Hypertens Res. 2023 Jan 16. doi: 10.1038/s41440-023-01176-3. Online ahead of print.

ABSTRACT

The pathogenesis of hypertension is multifactorial and highly complex. Basic research plays critical roles in elucidating the complex pathogenesis of hypertension and developing its treatment. This review covers recent topics in basic research related to hypertension in the following six parts: brain/autonomic nervous system, kidney, vascular system, potential treatments, extracellular vesicles, and gut microbiota. The brain receives afferent nerve inputs from peripheral organs, including the heart, kidneys, and adipose tissue, and humoral inputs from circulating factors such as proinflammatory cytokines and leptin, which are involved in the regulation of central sympathetic outflow. In the kidneys, changes in Wnt/β-catenin signaling have been reported in several hypertensive models. New findings on the renin-angiotensin-aldosterone system in the kidneys have also been reported. Sirtuin 6, which participates in various cellular functions, including DNA repair, has been shown to have protective effects on the vascular system. Skin water conservation, mediated by skin vasoconstriction and the accumulation of osmolytes such as sodium, has been found to contribute to hypertension. Studies of rivaroxaban and sodium-glucose cotransporter-2 inhibitors as drug repositioning candidates have been performed. Extracellular vesicles have been shown to be involved in novel diagnostic approaches and treatments for hypertension as well as other diseases. In gut microbiota studies, interactions between microbiota and antihypertensive drugs and potential pathophysiology linking microbiota and COVID-19 have been reported. It can be seen that inter-organ communication has received particular attention from these recent research topics. To truly understand the pathogenesis of hypertension and to develop treatments for conquering hypertension, interresearcher communication and collaboration should be further facilitated. This mini-review focuses on recent topics on basic research in hypertension from the several points of view. The recent topics indicate that inter-organ communication has received particular attention. Interresearcher communication and collaboration should also be further facilitated to truly understand the complex pathogenesis of hypertension and to develop the treatments.

PMID:36646880 | DOI:10.1038/s41440-023-01176-3

SLAS Discov. 2023 Jan 13:S2472-5552(23)00001-1. doi: 10.1016/j.slasd.2023.01.001. Online ahead of print.

ABSTRACT

The SARS coronavirus 2 (SARS-CoV-2) pandemic remains a major problem in many parts of the world and infection rates remain at extremely high levels. This high prevalence drives the continued emergence of new variants, and possibly ones that are more vaccine-resistant and that can drive infections even in highly vaccinated populations. The high rate of variant evolution makes clear the need for new therapeutics that can be clinically applied to minimize or eliminate the effects of COVID-19. With a hurdle of 10 years, on average, for first in class small molecule therapeutics to achieve FDA approval, the fastest way to identify therapeutics is by drug repurposing. To this end, we developed a high throughput cell-based screen that incorporates the essential viral 3C-like protease and its peptide cleavage site into a luciferase complementation assay to evaluate the efficacy of known drugs encompassing approximately 15,000 clinical-stage or FDA-approved small molecules. Confirmed inhibitors were also tested to determine their cytotoxic properties. Medicinal chemistry efforts to optimize the hits identified Tranilast as a potential lead. Here, we report the rapid screening and identification of potentially relevant drugs that exhibit selective inhibition of the SARS-CoV-2 viral 3C-like protease.

PMID:36646172 | DOI:10.1016/j.slasd.2023.01.001

Cancer Med. 2023 Jan 16. doi: 10.1002/cam4.5594. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) is a common gastrointestinal malignancy with high morbidity and fatality. Chemotherapy, as traditional therapy for CRC, has exerted well antitumor effect and greatly improved the survival of CRC patients. Nevertheless, chemoresistance is one of the major problems during chemotherapy for CRC and significantly limits the efficacy of the treatment and influences the prognosis of patients. To overcome chemoresistance in CRC, many strategies are being investigated. Here, we review the common and novel measures to combat the resistance, including drug repurposing (nonsteroidal anti-inflammatory drugs, metformin, dichloroacetate, enalapril, ivermectin, bazedoxifene, melatonin, and S-adenosylmethionine), gene therapy (ribozymes, RNAi, CRISPR/Cas9, epigenetic therapy, antisense oligonucleotides, and noncoding RNAs), protein inhibitor (EFGR inhibitor, S1PR2 inhibitor, and DNA methyltransferase inhibitor), natural herbal compounds (polyphenols, terpenoids, quinones, alkaloids, and sterols), new drug delivery system (nanocarriers, liposomes, exosomes, and hydrogels), and combination therapy. These common or novel strategies for the reversal of chemoresistance promise to improve the treatment of CRC.

PMID:36645225 | DOI:10.1002/cam4.5594

ACS Omega. 2022 Dec 29;8(1):56-73. doi: 10.1021/acsomega.2c05821. eCollection 2023 Jan 10.

ABSTRACT

Prostate cancer (PCA), the most common cancer in men, accounted for 1.3 million new incidences in 2018. An increase in incidences is an issue of concern that should be addressed. Of all the reported prostate cancers, 85% were detected in stages III and IV, making them difficult to treat. Conventional drugs gradually lose their efficacy due to the developed resistance against them, thus requiring newer therapeutic agents to be used as monotherapy or combination. Recent research regarding treatment options has attained remarkable speed and development. Therefore, in this context, drug repurposing comes into the picture, which is defined as the "investigation of the off-patent, approved and marketed drugs for a novel therapeutic indication" which saves at least 30% of the time and cost, reducing the cost of treatment for patients, which usually runs high in cancer patients. The anticancer property of cardiac glycosides in cancers was tested in the early 1980s. The trend then shifts toward treating prostate cancer by repurposing other cardiovascular drugs. The current review mainly emphasizes the advantageous antiprostate cancer profile of conventional CVS drugs like cardiac glycosides, RAAS inhibitors, statins, heparin, and beta-blockers with underlying mechanisms.

PMID:36643505 | PMC:PMC9835086 | DOI:10.1021/acsomega.2c05821

Free Radic Res. 2023 Jan 15:1-18. doi: 10.1080/10715762.2022.2146500. Online ahead of print.

ABSTRACT

Drug repurposing allows searching for new biological targets, especially against emerging diseases such as Covid-19. Drug colchicine (COL) presents recognized anti-inflammatory action, while the nanotechnology purpose therapies with low doses, efficacy, and decrease the drug's side-effects. This study aims to evaluate the effects of COL and colchicine nanocapsules (NCCOL) on survival, LC50, activity locomotor, and oxidative stress parameters, elucidating the toxicity profile in acute and chronic exposure in Drosophila melanogaster. Three-day-old flies were investigated into groups: Control, 0.001, 0.0025, 0.005, and 0.010 mg/mL of COL or NCCOL. The survival rate, open field test, LC50, oxidative stress markers (reactive species (RS) production, thiobarbituric acid reactive substances), antioxidant enzyme activity (catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase), protein thiols, nonprotein thiols, acetylcholinesterase activity, and cell viability were measured. As a result, acute exposure to the COL decreases the number of crosses in the open field and increases CAT activity. NCCOL reduced RS levels, increased lipoperoxidation and SOD activity. Chronic exposure to the COL and NCCOL in high concentrations implied high mortality and enzymatic inhibition of the CAT and AChE, and only the COL caused locomotor damage in the open field test. Thus, NCCOL again reduced the formation of RS while COL increased. In this comparative study, NCCOL was less toxic to the antioxidant system than COL and showed notable involvement of oxidative stress as one of their toxicity mechanisms. Future studies are needed to elucidate all aspects of nanosafety related to the NCCOL.

PMID:36641780 | DOI:10.1080/10715762.2022.2146500

BMC Psychiatry. 2023 Jan 14;23(1):40. doi: 10.1186/s12888-023-04543-z.

ABSTRACT

Schizophrenia (SCZ) is a severe mental illness mainly characterized by a number of psychiatric symptoms. Obsessive-compulsive disorder (OCD) is a long-lasting and devastating mental disorder. SCZ has high co-occurrence with OCD resulting in the emergence of a concept entitled "schizo-obsessive disorder" as a new specific clinical entity with more severe psychiatric symptoms. Many studies have been done on SCZ and OCD, but the common pathogenesis between them is not clear yet. Therefore, this study aimed to identify shared genetic basis, potential biomarkers and therapeutic targets between these two disorders. Gene sets were extracted from the Geneweaver and Harmonizome databases for each disorder. Interestingly, the combination of both sets revealed 89 common genes between SCZ and OCD, the most important of which were BDNF, SLC6A4, GAD1, HTR2A, GRIN2B, DRD2, SLC6A3, COMT, TH and DLG4. Then, we conducted a comprehensive bioinformatics analysis of the common genes. Receptor activity as the molecular functions, neuron projection and synapse as the cellular components as well as serotonergic synapse, dopaminergic synapse and alcoholism as the pathways were the most significant commonalities in enrichment analyses. In addition, transcription factor (TFs) analysis predicted significant TFs such as HMGA1, MAPK14, HINFP and TEAD2. Hsa-miR-3121-3p and hsa-miR-495-3p were the most important microRNAs (miRNAs) associated with both disorders. Finally, our study predicted 19 existing drugs (importantly, Haloperidol, Fluoxetine and Melatonin) that may have a potential influence on this co-occurrence. To summarize, this study may help us to better understand and handle the co-occurrence of SCZ and OCD by identifying potential biomarkers and therapeutic targets.

PMID:36641432 | DOI:10.1186/s12888-023-04543-z

J Exp Clin Cancer Res. 2023 Jan 14;42(1):22. doi: 10.1186/s13046-022-02590-0.

ABSTRACT

BACKGROUND: Nitric oxide-releasing drugs are used for cardiovascular diseases; however, their effects on the tumor immune microenvironment are less clear. Therefore, this study explored the impact of nitric oxide donors on tumor progression in immune-competent mice.

METHODS: The effects of three different nitric oxide-releasing compounds (SNAP, SNP, and ISMN) on tumor growth were studied in tumor-bearing mouse models. Three mouse tumor models were used: B16F1 melanoma and LL2 lung carcinoma in C57BL/6 mice, CT26 colon cancer in BALB/c mice, and LL2 lung carcinoma in NOD/SCID mice. After nitric oxide treatment, splenic cytokines and lymphocytes were analyzed by cytokine array and flow cytometry, and tumor-infiltrating lymphocytes in the TME were analyzed using flow cytometry and single-cell RNA sequencing.

RESULTS: Low doses of three exogenous nitric oxide donors inhibited tumor growth in two immunocompetent mouse models but not in NOD/SCID immunodeficient mice. Low-dose nitric oxide donors increase the levels of splenic cytokines IFN-γ and TNF-α but decrease the levels of cytokines IL-6 and IL-10, suggesting an alteration in Th2 cells. Nitric oxide donors increased the number of CD8+ T cells with activation gene signatures, as indicated by single-cell RNA sequencing. Flow cytometry analysis confirmed an increase in infiltrating CD8+ T cells and dendritic cells. The antitumor effect of nitric oxide donors was abolished by depletion of CD8+ T cells, indicating the requirement for CD8+ T cells. Tumor inhibition correlated with a decrease in a subtype of protumor macrophages and an increase in a subset of Arg1-positive macrophages expressing antitumor gene signatures. The increase in this subset of macrophages was confirmed by flow cytometry analysis. Finally, the combination of low-dose nitric oxide donor and cisplatin induced an additive cancer therapeutic effect in two immunocompetent animal models. The enhanced therapeutic effect was accompanied by an increase in the cells expressing the gene signature of NK cell.

CONCLUSIONS: Low concentrations of exogenous nitric oxide donors inhibit tumor growth in vivo by regulating T cells and macrophages. CD8+ T cells are essential for antitumor effects. In addition, low-dose nitric oxide donors may be combined with chemotherapeutic drugs in cancer therapy in the future.

PMID:36639681 | PMC:PMC9840268 | DOI:10.1186/s13046-022-02590-0

FEBS Open Bio. 2023 Jan 13. doi: 10.1002/2211-5463.13553. Online ahead of print.

ABSTRACT

Despite advancements in treatment, high grade serous ovarian cancer (HGSOC) is still characterized by poor patient outcomes. To understand the molecular heterogeneity of this disease which underlies the challenge in selecting optimal treatments for HGSOC patients, we have integrated genomic, transcriptomic and epigenetic information to identify seven new HGSOC subtypes using a multi-scale clustering method. These subtypes not only have significantly distinct overall survival, but also exhibit unique patterns of gene expression, microRNA expression, DNA methylation, and copy number alterations. As determined by our analysis, patients with similar clinical outcomes have distinct profiles of activated or repressed cellular processes, including cell cycle, epithelial to mesenchymal transition, immune activation, interferon response and cilium organization. Furthermore, we performed a multiscale gene co-expression network analysis to identify subtype-specific key regulators, and predicted optimal targeted therapies based on subtype-specific gene expression. In summary, this study provides new insights into the cellular heterogeneity of the HGSOC genomic, epigenetic and transcriptomic landscapes, and provides a basis for future studies into precision medicine for HGSOC patients.

PMID:36637997 | DOI:10.1002/2211-5463.13553

J Sep Sci. 2023 Jan 13:e2200921. doi: 10.1002/jssc.202200921. Online ahead of print.

ABSTRACT

Gliflozins are successfully marketed antidiabetic agents with a reported neuroprotective effect, this study tests their blood-brain barrier crossing ability. Henceforward, a computational hypothesis interpreting their effects was reasonable after failure to cross into the brain. A chromatographic bioassay for Canagliflozin, Dapagliflozin, and Empagliflozin was developed, validated, and applied to the rat's plasma and rat's brain. HPLC method robustness was tested over two levels using Design of Experiment on MINITAB®. It's the first method for gliflozins' detection in rats' brain tissue. The method was applied on eighteen rats, six for each drug. Concentrations in plasma were determined but neither of them was detected in brain at the described chromatographic conditions. A computational study for the three drugs was endorsing two techniques. Firstly, Ligand Based Target Fishing reveals possible targets for gliflozins. They showed an ability to bind with human Equilibrative Nucleoside Transporter 1, a regulator of adenosine extracellularly. Secondly, a docking study was carried out on this protein receptor. Results showed perfect alignment with a minimum of one hydrogen bond. Dapagliflozin achieved the lowest energy score with two hocking hydrogen bonds. This is proposing gliflozins ability to regulate Equilibrative Nucleoside Transporter 1 receptors in peripheries, elevating the centrally acting neuroprotective adenosine. This article is protected by copyright. All rights reserved.

PMID:36637096 | DOI:10.1002/jssc.202200921

Drug Discov Today. 2023 Jan 9:103489. doi: 10.1016/j.drudis.2023.103489. Online ahead of print.

ABSTRACT

The beginning of the 20th decade has witnessed an increase in drug development programs for myotonic dystrophy type 1 (DM1). We have collected nearly 20 candidate drugs with accomplished preclinical and clinical phases, updating our previous drug development pipeline review with new entries and relevant milestones for pre-existing candidates. Three interventional first-in-human clinical trials got underway with distinct drug classes, namely AOC 1001 and DYNE-101 nucleic acid-based therapies, and the small molecule pitolisant, which joins the race toward market authorization with other repurposed drugs, including tideglusib, metformin, or mexiletine, already in clinical evaluation. Furthermore, newly disclosed promising preclinical data for several additional nucleic-acid therapeutic candidates and a CRISPR-based approach, as well as the advent into the pipeline of novel therapeutic programs, increase the plausibility of success in the demanding task of providing valid treatments to patients with DM1.

PMID:36634841 | DOI:10.1016/j.drudis.2023.103489

Oncotarget. 2023 Jan 12;14:14-20. doi: 10.18632/oncotarget.28342.

ABSTRACT

Overexpression of the dihydrolipoamide S-succinyltransferase (DLST) is associated with poor outcome in neuroblastoma patients and triple-negative breast cancer (TNBC) and specifically with the oxidative phosphorylation (OXPHOS) pathway. Inhibitors of OXPHOS were previously suggested as a potential therapeutic strategy for a subset of patients with high-risk neuroblastoma. Here, we tested if cell lines with DLST amplifications or high mRNA levels were associated with sensitivity to 250 drugs from the Genomics of Drug Sensitivity in Cancer (GDSC) dataset by comparing them to cell lines without these changes. DLST-altered cell lines were more sensitive to 7 approved drugs, among these obatoclax mesylate, a BCL2 inhibitor that reduces OXPHOS in human leukemia stem cells. Moreover, several protein kinase inhibitors were identified to be efficient in cell lines with DLST amplifications or high mRNA levels, suggesting a vulnerability of DLST-altered cell lines for drugs targeting the ERK/MAPK pathway. Furthermore, increased DLST expression in cell lines with driver mutations in KRAS supported this relationship. We therefore conclude that, in addition to OXPHOS, protein kinases could be potential targets of therapy in the presence of DLST amplifications or high mRNA levels. The new drug candidates proposed here could serve in experimental testing on drug efficacy in knock-in cell lines and DLST-activated tumors.

PMID:36634214 | DOI:10.18632/oncotarget.28342

Bipolar Disord. 2023 Jan 12. doi: 10.1111/bdi.13295. Online ahead of print.

ABSTRACT

OBJECTIVE: Due to the phenotypic heterogeneity and etiological complexity of bipolar disorder (BD), many patients do not respond well to the current medications, and developing novel effective treatment is necessary. Whether any BD genome-wide association study (GWAS) risk genes were targets of existing drugs or novel drugs that can be repurposed in the clinical treatment of BD is a hot topic in the GWAS era of BD.

METHODS: A list of 425 protein-coding BD risk genes was distilled through the BD GWAS, and 4479 protein-coding druggable targets were retrieved from the druggable genome. The overlapped genes/targets were subjected to further analyses in DrugBank, Pharos, and DGIdb datasets in terms of their FDA status, mechanism of action and primary indication, to identify their potential for repurposing.

RESULTS: We identified 58 BD GWAS risk genes grouped as the druggable targets, and several genes were given higher priority. These BD risk genes were targets of antipsychotics, antidepressants, antiepileptics, calcium channel antagonists, as well as anxiolytics and analgesics, either existing clinically-approved drugs for BD or the drugs than can be repurposed for treatment of BD in the future. Those genes were also likely relevant to BD pathophysiology, as many of them encode ion channel, ion transporter or neurotransmitter receptor, or the mice manipulating those genes are likely to mimic the phenotypes manifest in BD patients.

CONCLUSIONS: This study identifies several targets that may facilitate the discovery of novel treatments in BD, and implies the value of conducting GWAS into clinical translation.

PMID:36633396 | DOI:10.1111/bdi.13295

Microbiol Spectr. 2023 Jan 10:e0380122. doi: 10.1128/spectrum.03801-22. Online ahead of print.

ABSTRACT

Oropharyngeal candidiasis (OPC), which has a high incidence in immunocompromised and denture stomatitis patients, is commonly caused by Candida albicans infection and in some cases develops into disseminated candidiasis throughout the throat and esophagus, resulting in high mortality. New drugs are needed to combat OPC because of the limited treatment options currently available and increasing resistance to existing drugs. Here, we confirmed that riboflavin (RF), a cofactor of flavin adenine mononucleotide and flavin adenine dinucleotide, has broad-spectrum anti-Candida activity. The formation of C. albicans hyphae and biofilm was inhibited by RF. Mechanistically, RF disrupted membrane and cell wall integrity, as well as promoting reactive oxygen species and pyruvate accumulation. Furthermore, RF targeted multiple essential pathways via functional disruption of thiamine and RF metabolic pathways, central carbon metabolism, and ribosome metabolism. Similar to the results in vitro, the inhibitory effect of RF on C. albicans hyphae was confirmed in a mouse model of OPC. Moreover, after 5 consecutive days of intraperitoneal injection, RF exhibited therapeutic efficacy, as demonstrated by phenotype investigation, the fungal burden, and histopathological analysis. These findings revealed that RF exerts a multifaceted anti-Candida effect and has potential benefits in the treatment of OPC. IMPORTANCE Candida species are common pathogens in fungal infections, causing mucosal infection and invasive infection in immunodeficient patients. Given the limited classes of drugs and resistance to these drugs, new antifungal agents need to be developed. Drug repurposing is a potential method for antifungal drug development. This study demonstrated that riboflavin (RF) exhibited broad-spectrum anti-Candida activity. RF affected multiple targets involving the membrane and cell wall integrity, the accumulation of reactive oxygen species and pyruvate, and the altered metabolic pathways in C. albicans. Moreover, RF exhibited efficacy in the treatment of C. albicans in an oropharyngeal candidiasis mouse model. Taken together, the antifungal activity and the promising clinical application of RF were highlighted.

PMID:36625571 | DOI:10.1128/spectrum.03801-22

J Med Chem. 2023 Jan 9. doi: 10.1021/acs.jmedchem.2c01772. Online ahead of print.

ABSTRACT

Chromosomal region maintenance protein 1 (CRM1) is a validated anticancer drug target, and its covalent inhibitor KPT-330 has been approved for marketing. However, the development of CRM1 inhibitors, especially the noncovalent ones, is still very limited. Drug repurposing is an effective strategy to develop drug leads for new targets. In this work, we virtually screened a library of marketed drugs and identified zafirlukast as a new CRM1 inhibitor. Biochemical and structural analysis revealed that zafirlukast was a noncovalent CRM1 inhibitor that bound to four subpockets in the nuclear-export-signal (NES) groove. Methylation of the sulfonamide group rendered zafirlukast completely inactive against CRM1. Zafirlukast inhibited the growth of a variety of cancer cells and worked synergistically with the drug doxorubicin. Taken together, these works laid a solid foundation for reshaping zafirlukast as a valuable lead compound for further design of noncovalent, specific, and potent CRM1 inhibitors toward the treatment of various cancers.

PMID:36622814 | DOI:10.1021/acs.jmedchem.2c01772

J Biomol Struct Dyn. 2023 Jan 9:1-14. doi: 10.1080/07391102.2022.2163425. Online ahead of print.

ABSTRACT

The inhibition of protein-protein interactions (PPIs) by small molecules is an exciting drug discovery strategy. Here, we aimed to develop a pipeline to identify candidate small molecules to inhibit PPIs. Therefore, KPI, a Knowledge-based Protein-Protein Interaction Inhibition pipeline, was introduced to improve the discovery of PPI inhibitors. Then, phytochemicals from a collection of known Middle Eastern antiviral herbs were screened to identify potential inhibitors of key PPIs involved in COVID-19. Here, the following investigations were sequenced: 1) Finding the binding partner and the interface of the proteins in PPIs, 2) Performing the blind ligand-protein inhibition (LPI) simulations, 3) Performing the local LPI simulations, 4) Simulating the interactions of the proteins and their binding partner in the presence and absence of the ligands, and 5) Performing the molecular dynamics simulations. The pharmacophore groups involved in the LPI were also characterized. Aloin, Genistein, Neoglucobrassicin, and Rutin are our new pipeline candidates for inhibiting PPIs involved in COVID-19. We also propose KPI for drug repositioning studies.Communicated by Ramaswamy H. Sarma.

PMID:36622367 | DOI:10.1080/07391102.2022.2163425

Ther Adv Neurol Disord. 2023 Jan 2;16:17562864221137129. doi: 10.1177/17562864221137129. eCollection 2023.

ABSTRACT

Despite advances in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and other common autoimmune neuropathies (AN), still-many patients with these diseases do not respond satisfactorily to the available treatments. Repurposing of disease-modifying therapies (DMTs) from other autoimmune conditions, particularly multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), is a promising strategy that may accelerate the establishment of novel treatment choices for AN. This approach appears attractive due to homologies in the pathogenesis of these diseases and the extensive post-marketing experience that has been gathered from treating MS and NMOSD patients. The idea is also strengthened by a number of studies that explored the efficacy of DMTs in animal models of AN but also in some CIDP patients. We here review the available preclinical and clinical data of approved MS therapeutics in terms of their applicability to AN, especially CIDP. Promising therapeutic approaches appear to be B cell-directed and complement-targeting strategies, such as anti-CD20/anti-CD19 agents, Bruton's tyrosine kinase inhibitors and anti-C5 agents, as they exert their effects in the periphery. This is a major advantage because, in contrast to MS, their action in the periphery is sufficient to exert significant immunomodulation.

PMID:36620728 | PMC:PMC9810996 | DOI:10.1177/17562864221137129

Front Oncol. 2022 Dec 22;12:1106610. doi: 10.3389/fonc.2022.1106610. eCollection 2022.

NO ABSTRACT

PMID:36620606 | PMC:PMC9815525 | DOI:10.3389/fonc.2022.1106610

3 Biotech. 2023 Jan;13(1):36. doi: 10.1007/s13205-022-03450-6. Epub 2023 Jan 5.

ABSTRACT

In the last three years, COVID-19 has impacted the world with back-to-back waves leading to devastating consequences. SARS-CoV-2, the causative agent of COVID-19, was first detected in 2019 and since then has spread to 228 countries. Even though the primary focus of research groups was diverted to fight against COVID-19, yet no dedicated drug has been developed to combat the emergent life-threatening medical conditions. In this study, 35 phytocompounds and 43 drugs were investigated for comparative docking analysis. Molecular docking and virtual screening were performed against SARS-CoV-2 spike glycoprotein of 13 variants using AutoDock Vina tool 1.5.6 and Discovery Studio, respectively, to identify the most efficient drugs. Selection of the most suitable compounds with the best binding affinity was done after screening for toxicity, ADME (absorption, distribution, metabolism and excretion) properties and drug-likeliness. The potential candidates were discovered to be Liquiritin (binding affinities ranging between -7.0 and -8.1 kcal/mol for the 13 variants) and Apigenin (binding affinities ranging between -6.8 and -7.3 kcal/mol for the 13 variants) based on their toxicity and consistent binding affinity with the Spike protein of all variants. The stability of the protein-ligand complex was determined using Molecular dynamics (MD) simulation of Apigenin with the Delta plus variant of SARS-CoV-2. Furthermore, Liquiritin and Apigenin were also found to be less toxic than the presently used drugs and showed promising results based on in silico studies, though, confirmation using in vitro studies is required. This in-depth comparative investigation suggests potential drug candidates to fight against SARS-CoV-2 variants.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03450-6.

PMID:36619821 | PMC:PMC9815891 | DOI:10.1007/s13205-022-03450-6

Comput Struct Biotechnol J. 2022 Dec 19;21:425-431. doi: 10.1016/j.csbj.2022.12.014. eCollection 2023.

ABSTRACT

Several diverse proteins possess similar binding sites. Protein binding site comparison provides valuable insights for the drug discovery and development. Binding site similarities are useful in understanding polypharmacology, identifying potential off-targets and repurposing of known drugs. Many binding site analysis and comparison methods are available today, however, these methods may not be adequate to explain variation in the activity of a drug or a small molecule against a number of similar proteins. Water molecules surrounding the protein surface contribute to structure and function of proteins. Water molecules form diverse types of hydrogen-bonded cyclic water-ring networks known as topological water networks (TWNs). Analysis of TWNs in binding site of proteins may improve understanding of the characteristics of binding sites. We propose TWN-based residue encoding (TWN-RENCOD), a novel binding site comparison method which compares the aqueous environment in binding sites of similar proteins. As compared to other existing methods, results obtained using our method correlated better with differences in wide range of activity of a known drug (Sunitinib) against nine different protein kinases (KIT, PDGFRA, VEGFR2, PHKG2, ITK, HPK1, MST3, PAK6 and CDK2).

PMID:36618985 | PMC:PMC9798139 | DOI:10.1016/j.csbj.2022.12.014

Front Pharmacol. 2022 Dec 21;13:1056605. doi: 10.3389/fphar.2022.1056605. eCollection 2022.

ABSTRACT

Predicting new therapeutic effects (drug repositioning) of existing drugs plays an important role in drug development. However, traditional wet experimental prediction methods are usually time-consuming and costly. The emergence of more and more artificial intelligence-based drug repositioning methods in the past 2 years has facilitated drug development. In this study we propose a drug repositioning method, VGAEDR, based on a heterogeneous network of multiple drug attributes and a variational graph autoencoder. First, a drug-disease heterogeneous network is established based on three drug attributes, disease semantic information, and known drug-disease associations. Second, low-dimensional feature representations for heterogeneous networks are learned through a variational graph autoencoder module and a multi-layer convolutional module. Finally, the feature representation is fed to a fully connected layer and a Softmax layer to predict new drug-disease associations. Comparative experiments with other baseline methods on three datasets demonstrate the excellent performance of VGAEDR. In the case study, we predicted the top 10 possible anti-COVID-19 drugs on the existing drug and disease data, and six of them were verified by other literatures.

PMID:36618933 | PMC:PMC9812491 | DOI:10.3389/fphar.2022.1056605