Nanomedicine (Lond). 2021 Jul 15. doi: 10.2217/nnm-2021-0086. Online ahead of print.

ABSTRACT

While cancer remains a significant global health problem, advances in cancer biology, deep understanding of its underlaying mechanism and identification of specific molecular targets allowed the development of new therapeutic options. Drug repurposing poses several advantages as reduced cost and better safety compared with new compounds development. COX-2 inhibitors are one of the most promising drug classes for repurposing in cancer therapy. In this review, we provide an overview of the detailed mechanism and rationale of COX-2 inhibitors as anticancer agents and we highlight the most promising research efforts on nanotechnological approaches to enhance COX-2 inhibitors delivery with special focus on celecoxib as the most widely studied agent for chemoprevention or combined with chemotherapeutic and herbal drugs for combating various cancers.

PMID:34264123 | DOI:10.2217/nnm-2021-0086

Adv Exp Med Biol. 2021;1322:313-337. doi: 10.1007/978-981-16-0267-2_12.

ABSTRACT

Emerging and re-emerging viral diseases occur with regularity within the human population. The conventional 'one drug, one virus' paradigm for antivirals does not adequately allow for proper preparedness in the face of unknown future epidemics. In addition, drug developers lack the financial incentives to work on antiviral drug discovery, with most pharmaceutical companies choosing to focus on more profitable disease areas. Safe-in-man broad spectrum antiviral agents (BSAAs) can help meet the need for antiviral development by already having passed phase I clinical trials, requiring less time and money to develop, and having the capacity to work against many viruses, allowing for a speedy response when unforeseen epidemics arise. In this chapter, we discuss the benefits of repurposing existing drugs as BSAAs, describe the major steps in safe-in-man BSAA drug development from discovery through clinical trials, and list several database resources that are useful tools for antiviral drug repositioning.

PMID:34258746 | DOI:10.1007/978-981-16-0267-2_12

Adv Exp Med Biol. 2021;1322:195-218. doi: 10.1007/978-981-16-0267-2_8.

ABSTRACT

Infections by influenza virus constitute a major and recurrent threat for human health. Together with vaccines, antiviral drugs play a key role in the prevention and treatment of influenza virus infection and disease. Today, the number of antiviral molecules approved for the treatment of influenza is relatively limited, and their use is threatened by the emergence of viral strains with resistance mutations. There is therefore a real need to expand the prophylactic and therapeutic arsenal. This chapter summarizes the state of the art in drug discovery and development for the treatment of influenza virus infections, with a focus on both virus-targeting and host cell-targeting strategies. Novel antiviral strategies targeting other viral proteins or targeting the host cell, some of which are based on drug repurposing, may be used in combination to strengthen our therapeutic arsenal against this major pathogen.

PMID:34258742 | DOI:10.1007/978-981-16-0267-2_8

iScience. 2021 Jun 12;24(7):102722. doi: 10.1016/j.isci.2021.102722. eCollection 2021 Jul 23.

ABSTRACT

Clear cell renal cell carcinoma (ccRCC) is the most common histological type of kidney cancer and has high heterogeneity. Stratification of ccRCC is important since distinct subtypes differ in prognosis and treatment. Here, we applied a systems biology approach to stratify ccRCC into three molecular subtypes with different mRNA expression patterns and prognosis of patients. Further, we developed a set of biomarkers that could robustly classify the patients into each of the three subtypes and predict the prognosis of patients. Then, we reconstructed subtype-specific metabolic models and performed essential gene analysis to identify the potential drug targets. We identified four drug targets, including SOAT1, CRLS1, and ACACB, essential in all the three subtypes and GPD2, exclusively essential to subtype 1. Finally, we repositioned mitotane, an FDA-approved SOAT1 inhibitor, to treat ccRCC and showed that it decreased tumor cell viability and inhibited tumor cell growth based on in vitro experiments.

PMID:34258555 | PMC:PMC8253978 | DOI:10.1016/j.isci.2021.102722

Nanomedicine (Lond). 2021 Jul 14. doi: 10.2217/nnm-2021-0130. Online ahead of print.

ABSTRACT

Despite the high incidence of breast cancer, there are few pharmacological prevention strategies for the high-risk population and those that are available have low adherence. Strategies that deliver drugs directly to the breasts may increase drug local concentrations, improving efficacy, safety and acceptance. The skin of the breast has been proposed as an administration route for local transdermal therapy, which may improve drug levels in the mammary tissue, due to both deep local penetration and percutaneous absorption. In this review, we discuss the application of nanotechnology-based strategies for the delivery of well established and new agents as well as drug repurposing using the topical transdermal route to improve the outcomes of preventive therapy for breast cancer.

PMID:34256574 | DOI:10.2217/nnm-2021-0130

Comput Biol Med. 2021 Jul 6;135:104634. doi: 10.1016/j.compbiomed.2021.104634. Online ahead of print.

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused worldwide pandemic and is responsible for millions of worldwide deaths due to -a respiratory disease known as COVID-19. In the search for a cure of COVID-19, drug repurposing is a fast and cost-effective approach to identify anti-COVID-19 drugs from existing drugs. The receptor binding domain (RBD) of the SARS-CoV-2 spike protein has been a main target for drug designs to block spike protein binding to ACE2 proteins. In this study, we probed the conformational plasticity of the RBD using long molecular dynamics (MD) simulations, from which, representative conformations were identified using clustering analysis. Three simulated conformations and the original crystal structure were used to screen FDA approved drugs (2466 drugs) against the predicted binding site at the ACE2-RBD interface, leading to 18 drugs with top docking scores. Notably, 16 out of the 18 drugs were obtained from the simulated conformations, while the crystal structure suggests poor binding. The binding stability of the 18 drugs were further investigated using MD simulations. Encouragingly, 6 drugs exhibited stable binding with RBD at the ACE2-RBD interface and 3 of them (gonadorelin, fondaparinux and atorvastatin) showed significantly enhanced binding after the MD simulations. Our study shows that flexibility modeling of SARS-CoV-2 RBD using MD simulation is of great help in identifying novel agents which might block the interaction between human ACE2 and the SARS-CoV-2 RBD for inhibiting the virus infection.

PMID:34256255 | DOI:10.1016/j.compbiomed.2021.104634

Recent Pat Anticancer Drug Discov. 2021 Jul 11. doi: 10.2174/1574892816666210712113739. Online ahead of print.

ABSTRACT

BACKGROUND: Malignant Mesothelioma (MM), an orphan but aggressive malignancy of the mesothelial membrane, is a fatal tumor. Global epidemic related to malignant pleural mesothelioma is on the rise, so there is a need to explore novel biomarkers and ingenious therapeutic approaches to stalk this silent killer.

OBJECTIVE: The main aim of the present review is to provide a consolidated overview of the recent active patents related to diagnosis and therapy in MM that will affect its future management.

METHOD: A search of existing literature was conducted from a PubMed database search. Recent patent information was fetched out from online accessible open-access databases. For related clinical trials, www.clinicaltrial.gov was searched.

RESULTS: Patent search data showed 72 active patents related to diagnosis and therapy in the field of MM, which we classified into eight broad categories. Of these, a maximum of 17 patents was attributed to immunotherapy, and 13 each were attributed to "Drug Repositioning" and "Biological / synthetic" based candidates. The remaining 17 patents were distributed amongst virotherapy and various miscellaneous categories. A relatively low number of patents accounts for gene signature (7), epigenetics (3), and microRNA (2) based diagnosis and therapy. Furthermore, our clinical trial-based investigation revealed the futuristic impact of listed patents in MM patient management.

CONCLUSION: This review article has provided an overview of patent-based advancement in MM, which might become the apex in clinical settings in the future. Interestingly, immunotherapy and "drug repositioning" based therapy seems to be the front-runners in the race to provide relief.

PMID:34254929 | DOI:10.2174/1574892816666210712113739

Curr Stem Cell Res Ther. 2021 Jul 12. doi: 10.2174/1574888X16666210712213102. Online ahead of print.

ABSTRACT

Nanomachines hold promise for the next generation of emerging technology; however, nanomachines are not a new concept, viruses, nature's nanomachines, have already existed for thousands of years. In 2019, the whole world has had to come together to confront a life-threatening nanomachine named "SARS-CoV-2", which causes COVID-19 illness. SARS-CoV-2, a smart nanomachine, attaches itself onto the ACE2 and CD147 receptors present on the cell surfaces of the lungs, kidneys, heart, brain, intestines, and testes, etc. and triggers pathogenesis. Cell entry triggers a cascade of inflammatory responses resulting in tissue damage, with the worst affected cases leading to death. SARS-CoV-2 influences several receptors and signalling pathways; therefore, finding a biomaterial that caps these signalling pathways and ligand sites is of interest. This research aimed to compare the similarities and differences between COVID-19 and its elderly sisters', MERS and SARS. Furthermore, we glanced at emerging therapeutics that carry potential in eliminating SARS-CoV-2, and the tissue damage it causes. Simple prophylactic and therapeutic strategies for the treatment of COVID-19 infection have been put forward.

PMID:34254928 | DOI:10.2174/1574888X16666210712213102

J Biomol Struct Dyn. 2021 Jul 13:1-14. doi: 10.1080/07391102.2021.1946715. Online ahead of print.

ABSTRACT

The main objective of this study is to find out the anti-SARS-CoV-2 potential of emetine by using molecular docking and dynamic simulation approaches. Interestingly, molecular docking studies suggest that Emetine showed significant binding affinity toward Nsp15 (-10.8 kcal/mol) followed by Nsp12 (-9.5 kcal/mol), RNA-dependent RNA polymerase, RdRp (-9.5 kcal/mol), Nsp16 (-9.4 kcal/mol), Nsp10 (-9.2 kcal/mol), Papain-like protein (-9.0 kcal/mol), Nsp13 (-9.0 kcal/mol), Nsp14 (-8.9 kcal/mol) and Spike Protein Receptor Domain (-8.8 kcal/mol) and chymotrypsin-like protease, 3CLpro (-8.5 kcal/mol), respectively, which are essential for viral infection and replication. In addition, molecular dynamic simulation (MD) was also performed for 140 ns to explore the stability behavior of the main targets and inhibitor complexes as well as the binding mechanics of the ligand to the target proteins. The obtained MD results followed by absolute binding energy calculation confirm that the binding of emetine at the level of the various receptors is more stable. The complex EmetineNSP15, mechanistically was stabilized as follows: Emetine first binds to the monomer, after, binds to the second inducing the formation of a dimer which in turn leading to the formation of complex that simulation stabilizes it at a value less than 5 Å. Overall, supported by the powerful and good pharmacokinetic data of Emetine, our findings with clinical trials may be helpful to confirm that Emetine could be promoted in the prevention and eradication of COVID-19 by reducing the severity in the infected persons and therefore can open possible new strategies for drug repositioning. Communicated by Ramaswamy H. Sarma.

PMID:34254564 | DOI:10.1080/07391102.2021.1946715

Eur Heart J. 2021 Jul 13:ehab427. doi: 10.1093/eurheartj/ehab427. Online ahead of print.

NO ABSTRACT

PMID:34254122 | DOI:10.1093/eurheartj/ehab427

J Pharmacol Exp Ther. 2021 Jul 12:JPET-AR-2021-000619. doi: 10.1124/jpet.121.000619. Online ahead of print.

ABSTRACT

In the wake of the COVID-19 pandemic, drug repurposing has been highlighted for rapid introduction of therapeutics. Proposed drugs with activity against SARS-CoV-2 include compounds with positive charges at physiological pH, making them potential targets for the organic cation (OC) secretory transporters of kidney and liver, i.e., the basolateral Organic Cation Transporters, OCT1 and OCT2; and the apical Multidrug And Toxin Extruders, MATE1 and MATE2-K. We selected several compounds proposed to have in vitro activity against SARS-CoV-2 (chloroquine, hydroxychloroquine, quinacrine, tilorone, pyronaridine, cetylpyridinium and miramistin), to test their interaction with OCT and MATE transporters. We used Bayesian Machine learning models to generate predictions for each molecule with each transporter and also experimentally determined IC50 values for each compound against labelled substrate transport into CHO cells that stably expressed OCT2, MATE1 or MATE2-K using three structurally distinct substrates (atenolol, metformin and 1-methyl-4-phenylpyridinium (MPP)) to assess the impact of substrate structure on inhibitory efficacy. For the OCTs substrate identity influenced IC50 values, though the effect was larger and more systematic for OCT2. In contrast, inhibition of MATE1-mediated transport was largely insensitive to substrate identity. Unlike MATE1, inhibition of MATE2-K was influenced, albeit modestly, by substrate identity. Cu,max/IC50 ratios were used to identify potential clinical DDI recommendations; all the compounds interacted with the OCT/MATE secretory pathway, most with sufficient avidity to represent potential DDI issues for secretion of cationic drugs. This should be considered when proposing cationic agents as repurposed antivirals. Significance Statement Drugs proposed as potential COVID-19 therapeutics based on in vitro activity data against SARS-CoV-2 include compounds with positive charges at physiological pH, making them potential interactors with the OCT/MATE renal secretory pathway. We tested seven such molecules as inhibitors of OCT1/2 and MATE1/2-K. All the compounds blocked transport activity regardless of substrate used to monitor activity. Suggesting that plasma concentrations achieved by normal clinical application of the test agents could be expected to influence the pharmacokinetics of selected cationic drugs.

PMID:34253645 | DOI:10.1124/jpet.121.000619

Curr Pharm Biotechnol. 2021 Jul 9. doi: 10.2174/1389201022666210709141320. Online ahead of print.

ABSTRACT

In order to curve the ongoing trend of the COVID-19 pandemic and save more lives, effective treatments against COVID-19 are urgently needed. Comparing to developing new drugs, which may take too much time, it's more efficient and cost-effective to repurpose existing drugs in the treatment of COVID-19. Fortunately, some of the shared features of COVID-19 and other well-known diseases make it possible to use old strategies to combat this new challenge. In this paper, we reviewed various possible strategies of drug repurposing in the treatment of COVID-19 and explored the possible scientific mechanisms behind each strategy.

PMID:34250872 | DOI:10.2174/1389201022666210709141320

Front Oncol. 2021 Jun 24;11:665276. doi: 10.3389/fonc.2021.665276. eCollection 2021.

ABSTRACT

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer, with high incidence and mortality. To improve the curative effect and prolong the survival of patients, it is necessary to find new biomarkers to accurately predict the prognosis of patients and explore new strategy to treat high-risk LUAD.

METHODS: A comprehensive genome-wide profiling analysis was conducted using a retrospective pool of LUAD patient data from the previous datasets of Gene Expression Omnibus (GEO) including GSE18842, GSE19188, GSE40791 and GSE50081 and The Cancer Genome Atlas (TCGA). Differential gene analysis and Cox proportional hazard model were used to identify differentially expressed genes with survival significance as candidate prognostic genes. The Kaplan-Meier with log-rank test was used to assess survival difference. A risk score model was developed and validated using TCGA-LUAD and GSE50081. Additionally, The Connectivity Map (CMAP) was used to predict drugs for the treatment of LUAD. The anti-cancer effect and mechanism of its candidate drugs were studied in LUAD cell lines.

RESULTS: We identified a 5-gene signature (KIF20A, KLF4, KRT6A, LIFR and RGS13). Risk Score (RS) based on 5-gene signature was significantly associated with overall survival (OS). Nomogram combining RS with clinical pathology parameters could potently predict the prognosis of patients with LUAD. Moreover, gliclazide was identified as a candidate drug for the treatment of high-RS LUAD. Finally, gliclazide was shown to induce cell cycle arrest and apoptosis in LUAD cells possibly by targeting CCNB1, CCNB2, CDK1 and AURKA.

CONCLUSION: This study identified a 5-gene signature that can predict the prognosis of patients with LUAD, and Gliclazide as a potential therapeutic drug for LUAD. It provides a new direction for the prognosis and treatment of patients with LUAD.

PMID:34249701 | PMC:PMC8264429 | DOI:10.3389/fonc.2021.665276

Front Immunol. 2021 Jun 24;12:665785. doi: 10.3389/fimmu.2021.665785. eCollection 2021.

ABSTRACT

Tuberculosis (TB) remains a challenging global health concern and claims more than a million lives every year. We lack an effective vaccine and understanding of what constitutes protective immunity against TB to inform rational vaccine design. Moreover, treatment of TB requires prolonged use of multi-drug regimens and is complicated by problems of compliance and drug resistance. While most Mycobacterium tuberculosis (Mtb) bacilli are quickly killed by the drugs, the prolonged course of treatment is required to clear persistent drug-tolerant subpopulations. Mtb's differential sensitivity to drugs is, at least in part, determined by the interaction between the bacilli and different host macrophage populations. Therefore, to design better treatment regimens for TB, we need to understand and modulate the heterogeneity and divergent responses that Mtb bacilli exhibit within macrophages. However, developing drugs de-novo is a long and expensive process. An alternative approach to expedite the development of new TB treatments is to repurpose existing drugs that were developed for other therapeutic purposes if they also possess anti-tuberculosis activity. There is growing interest in the use of immune modulators to supplement current anti-TB drugs by enhancing the host's antimycobacterial responses. Ion channel blocking agents are among the most promising of the host-directed therapeutics. Some ion channel blockers also interfere with the activity of mycobacterial efflux pumps. In this review, we discuss some of the ion channel blockers that have shown promise as potential anti-TB agents.

PMID:34248944 | PMC:PMC8264357 | DOI:10.3389/fimmu.2021.665785

Front Immunol. 2021 Jun 24;12:648250. doi: 10.3389/fimmu.2021.648250. eCollection 2021.

ABSTRACT

BACKGROUND: The newly identified betacoronavirus SARS-CoV-2 is the causative pathogen of the coronavirus disease of 2019 (COVID-19) that killed more than 3.5 million people till now. The cytokine storm induced in severe COVID-19 patients causes hyper-inflammation, is the primary reason for respiratory and multi-organ failure and fatality. This work uses a rational computational strategy to identify the existing drug molecules to target host pathways to reduce the cytokine storm.

RESULTS: We used a "host response signature network" consist of 36 genes induced by SARS-CoV-2 infection and associated with cytokine storm. In order to attenuate the cytokine storm, potential drug molecules were searched against "host response signature network". Our study identified that drug molecule andrographolide, naturally present in a medicinal plant Andrographis paniculata, has the potential to bind with crucial proteins to block the TNF-induced NFkB1 signaling pathway responsible for cytokine storm in COVID-19 patients. The molecular docking method showed the binding of andrographolide with TNF and covalent binding with NFkB1 proteins of the TNF signaling pathway.

CONCLUSION: We used a rational computational approach to repurpose existing drugs targeting host immunomodulating pathways. Our study suggests that andrographolide could bind with TNF and NFkB1 proteins, block TNF-induced cytokine storm in COVID-19 patients, and warrant further experimental validation.

PMID:34248936 | PMC:PMC8264290 | DOI:10.3389/fimmu.2021.648250

Front Pharmacol. 2021 Jun 24;12:603997. doi: 10.3389/fphar.2021.603997. eCollection 2021.

NO ABSTRACT

PMID:34248612 | PMC:PMC8265778 | DOI:10.3389/fphar.2021.603997

Bioinform Biol Insights. 2021 Jun 24;15:11779322211027403. doi: 10.1177/11779322211027403. eCollection 2021.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has increased the importance of computational tools to design a drug or vaccine in reduced time with minimum risk. Earlier studies have emphasized the important role of RNA-dependent RNA polymerase (RdRp) in SARS-CoV-2 replication as a potential drug target. In our study, comprehensive computational approaches were applied to identify potential compounds targeting RdRp of SARS-CoV-2. To study the binding affinity and stability of the phytocompounds from Phyllanthus emblica and Aegel marmelos within the defined binding site of SARS-CoV-2 RdRp, they were subjected to molecular docking, 100 ns molecular dynamics (MD) simulation followed by post-simulation analysis. Furthermore, to assess the importance of features involved in the strong binding affinity, molecular field-based similarity analysis was performed. Based on comparative molecular docking and simulation studies of the selected phytocompounds with SARS-CoV-2 RdRp revealed that EBDGp possesses a stronger binding affinity (-23.32 kcal/mol) and stability than other phytocompounds and reference compound, Remdesivir (-19.36 kcal/mol). Molecular field-based similarity profiling has supported our study in the validation of the importance of the presence of hydroxyl groups in EBDGp, involved in increasing its binding affinity toward SARS-CoV-2 RdRp. Molecular docking and dynamic simulation results confirmed that EBDGp has better inhibitory potential than Remdesivir and can be an effective novel drug for SARS-CoV-2 RdRp. Furthermore, binding free energy calculations confirmed the higher stability of the SARS-CoV-2 RdRp-EBDGp complex. These results suggest that the EBDGp compound may emerge as a promising drug against SARS-CoV-2 and hence requires further experimental validation.

PMID:34248355 | PMC:PMC8236766 | DOI:10.1177/11779322211027403

Drug Discov Today. 2021 Jul 7:S1359-6446(21)00308-1. doi: 10.1016/j.drudis.2021.07.002. Online ahead of print.

ABSTRACT

Over the past few decades, the number of health and 'omics-related data generated and stored has grown exponentially. Patient information can be collected in real time and explored using various artificial intelligence (AI) tools in clinical trials; mobile devices can also be used to improve aspects of both the diagnosis and treatment of diseases. In addition, AI can be used in the development of new drugs or for drug repurposing, in the faster diagnosis and more efficient treatment of various diseases, as well as to design data-driven hypotheses for scientists. In this review, we discuss how AI is starting to revolutionize the life sciences sector.

PMID:34245910 | DOI:10.1016/j.drudis.2021.07.002

Brief Bioinform. 2021 Jul 9:bbab249. doi: 10.1093/bib/bbab249. Online ahead of print.

ABSTRACT

The global efforts in the past year have led to the discovery of nearly 200 drug repurposing candidates for COVID-19. Gaining more insights into their mechanisms of action could facilitate a better understanding of infection and the development of therapeutics. Leveraging large-scale drug-induced gene expression profiles, we found 36% of the active compounds regulate genes related to cholesterol homeostasis and microtubule cytoskeleton organization. Following bioinformatics analyses revealed that the expression of these genes is associated with COVID-19 patient severity and has predictive power on anti-SARS-CoV-2 efficacy in vitro. Monensin, a top new compound that regulates these genes, was further confirmed as an inhibitor of SARS-CoV-2 replication in Vero-E6 cells. Interestingly, drugs co-targeting cholesterol homeostasis and microtubule cytoskeleton organization processes more likely present a synergistic effect with antivirals. Therefore, potential therapeutics could be centered around combinations of targeting these processes and viral proteins.

PMID:34245241 | DOI:10.1093/bib/bbab249

Proteins. 2021 Jul 10. doi: 10.1002/prot.26176. Online ahead of print.

ABSTRACT

The expansion of three-dimensional protein structures and enhanced computing power have significantly facilitated our understanding of protein sequence/structure/function relationships. A challenge in structural genomics is to predict the function of uncharacterized proteins. Protein function deconvolution based on global sequence or structural homology is impracticable when a protein relates to no other proteins with known function, and in such cases, functional relationships can be established by detecting their local ligand binding site similarity. Here, we introduce a sequence order-independent comparison algorithm, PocketShape, for structural proteome-wide exploration of protein functional site by fully considering the geometry of the backbones, orientation of the sidechains and physiochemical properties of the pocket-lining residues. PocketShape is efficient in distinguishing similar from dissimilar ligand binding site pairs by retrieving 99.3% of the similar pairs while rejecting 100% of the dissimilar pairs on a dataset containing 1538 binding site pairs. This method successfully classifies 83 enzyme structures with diverse functions into 12 clusters, which is highly in accordance with the actual SCOP classification. PocketShape also achieves superior performances than other methods in protein profiling based on experimental data. Potential new applications for representative SARS-CoV-2 drugs Remdesivir and 11a are predicted. The high accuracy and time-efficient characteristics of PocketShape will undoubtedly make it a promising complementary tool for proteome-wide protein function inference and drug repurposing study. This article is protected by copyright. All rights reserved.

PMID:34245187 | DOI:10.1002/prot.26176