exploratory insights for drug discovery. The case study on Omicron variants of SARS-CoV-2 illustrates the efficient utilization of drug repurposing in COVID-19.

AVAILABILITY: The source code and data are available at https://github.com/hehh77/NHGNN-DTA.

PMID:37252835 | DOI:10.1093/bioinformatics/btad355

J Agric Food Res. 2023 Sep;13:100632. doi: 10.1016/j.jafr.2023.100632. Epub 2023 May 20.

ABSTRACT

Worldwide, Severe acute respiratory syndrome Coronavirus (SARS-CoV-2) pandemic crisis, causing many morbidities, mortality, and devastating impact on economies, so the current outbreak of the CoV-2 is a major concern for global health. The infection spread quickly and caused chaos in many countries around the world. The slow discovery of CoV-2 and the limited treatment options are among the main challenges. Therefore, the development of a drug that is safe and effective against CoV-2 is urgently needed. The present overview briefly summarizes CoV-2 drug targets ex: RNA-dependent RNA polymerase (RdRp), papain-like protease (PLpro), 3-chymotrypsin-like protease (3CLpro), transmembrane serine protease enzymes (TMPRSS2), angiotensin-converting enzyme 2 (ACE2), structural protein (N, S, E, and M), and virulence factors (NSP1, ORF7a, and NSP3c) for which drug design perspective can be considered. In addition, summarize all anti-COVID-19 medicinal plants and phytocompounds and their mechanisms of action to be used as a guide for further studies.

PMID:37251276 | PMC:PMC10198795 | DOI:10.1016/j.jafr.2023.100632

Psychiatry Investig. 2023 May 30. doi: 10.30773/pi.2022.0343. Online ahead of print.

ABSTRACT

OBJECTIVE: New drugs are needed to treat antipsychotic-resistant schizophrenia, especially those with clozapine-resistant schizophrenia. Atypical antipsychotics have predominantly 5-HT2A and dopaminergic antagonism, but also require investigation of other receptors.

METHODS: In this study, the binding affinities between clozapine, olanzapine, and quetiapine with neuropharmacological, immunological, and metabolic receptors were measured using GNINA (Deep Learning Based Molecular Docking) and AlphaFold (Predicted Protein Structures).

RESULTS: Through this study, it was determined that these antipsychotics showed high binding affinity to a variety of receptors, such as CB2, 5-HT1BR, NPYR4, and CCR5. Cyclosporin A and everolimus which show high affinities with those receptors could be used for the development of new antipsychotic drugs based on these drugs.

CONCLUSION: In the future, the method used in this study will be applied to the development of new antipsychotic drugs, including drug repositioning, and to the discovery of the pathophysiology of schizophrenia.

PMID:37248690 | DOI:10.30773/pi.2022.0343

Arch Toxicol. 2023 May 29. doi: 10.1007/s00204-023-03529-w. Online ahead of print.

ABSTRACT

Acid sphingomyelinase (ASMase) serves as one of the most remarkable enzymes in sphingolipid biology. ASMase facilitates the hydrolysis of sphingomyelin, yielding ceramide and phosphorylcholine via the phospholipase C signal transduction pathway. Owing to its prominent intervention in apoptosis, ASMase, and its product ceramide is now at the bleeding edge of lipid research due to the coalesced efforts of several research institutions over the past 40 years. ASMase-catalyzed ceramide synthesis profoundly alters the physiological properties of membrane structure in response to a broad range of stimulations, orchestrating signaling cascades for endoplasmic reticulum stress, autophagy, and lysosomal membrane permeabilization, which influences the development of hepatic disorders, such as steatohepatitis, hepatic fibrosis, drug-induced liver injury, and hepatocellular carcinoma. As a result, the potential to modulate the ASMase action with appropriate pharmaceutical antagonists has sparked a lot of curiosity. This article emphasizes the fundamental mechanisms of the systems that govern ASMase aberrations in various hepatic pathologies. Furthermore, we present an insight into the potential therapeutic agents used to mitigate ASMase irregularities and the paramountcy of such inhibitors in drug repurposing.

PMID:37248308 | DOI:10.1007/s00204-023-03529-w

Nat Commun. 2023 May 29;14(1):3079. doi: 10.1038/s41467-023-38668-2.

ABSTRACT

Cancer cells utilize the main de novo pathway and the alternative salvage pathway for deoxyribonucleotide biosynthesis to achieve adequate nucleotide pools. Deoxycytidine kinase is the rate-limiting enzyme of the salvage pathway and it has recently emerged as a target for anti-proliferative therapies for cancers where it is essential. Here, we present the development of a potent inhibitor applying an iterative multidisciplinary approach, which relies on computational design coupled with experimental evaluations. This strategy allows an acceleration of the hit-to-lead process by gradually implementing key chemical modifications to increase affinity and activity. Our lead compound, OR0642, is more than 1000 times more potent than its initial parent compound, masitinib, previously identified from a drug repositioning approach. OR0642 in combination with a physiological inhibitor of the de novo pathway doubled the survival rate in a human T-cell acute lymphoblastic leukemia patient-derived xenograft mouse model, demonstrating the proof-of-concept of this drug design strategy.

PMID:37248212 | DOI:10.1038/s41467-023-38668-2

Drug Chem Toxicol. 2023 May 29:1-9. doi: 10.1080/01480545.2023.2217696. Online ahead of print.

ABSTRACT

Acetaminophen (APAP) overdosing is the most common cause of drug-induced liver failure. Despite extensive study, N-acetylcysteine is currently the only antidote utilized for treatment. The purpose of this study was to evaluate the effect and mechanisms of phenelzine, an FDA-approved antidepressant, on APAP-induced toxicity in HepG2 cells. The human liver hepatocellular cell line HepG2 was used to investigate APAP-induced cytotoxicity. The protective effects of phenelzine were determined by examining the cell viability, combination index calculation, Caspase 3/7 activation, Cytochrome c release, H2O2 levels, NO levels, GSH activity, PERK protein levels, and pathway enrichment analysis. Elevated H2O2 production and decreased glutathione (GSH) levels were indicators of APAP-induced oxidative stress. The combination index of 2.04 indicated that phenelzine had an antagonistic effect on APAP-induced toxicity. When compared to APAP alone, phenelzine treatment considerably reduced caspase 3/7 activation, cytochrome c release, and H2O2 generation. However, phenelzine had minimal effect on NO and GSH levels and did not alleviate ER stress. Pathway enrichment analysis revealed a potential connection between APAP toxicity and phenelzine metabolism. These findings suggested that phenelzine's protective effect against APAP-induced cytotoxicity could be attributed to the drug's capacity to reduce APAP-mediated apoptotic signaling.

PMID:37246945 | DOI:10.1080/01480545.2023.2217696

Chin J Nat Med. 2023 May;21(5):323-332. doi: 10.1016/S1875-5364(23)60429-7.

ABSTRACT

Pharmacodynamics material basis and effective mechanisms are the two main issues to decipher the mechnisms of action of Traditional Chinese medicines (TCMs) for the treatment of diseases. TCMs, in "multi-component, multi-target, multi-pathway" paradigm, show satisfactory clinical results in complex diseases. New ideas and methods are urgently needed to explain the complex interactions between TCMs and diseases. Network pharmacology (NP) provides a novel paradigm to uncover and visualize the underlying interaction networks of TCMs against multifactorial diseases. The development and application of NP has promoted the safety, efficacy, and mechanism investigations of TCMs, which then reinforces the credibility and popularity of TCMs. The current organ-centricity of medicine and the "one disease-one target-one drug" dogma obstruct the understanding of complex diseases and the development of effective drugs. Therefore, more attentions should be paid to shift from "phenotype and symptom" to "endotype and cause" in understanding and redefining current diseases. In the past two decades, with the advent of advanced and intelligent technologies (such as metabolomics, proteomics, transcriptomics, single-cell omics, and artificial intelligence), NP has been improved and deeply implemented, and presented its great value and potential as the next drug-discovery paradigm. NP is developed to cure causal mechanisms instead of treating symptoms. This review briefly summarizes the recent research progress on NP application in TCMs for efficacy research, mechanism elucidation, target prediction, safety evaluation, drug repurposing, and drug design.

PMID:37245871 | DOI:10.1016/S1875-5364(23)60429-7

Viruses. 2023 Apr 27;15(5):1068. doi: 10.3390/v15051068.

ABSTRACT

Zika virus (ZIKV), belonging to the Flavivirus family and mainly transmitted by mosquitoes, causes a variety of adverse outcomes, including Guillain-Barré syndrome, microcephaly, and meningoencephalitis. However, there are no approved vaccines or drugs available for ZIKV. The discovery and research on drugs for ZIKV are still essential. In this study, we identified doramectin, an approved veterinary antiparasitic drug, as a novel anti-ZIKV agent (EC50 value from 0.85 μM to 3.00 μM) with low cytotoxicity (CC50 > 50 μM) in multiple cellular models. The expression of ZIKV proteins also decreased significantly under the treatment of doramectin. Further study showed that doramectin directly interacted with the key enzyme for ZIKV genome replication, RNA-dependent RNA polymerase (RdRp), with a stronger affinity (Kd = 16.9 μM), which may be related to the effect on ZIKV replication. These results suggested that doramectin might serve as a promising drug candidate for anti-ZIKV.

PMID:37243154 | PMC:PMC10221537 | DOI:10.3390/v15051068

Kidney Int. 2023 May 25:S0085-2538(23)00390-3. doi: 10.1016/j.kint.2023.04.027. Online ahead of print.

ABSTRACT

Nephronophthisis is an autosomal recessive tubulo-interstitial nephropathy, belonging to the ciliopathy disorders, characterized by fibrosis and/or cysts. It is the most common genetic cause of renal failure in children and young adults. Clinically and genetically heterogeneous, it is caused by variants in ciliary genes resulting in either an isolated kidney disease or syndromic forms in association with other manifestations of ciliopathy disorders. No curative treatment is currently available. Over the past two decades, advances in understanding disease mechanisms have identified several dysregulated signaling pathways, some shared with other cystic kidney diseases. Notably, molecules previously developed to target these pathways have shown promising beneficial effects in orthologous mouse models. In addition to these knowledge-based repurposing approaches, unbiased "in cellulo" phenotypic screens of "repurposing" libraries identified small molecules able to rescue the ciliogenesis defects observed in nephronophthisis conditions. Those compounds appeared to act on relevant pathways and, when tested, showed beneficial nephronophthisis-associated kidney and/or extra-renal defects in mice. In this review, we have summarized those studies which highlight the drug repurposing strategies in the context of a rare disorders such as nephronophthisis-related ciliopathies, with broad genetic heterogeneity and systemic manifestations but with shared disease mechanisms.

PMID:37244473 | DOI:10.1016/j.kint.2023.04.027

Eur J Med Chem. 2023 May 22;257:115491. doi: 10.1016/j.ejmech.2023.115491. Online ahead of print.

ABSTRACT

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication and transcription and represents an attractive drug target for fighting COVID-19. Many SARS-CoV-2 Mpro inhibitors have been reported, including covalent and noncovalent inhibitors. The SARS-CoV-2 Mpro inhibitor PF-07321332 (Nirmatrelvir) designed by Pfizer has been put on the market. This paper briefly introduces the structural characteristics of SARS-CoV-2 Mpro and summarizes the research progress of SARS-CoV-2 Mpro inhibitors from the aspects of drug repurposing and drug design. These information will provide a basis for the drug development of treating the infection of SARS-CoV-2 and even other coronaviruses in the future.

PMID:37244162 | DOI:10.1016/j.ejmech.2023.115491

Adv Exp Med Biol. 2023 May 28. doi: 10.1007/5584_2023_775. Online ahead of print.

ABSTRACT

In the past few years, development of approved drug candidates has improved the disease management of multiple myeloma (MM). However, due to drug resistance, some of the patients do not respond positively, while some of the patients acquire drug resistance, thereby these patients eventually relapse. Hence, there are no other therapeutic options for multiple myeloma patients. Therefore, this necessitates a precision-based approach to multiple myeloma therapy. The use of patient's samples to test drug sensitivity to increase efficacy and reduce treatment-related toxicities is the goal of functional precision medicine. Platforms such as high-throughput-based drug repurposing technology can be used to select effective single drug and drug combinations based on the efficacy and toxicity studies within a time frame of couple of weeks. In this article, we describe the clinical and cytogenetic features of MM. We highlight the various treatment strategies and elaborate on the role of high-throughput screening platforms in a precision-based approach towards clinical treatment.

PMID:37243923 | DOI:10.1007/5584_2023_775

Viruses. 2023 May 18;15(5):1188. doi: 10.3390/v15051188.

ABSTRACT

SARS-CoV-2 and its many variants have caused a worldwide emergency. Host cells colonised by SARS-CoV-2 present a significantly different gene expression landscape. As expected, this is particularly true for genes that directly interact with virus proteins. Thus, understanding the role that transcription factors can play in driving differential regulation in patients affected by COVID-19 is a focal point to unveil virus infection. In this regard, we have identified 19 transcription factors which are predicted to target human proteins interacting with Spike glycoprotein of SARS-CoV-2. Transcriptomics RNA-Seq data derived from 13 human organs are used to analyse expression correlation between identified transcription factors and related target genes in both COVID-19 patients and healthy individuals. This resulted in the identification of transcription factors showing the most relevant impact in terms of most evident differential correlation between COVID-19 patients and healthy individuals. This analysis has also identified five organs such as the blood, heart, lung, nasopharynx and respiratory tract in which a major effect of differential regulation mediated by transcription factors is observed. These organs are also known to be affected by COVID-19, thereby providing consistency to our analysis. Furthermore, 31 key human genes differentially regulated by the transcription factors in the five organs are identified and the corresponding KEGG pathways and GO enrichment are also reported. Finally, the drugs targeting those 31 genes are also put forth. This in silico study explores the effects of transcription factors on human genes interacting with Spike glycoprotein of SARS-CoV-2 and intends to provide new insights to inhibit the virus infection.

PMID:37243274 | DOI:10.3390/v15051188

Viruses. 2023 May 9;15(5):1128. doi: 10.3390/v15051128.

ABSTRACT

During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of compounds showed a significant influence on the virus-induced cytopathic effect (CPE) partly attributed to the intrinsic anti-metabolic activity of these drugs, but also to a specific anti-viral function. To elucidate the molecular mechanisms, we took advantage of our EXSCALATE platform for in-silico molecular modelling and further validated the influence of these inhibitors on nsp13 and viral entry. Interestingly, pralatrexate and trimetrexate showed superior effects in counteracting the viral infection compared to other DHFR inhibitors. Our results indicate that their higher activity is due to their polypharmacological and pleiotropic profile. These compounds can thus potentially give a clinical advantage in the management of SARS-CoV-2 infection in patients already treated with this class of drugs.

PMID:37243214 | DOI:10.3390/v15051128