Molecules. 2021 May 27;26(11):3213. doi: 10.3390/molecules26113213.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) global pandemic. The first step of viral infection is cell attachment, which is mediated by the binding of the SARS-CoV-2 receptor binding domain (RBD), part of the virus spike protein, to human angiotensin-converting enzyme 2 (ACE2). Therefore, drug repurposing to discover RBD-ACE2 binding inhibitors may provide a rapid and safe approach for COVID-19 therapy. Here, we describe the development of an in vitro RBD-ACE2 binding assay and its application to identify inhibitors of the interaction of the SARS-CoV-2 RBD to ACE2 by the high-throughput screening of two compound libraries (LOPAC®1280 and DiscoveryProbeTM). Three compounds, heparin sodium, aurintricarboxylic acid (ATA), and ellagic acid, were found to exert an effective binding inhibition, with IC50 values ranging from 0.6 to 5.5 µg/mL. A plaque reduction assay in Vero E6 cells infected with a SARS-CoV-2 surrogate virus confirmed the inhibition efficacy of heparin sodium and ATA. Molecular docking analysis located potential binding sites of these compounds in the RBD. In light of these findings, the screening system described herein can be applied to other drug libraries to discover potent SARS-CoV-2 inhibitors.

PMID:34072087 | DOI:10.3390/molecules26113213

Pharmaceuticals (Basel). 2021 May 28;14(6):521. doi: 10.3390/ph14060521.

ABSTRACT

Triple-negative breast cancer (TNBC) is considered to be the most aggressive and malignant neoplasm and is highly metastatic in nature. In the current study, we investigated the anti-metastatic potential of atovaquone, a protozoal drug prescribed for Pneumocystis pneumonia. We showed that atovaquone induced apoptosis and reduced the survival of several aggressive metastatic TNBC cell lines including metastatic patient-derived cells by reducing the expression of integrin α6, integrin β4, FAK, Src, and Vimentin. In order to study the efficacy of atovaquone in suppressing metastasized breast tumor cells in brain and lungs, we performed three in vivo experiments. We demonstrated that oral administration of 50 mg/kg of atovaquone suppressed MDA-MB-231 breast tumor growth by 90% in lungs in an intravenous metastatic tumor model. Anti-metastatic effect of atovaquone was further determined by intracardiac injection of 4T1-luc breast tumor cells into the left ventricle of mouse heart. Our results showed that atovaquone treatment suppressed the growth of metastatic tumors in lungs, liver and brain by 70%, 50% and 30% respectively. In an intracranial model, the growth of HCC1806-luc brain tumors in atovaquone treated mice was about 55% less than that of control. Taken together, our results indicate the anti-metastatic effects of atovaquone in vitro and in vivo in various breast tumor metastasis models.

PMID:34071408 | DOI:10.3390/ph14060521

J Fungi (Basel). 2021 May 28;7(6):424. doi: 10.3390/jof7060424.

ABSTRACT

The repurposing strategy was applied herein to evaluate the effects of lopinavir, an aspartic protease inhibitor currently used in the treatment of HIV-infected individuals, on the globally widespread opportunistic human fungal pathogen Candida albicans by using in silico, in vitro and in vivo approaches in order to decipher its targets on fungal cells and its antifungal mechanisms of action. Secreted aspartic proteases (Saps) are the obviously main target of lopinavir. To confirm this hypothesis, molecular docking assays revealed that lopinavir bound to the Sap2 catalytic site of C. albicans as well as inhibited the Sap hydrolytic activity in a typically dose-dependent manner. The inhibition of Saps culminated in the inability of C. albicans yeasts to assimilate the unique nitrogen source (albumin) available in the culture medium, culminating with fungal growth inhibition (IC50 = 39.8 µM). The antifungal action of lopinavir was corroborated by distinct microscopy analyses, which evidenced drastic and irreversible changes in the morphology that justified the fungal death. Furthermore, our results revealed that lopinavir was able to (i) arrest the yeasts-into-hyphae transformation, (ii) disturb the synthesis of neutral lipids, including ergosterol, (iii) modulate the surface-located molecules, such as Saps and mannose-, sialic acid- and N-acetylglucosamine-containing glycoconjugates, (iv) diminish the secretion of hydrolytic enzymes, such as Saps and esterase, (v) negatively influence the biofilm formation on polystyrene surface, (vi) block the in vitro adhesion to epithelial cells, (vii) contain the in vivo infection in both immunocompetent and immunosuppressed mice and (viii) reduce the Sap production by yeasts recovered from kidneys of infected animals. Conclusively, the exposed results highlight that lopinavir may be used as a promising repurposing drug against C. albicans infection as well as may be used as a lead compound for the development of novel antifungal drugs.

PMID:34071195 | DOI:10.3390/jof7060424

Cancers (Basel). 2021 May 30;13(11):2703. doi: 10.3390/cancers13112703.

ABSTRACT

The SP/NK1R-complex plays an important role in tumor proliferation. Targeting of the neurokinin-1 receptor in previous studies with its antagonist aprepitant (AP) resulted in anti-tumoral effects in colorectal cancer and hepatoblastoma. However, there is still a lack of knowledge regarding its effects on pancreatic cancer. Therefore, we treated human pancreatic ductal adenocarcinoma (PDAC) cell lines (Capan-1, DanG, HuP-T3, Panc-1, and MIA PaCa-2) and their cancer stem cell-like cells (CSCs) with AP and analyzed functional effects by MTT-, colony, and sphere formation assays, respectively; moreover, we monitored downstream mechanisms by flow cytometry. NK1R inhibition resulted in dose-dependent growth reduction in both CSCs and non-CSCs without induction of apoptosis in most PDAC cell lines. More importantly, we identified striking AP dependent cell cycle arrest in all parental cells. Furthermore, gene expression and the importance of key genes in PDAC tumorigenesis were analyzed combining RT-qPCR in eight PDAC cell lines with publicly available datasets (TCGA, GEO, CCLE). Surprisingly, we found a better overall survival in patients with high NK1R levels, while at the same time, NK1R was significantly decreased in PDAC tissue compared to normal tissue. Interestingly, there is currently no differentiation between the isoforms of NK1R (truncated and full; NK1R-tr and -fl) in any of the indicated public transcriptomic records, although many publications already emphasize on important regulatory differences between the two isoforms of NK1R in many cancer entities. In conclusion, analysis of splice variants might potentially lead to a stratification of PDAC patients for NK1R-directed therapies. Furthermore, we presume PDAC patients with high expressions of NK1R-tr might benefit from treatment with AP to improve chemoresistance. Therefore, analysis of splice variants might potentially lead to a stratification of PDAC patients for NK1R-directed therapies.

PMID:34070805 | DOI:10.3390/cancers13112703

Pharmaceutics. 2021 May 30;13(6):815. doi: 10.3390/pharmaceutics13060815.

ABSTRACT

The pandemic of the coronavirus disease 2019 (COVID-19) represents an unprecedented challenge to identify effective drugs for prevention and treatment. While the world's attention is focused on news of COVID-19 vaccine updates, clinical management still requires improvement. Due to the similarity of cancer-induced inflammation, immune dysfunction, and coagulopathy to COVID-19, anticancer drugs, such as Interferon, Pembrolizumab or Bicalutamide, are already being tested in clinical trials for repurposing, alone or in combination. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected, clinicians need effective medical treatments for this infection.

PMID:34070725 | DOI:10.3390/pharmaceutics13060815

Biomolecules. 2021 May 25;11(6):794. doi: 10.3390/biom11060794.

ABSTRACT

Inflammation, by inducing a tumor-promoting microenvironment, is a hallmark for prostate cancer (PCa) progression. NOD-like receptor protein 3 (NLRP3)-inflammasome activation, interleukin-1β (IL-1β) secretion, and cancer cell-released extracellular vesicles (EVs) contribute to the establishment of tumor microenvironment. We have shown that PC3-derived EVs (PC3-EVs) activate inflammasome cascade in non-cancerous PNT2 cells. It is known that the endogenous biomolecules and Natriuretic Peptides (NPs), such as ANP and BNP, inhibit inflammasome activation in immune cells. Here we investigated whether ANP and BNP modify PCa inflammatory phenotype in vitro. By using PNT2, LNCaP, and PC3 cell lines, which model different PCa progression stages, we analyzed inflammasome activation and the related pathways by Western blot and IL-1β secretion by ELISA. We found that tumor progression is characterized by constitutive inflammasome activation, increased IL-1β secretion, and reduced endogenous NPs expression. The administration of exogenous ANP and BNP, via p38-MAPK or ERK1/2-MAPK, by inducing NLRP3 phosphorylation, counteract inflammasome activation and IL-1β maturation in PC3 and PC3-EVs-treated PNT2 cells, respectively. Our results demonstrate that NPs, by interfering with cell-specific signaling pathways, exert pleiotropic anti-inflammatory effects converging toward inflammasome phosphorylation and suggest that NPs can be included in a drug repurposing process for PCa.

PMID:34070682 | DOI:10.3390/biom11060794

J Biomol Struct Dyn. 2021 Jun 1:1-25. doi: 10.1080/07391102.2021.1931451. Online ahead of print.

ABSTRACT

In view of many European countries and the USA leading to the second wave of COVID-19 pandemic, winter season, the evolution of new mutations in the spike protein, and no registered drugs and vaccines for COVID-19 treatment, the discovery of effective and novel therapeutic agents is urgently required. The degrees and frequencies of COVID-19 clinical complications are related to uncontrolled immune responses, secondary bacterial infections, diabetes, cardiovascular disease, hypertension, and chronic pulmonary diseases. It is essential to recognize that the drug repurposing strategy so far remains the only means to manage the disease burden of COVID-19. Despite some success of using single-target drugs in treating the disease, it is beyond suspicion that the virus will acquire drug resistance by acquiring mutations in the drug target. The possible synergistic inhibition of drug efficacy due to drug-drug interaction cannot be avoided while treating COVID-19 and allied clinical complications. Hence, to avoid the unintended development drug resistance and loss of efficacy due to drug-drug interaction, multi-target drugs can be promising tools for the most challenging disease. In the present work, we have carried out molecular docking studies of compounds from the FDA approved drug library, and the FDA approved and passed phase -1 drug libraries with ten therapeutic targets of COVID-19. Results showed that known drugs, including nine anti-inflammatory compounds, four antibiotics, six antidiabetic compounds, and one cardioprotective compound, could effectively inhibit multiple therapeutic targets of COVID-19. Further in-vitro, in vivo, and clinical studies will guide these drugs' proper allocation to treat COVID-19.Communicated by Ramaswamy H. Sarma.

PMID:34062110 | DOI:10.1080/07391102.2021.1931451

Biomed Pharmacother. 2021 May 28;140:111769. doi: 10.1016/j.biopha.2021.111769. Online ahead of print.

ABSTRACT

Traumatic brain injury (TBI) is characterized by a complex network of signals mediating inflammatory, proliferative and apoptotic processes during its acute and chronic phases. Current therapies mitigate damage and are mainly for palliative care and there are currently no effective therapies for secondary damage. This suggests a need to discover a compound with a greater spectrum of action that can control various pathological aspects of TBI. Here we used a network pharmacology approach to explore the benefits of tibolone, an estrogen and androgen receptor agonist with broader actions in cells, as a possible repurposing drug for TBI therapy. Using different databases we retrieved the targets significantly associated to TBI and tibolone, obtaining 2700 and 652, respectively. The top 10 GO enriched terms were mostly related to cell proliferation, apoptosis and inflammation. Following protein-protein functional analysis, the top connected proteins were related to kinase activity (MAPK1/14/3, AKT1 PIK3R1), apoptosis (TP53, CASP3), growth factors (EGFR), estrogen signalling (ESR1) and inflammation (IL6, TNF), with IL6 as an important signalling hub belonging to the top GO categories. Thus, we identified IL6 as a cellular node which we then validated using molecular mechanics-generalized born surface area (MMGBSA) and docking to explore which tibolone metabolite might interact with this protein. Both 3α and 3β-OH tibolone seemed to bind better to IL6 at important sites responsible for its binding to IL6R. In conclusion, our study demonstrates key hubs involved in TBI pathology which indicates IL6 as a target molecule of tibolone as drug repurposing for TBI therapy.

PMID:34058440 | DOI:10.1016/j.biopha.2021.111769

Immunopharmacol Immunotoxicol. 2021 May 31:1-15. doi: 10.1080/08923973.2021.1931302. Online ahead of print.

ABSTRACT

A global threat has emerged in 2019 due to the rapid spread of Coronavirus disease (COVID-19). As of January 2021, the number of cases worldwide reached 103 million cases and 2.22 million deaths which were confirmed as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This global pandemic galvanized the scientific community to study the causative virus (SARS-CoV2) pathogenesis, transmission, and clinical symptoms. Remarkably, the most common complication associated with this disease is the cytokine storm which is responsible for COVID-19 mortality. Thus, targeting the cytokine storm with new medications is needed to hamper COVID-19 complications where the most prominent strategy for the treatment is drug repurposing. Through this strategy, several steps are skipped especially those required for testing drug safety and thus may help in reducing the dissemination of this pandemic. Accordingly, the aim of this review is to outline the pathogenesis, clinical features, and immune complications of SARS-CoV2 in addition to suggesting several repurposed drugs with their plausible mechanism of action for possible management of severe COVID-19 cases.

PMID:34057871 | DOI:10.1080/08923973.2021.1931302

Cell Oncol (Dordr). 2021 May 31. doi: 10.1007/s13402-021-00613-0. Online ahead of print.

ABSTRACT

BACKGROUND: The aggressive, invasive and treatment resistant nature of glioblastoma makes it one of the most lethal cancers in humans. Total surgical resection is difficult, and a combination of radiation and chemotherapy is used to treat the remaining invasive cells beyond the tumour border by inducing DNA damage and activating cell death pathways in glioblastoma cells. Unfortunately, recurrence is common and a major hurdle in treatment, often met with a more aggressive and treatment resistant tumour. A mechanism of resistance is the response of DNA repair pathways upon treatment-induced DNA damage, which enact cell-cycle arrest and repair of DNA damage that would otherwise cause cell death in tumour cells.

CONCLUSIONS: In this review, we discuss the significance of DNA repair mechanisms in tumour formation, aggression and treatment resistance. We identify an underlying trend in the literature, wherein alterations in DNA repair pathways facilitate glioma progression, while established high-grade gliomas benefit from constitutively active DNA repair pathways in the repair of treatment-induced DNA damage. We also consider the clinical feasibility of inhibiting DNA repair in glioblastoma and current strategies of using DNA repair inhibitors as agents in combination with chemotherapy, radiation or immunotherapy. Finally, the importance of blood-brain barrier penetrance when designing novel small-molecule inhibitors is discussed.

PMID:34057732 | DOI:10.1007/s13402-021-00613-0

Front Oncol. 2021 May 13;11:688755. doi: 10.3389/fonc.2021.688755. eCollection 2021.

ABSTRACT

Vaccines used to prevent infections have long been known to stimulate immune responses to cancer as illustrated by the approval of the Bacillus Calmette-Guérin (BCG) vaccine to treat bladder cancer since the 1970s. The recent approval of immunotherapies has rejuvenated this research area with reports of anti-tumor responses with existing infectious diseases vaccines used as such, either alone or in combination with immune checkpoint inhibitors. Here, we have reviewed and summarized research activities using approved vaccines to treat cancer. Data supporting a cancer therapeutic use was found for 16 vaccines. For 10 (BCG, diphtheria, tetanus, human papillomavirus, influenza, measles, pneumococcus, smallpox, typhoid and varicella-zoster), clinical trials have been conducted or are ongoing. Within the remaining 6, preclinical evidence supports further evaluation of the rotavirus, yellow fever and pertussis vaccine in carefully designed clinical trials. The mechanistic evidence for the cholera vaccine, combined with the observational data in colorectal cancer, is also supportive of clinical translation. There is limited data for the hepatitis B and mumps vaccine (without measles vaccine). Four findings are worth highlighting: the superiority of intravesical typhoid vaccine instillations over BCG in a preclinical bladder cancer model, which is now the subject of a phase I trial; the perioperative use of the influenza vaccine to limit and prevent the natural killer cell dysfunction induced by cancer surgery; objective responses following intratumoral injections of measles vaccine in cutaneous T-cell lymphoma; objective responses induced by human papillomavirus vaccine in cutaneous squamous cell carcinoma. All vaccines are intended to induce or improve an anti-tumor (immune) response. In addition to the biological and immunological mechanisms that vary between vaccines, the mode of administration and sequence with other (immuno-)therapies warrant more attention in future research.

PMID:34055652 | PMC:PMC8155725 | DOI:10.3389/fonc.2021.688755

Comput Struct Biotechnol J. 2021 May 24. doi: 10.1016/j.csbj.2021.05.037. Online ahead of print.

ABSTRACT

The world is facing the COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Likewise, other viruses of the Coronaviridae family were responsible for causing epidemics earlier. To tackle these viruses, there is a lack of approved antiviral drugs. Therefore, we have developed robust computational methods to predict the repurposed drugs using machine learning techniques namely Support Vector Machine, Random Forest, k-Nearest Neighbour, Artificial Neural Network, and Deep Learning. We used the experimentally validated drugs/chemicals with anti-corona activity and their inhibition efficiencies (IC50/EC50) from 'DrugRepV' repository. The unique entries of SARS-CoV-2 (142), SARS (221), MERS (123), and overall Coronaviruses (414) were subdivided into the training/testing and independent validation datasets, followed by the extraction of chemical/structural descriptors and fingerprints (17968). The highly relevant features were filtered using the recursive feature selection algorithm. The selected chemical descriptors were used to develop prediction models with Pearson's correlation coefficients ranging from 0.60-0.90 on training/testing. The robustness of the predictive models was further ensured using external independent validation datasets, decoy datasets, applicability domain, and chemical analyses. The developed models were used to predict promising repurposed drug candidates against coronaviruses after scanning the DrugBank. Top predicted molecules for SARS-CoV-2 were further validated by molecular docking against the spike protein complex with ACE receptor. We found potential repurposed drugs namely, Verteporfin, Alatrofloxacin, Metergoline, Rescinnamine, Leuprolide, and Telotristat ethyl with high binding affinity. These computational methods would assist in antiviral drug discovery against SARS-CoV-2 and other Coronaviruses.

PMID:34055238 | PMC:PMC8141697 | DOI:10.1016/j.csbj.2021.05.037

Front Genet. 2021 Apr 8;12:657182. doi: 10.3389/fgene.2021.657182. eCollection 2021.

ABSTRACT

Drug repositioning is an application-based solution based on mining existing drugs to find new targets, quickly discovering new drug-disease associations, and reducing the risk of drug discovery in traditional medicine and biology. Therefore, it is of great significance to design a computational model with high efficiency and accuracy. In this paper, we propose a novel computational method MGRL to predict drug-disease associations based on multi-graph representation learning. More specifically, MGRL first uses the graph convolution network to learn the graph representation of drugs and diseases from their self-attributes. Then, the graph embedding algorithm is used to represent the relationships between drugs and diseases. Finally, the two kinds of graph representation learning features were put into the random forest classifier for training. To the best of our knowledge, this is the first work to construct a multi-graph to extract the characteristics of drugs and diseases to predict drug-disease associations. The experiments show that the MGRL can achieve a higher AUC of 0.8506 based on five-fold cross-validation, which is significantly better than other existing methods. Case study results show the reliability of the proposed method, which is of great significance for practical applications.

PMID:34054920 | PMC:PMC8153989 | DOI:10.3389/fgene.2021.657182

Virology. 2021 May 25;560:110-115. doi: 10.1016/j.virol.2021.05.009. Online ahead of print.

ABSTRACT

A recent study have reported that pre-use of azelastine is associated with a decrease in COVID-19 positive test results among susceptible elderly people. Besides, it has been reported that antihistamine drugs could prevent viruses from entering cells. The purpose of this study is to investigate whether azelastine have antiviral activity against SARS-CoV-2 in vitro and the possible mechanism. Here, we discovered antihistamine azelastine has an affinity to ACE2 by cell membrane chromatography (CMC); Then we determined the equilibrium dissociation constant (KD) of azelastine-ACE2 as (2.58 ± 0.48) × 10-7 M by surface plasmon resonance (SPR). The results of molecular docking showed that azelastine could form an obvious hydrogen bond with Lys353. The pseudovirus infection experiments showed that azelastine effectively inhibited viral entry (EC50 = 3.834 μM). Our work provides a new perspective for the screening method of drug repositioning for COVID-19, and an attractive and promising drug candidate for anti-SARS-CoV-2.

PMID:34052578 | DOI:10.1016/j.virol.2021.05.009

Biomed Pharmacother. 2021 May 18;140:111742. doi: 10.1016/j.biopha.2021.111742. Online ahead of print.

ABSTRACT

Here, drug repurposing and molecular docking were employed to screen approved MPP inhibitors and their derivatives to suggest a specific therapeutic agent for the treatment of COVID-19. The approved MPP inhibitors against HIV and HCV were prioritized, while RNA dependent RNA Polymerase (RdRp) inhibitor remdesivir including Favipiravir, alpha-ketoamide were studied as control groups. The target drug surface hotspot was also investigated through the molecular docking technique. Molecular dynamics was performed to determine the binding stability of docked complexes. Absorption, distribution, metabolism, and excretion analysis was conducted to understand the pharmacokinetics and drug-likeness of the screened MPP inhibitors. The results of the study revealed that Paritaprevir (-10.9 kcal/mol) and its analog (CID 131982844) (-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitors compared in this study, including remdesivir, Favipiravir, and alpha-ketoamide. A comparative study among the screened putative MPP inhibitors revealed that the amino acids T25, T26, H41, M49, L141, N142, G143, C145, H164, M165, E166, D187, R188, and Q189 are at potentially critical positions for being surface hotspots in the MPP of SARS-CoV-2. The top 5 predicted drugs (Paritaprevir, Glecaprevir, Nelfinavir, and Lopinavir) and the topmost analog showed conformational stability in the active site of the SARS-CoV-2 MP protein. The study also suggested that Paritaprevir and its analog (CID 131982844) might be effective against SARS-CoV-2. The current findings are limited to in silico analysis and lack in vivo efficacy testing; thus, we strongly recommend a quick assessment of Paritaprevir and its analog (CID 131982844) in a clinical trial.

PMID:34052565 | DOI:10.1016/j.biopha.2021.111742

J Biomed Inform. 2021 May 27:103821. doi: 10.1016/j.jbi.2021.103821. Online ahead of print.

ABSTRACT

AIM: Rapidly developing AI and machine learning (ML) technologies can expedite therapeutic development and in the time of current pandemic their merits are particularly in focus. The purpose of this study was to explore various ML approaches for molecular property prediction and illustrate their utility for identifying potential SARS-CoV-2 3CLpro inhibitors.

MATERIALS AND METHODS: We perform a series of drug discovery screenings based on supervised ML models operating in different ways on molecular representations, encompassing shallow learning methods based on fixed molecular fingerprints, Graph Convolutional Neural Network (Graph-CNN) with its self-learned molecular representations, as well as ML methods based on combining fixed and Graph-CNN learned representations.

RESULTS: Results of our ML models are compared both with respect to the aggregated predictive performance in terms of ROC-AUC based on the scaffold splits, as well as on the granular level of individual predictions, corresponding to the top ranked repurposing candidates. This comparison reveals both certain characteristic homogeneity regarding chemical and pharmacological classification, with a prevalence of sulfonamides and anticancer drugs, as well as identifies novel groups of potential drug candidates against COVID-19.

CONCLUSIONS: A series of ML approaches for molecular property prediction enables drug discovery screenings, illustrating the utility for COVID-19. We show that the obtained results correspond well with the already published research on COVID-19 treatment, as well as provide novel insights on potential antiviral characteristics inferred from in vitro data.

PMID:34052441 | DOI:10.1016/j.jbi.2021.103821

Bioorg Chem. 2021 May 7;113:104971. doi: 10.1016/j.bioorg.2021.104971. Online ahead of print.

ABSTRACT

Drug repurposing has gained much attention as a cost-effective strategy that plays an exquisite role in identifying undescribed biological activities in clinical drugs. In the present work, we report the repurposing of the antibacterial drug nitrofurazone (NFZ) as a potential anticancer agent against CaCo-2, MDA-MB 231 and HepG-2 cancer cell lines. Novel series of nitrofurazone analogs were then designed considering the important pharmacologic features present in NFZ. Synthesis and biological evaluation of the target compounds revealed their promising anticancer activities endowed with antimicrobial potential and possessing better lipophilicity than NFZ. Compound 7, exclusively, inhibited the growth of all tested cancer cells more potently than NFZ with the least cytotoxicity against normal cells, displaying anti Gram-positive bacterial activities and antifungal potential. Analysis of the stereo-electronic properties of compound 7 via investigating the energies of HOMO, LUMO, HOMO-LUMO energy gap and MEP maps demonstrated its high reactivity and the expected molecular mechanism of action through reduction of the 5-nitrofuryl moiety. Data of the bioactivity studies indicated that the potent anticancer activity of 7 is mainly through increasing intracellular ROS levels and induction of apoptosis via significantly down-regulating the expression of Bcl-2 while up-regulating BAX, p53 and caspase 3 expression levels. Compound 7 potently inhibited the cellular expression levels of antioxidant enzymes GPx1 and GR compared to NFZ. Antioxidant enzymes kinetic studies and blind molecular docking simulations disclosed the mechanistic and structural aspects of the interaction between 7 and both GR and GPx1. Thus, the successful discovery of 7 as a potential dual anticancer-antimicrobial nitrofurazone analog might validate the applicability of drug repurposing strategy in unravelling the unrecognized bioactivity of the present conventional drugs, besides furnishing the way towards more optimization and development studies.

PMID:34051413 | DOI:10.1016/j.bioorg.2021.104971

Int J Pharm. 2021 May 26:120750. doi: 10.1016/j.ijpharm.2021.120750. Online ahead of print.

ABSTRACT

The development of molecules for topical dermatology has primarily relied on drug repurposing or on combination therapies, leading to an average of only one New Chemical Entity (NCE) approved per year by the FDA. Topical products offer benefits to patients by enabling localized treatment, while minimizing systemic exposure and the likelihood of adverse events. New therapies are further justified by the burden skin diseases cause on patients' quality of life. Notwithstanding the opportunities, the selection of a topical NCE presents challenges, primarily derived from a target product profile uncommon to oral drugs. Beyond a more stringent range of physicochemical properties, the molecule must display adequate solubility and chemical stability in topical-relevant excipients; must effectively cross the stratum corneum, considerably less permeable than the intestinal epithelium, and elicit a local therapeutic response; and must enable a formulation with robust physical stability. A novel framework intended to de-risk NCE selection is presented and based on four calculated physicochemical properties: molecular weight, clog P, topological polar surface area, and aromatic ring count. The use of topical-relevant solvents to assess the molecule's solubility profile, and a 2-day accelerated chemical stability methodology, are also described as critical steps in early dermal development.

PMID:34051321 | DOI:10.1016/j.ijpharm.2021.120750

Nucleic Acids Res. 2021 May 28:gkab405. doi: 10.1093/nar/gkab405. Online ahead of print.

ABSTRACT

The Mergeomics web server is a flexible online tool for multi-omics data integration to derive biological pathways, networks, and key drivers important to disease pathogenesis and is based on the open source Mergeomics R package. The web server takes summary statistics of multi-omics disease association studies (GWAS, EWAS, TWAS, PWAS, etc.) as input and features four functions: Marker Dependency Filtering (MDF) to correct for known dependency between omics markers, Marker Set Enrichment Analysis (MSEA) to detect disease relevant biological processes, Meta-MSEA to examine the consistency of biological processes informed by various omics datasets, and Key Driver Analysis (KDA) to identify essential regulators of disease-associated pathways and networks. The web server has been extensively updated and streamlined in version 2.0 including an overhauled user interface, improved tutorials and results interpretation for each analytical step, inclusion of numerous disease GWAS, functional genomics datasets, and molecular networks to allow for comprehensive omics integrations, increased functionality to decrease user workload, and increased flexibility to cater to user-specific needs. Finally, we have incorporated our newly developed drug repositioning pipeline PharmOmics for prediction of potential drugs targeting disease processes that were identified by Mergeomics. Mergeomics is freely accessible at http://mergeomics.research.idre.ucla.edu and does not require login.

PMID:34048577 | DOI:10.1093/nar/gkab405

Sci Rep. 2021 May 27;11(1):11234. doi: 10.1038/s41598-021-90701-w.

ABSTRACT

Understanding the molecular basis of fibrosis, the lethal complication of COVID-19, is urgent. By the analysis of RNA-sequencing data of SARS-CoV-2-infected cells combined with data mining we identified genes involved in COVID-19 progression. To characterize their implication in the fibrosis development we established a correlation matrix based on the transcriptomic data of patients with idiopathic pulmonary fibrosis. With this method, we have identified a cluster of genes responsible for SARS-CoV-2-fibrosis including its entry receptor ACE2 and epidermal growth factor EGF. Then, we developed Vi-Fi scoring-a novel drug repurposing approach and simultaneously quantified antiviral and antifibrotic activities of the drugs based on their transcriptomic signatures. We revealed the strong dual antifibrotic and antiviral activity of EGFR/ErbB inhibitors. Before the in vitro validation, we have clustered 277 cell lines and revealed distinct COVID-19 transcriptomic signatures of the cells with similar phenotypes that defines their suitability for COVID-19 research. By ERK activity monitoring in living lung cells, we show that the drugs with predicted antifibrotic activity downregulate ERK in the host lung cells. Overall, our study provides novel insights on SARS-CoV-2 dependence on EGFR/ERK signaling and demonstrates the utility of EGFR/ErbB inhibitors for COVID-19 treatment.

PMID:34045585 | DOI:10.1038/s41598-021-90701-w