Biotechnol J. 2021 Oct 17:e2100417. doi: 10.1002/biot.202100417. Online ahead of print.

ABSTRACT

The use of anticancer peptides (ACPs) as an alternative/complementary strategy to conventional chemotherapy treatments has been shown to decrease drug resistance and/or severe side effects. However, the efficacy of the positively-charged ACP is inhibited by elevated levels of negatively-charged cell-surface components which trap the peptides and prevent their contact with the cell membrane. Consequently, this decreases ACP-mediated membrane pore formation and cell lysis. Negatively-charged heparan sulphate (HS) and chondroitin sulphate (CS) have been shown to inhibit the cytotoxic effect of ACPs. In this study, we propose a strategy to promote the broad utilization of ACPs. In this context, we developed a drug repositioning pipeline to analyse transcriptomics data generated for four different cancer cell lines (A549, HEPG2, HT29, and MCF7) treated with hundreds of drugs in the LINCS L1000 project. Based on previous studies identifying genes modulating levels of the glycosaminoglycans (GAGs) HS and CS at the cell surface, our analysis aimed at identifying drugs inhibiting genes correlated with high HS and CS levels. As a result, we identified six chemicals as likely repositionable drugs with the potential to enhance the performance of ACPs. The codes in R and Python programming languages are publicly available in https://github.com/ElyasMo/ACPs_HS_HSPGs_CS. As a conclusion, these six drugs are highlighted as excellent targets for synergistic studies with ACPs aimed at lowering the costs associated with ACP-treatment. This article is protected by copyright. All rights reserved.

PMID:34657375 | DOI:10.1002/biot.202100417

EBioMedicine. 2021 Oct 13;72:103629. doi: 10.1016/j.ebiom.2021.103629. Online ahead of print.

ABSTRACT

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) poses an unprecedented challenge to humanity. SARS-CoV-2 infections range from asymptomatic to severe courses of COVID-19 with acute respiratory distress syndrome (ARDS), multiorgan involvement and death. Risk factors for disease severity include older age, male sex, increased BMI and pre-existing comorbidities. Ethnicity is also relevant to COVID-19 susceptibility and severity. Host genetic predisposition to COVID-19 is now increasingly recognized and whole genome and candidate gene association studies regarding COVID-19 susceptibility have been performed. Several common and rare variants in genes related to inflammation or immune responses have been identified. We summarize research on COVID-19 host genetics and compile genetic variants associated with susceptibility to COVID-19 and disease severity. We discuss candidate genes that should be investigated further to understand such associations and provide insights relevant to pathogenesis, risk classification, therapy response, precision medicine, and drug repurposing.

PMID:34655949 | DOI:10.1016/j.ebiom.2021.103629

Biomed Pharmacother. 2021 Oct 12;144:112274. doi: 10.1016/j.biopha.2021.112274. Online ahead of print.

ABSTRACT

Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells, including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen receptor-alpha (ERα)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed at investigating the endocrine and immune activity of these SERMs in macrophages. Using primary cultures of female mouse macrophages, we analyzed the expression of immune mediators and activation of effector functions in competition experiments with SERMs and 17β-estradiol (E2) or the bacterial endotoxin LPS. We observed that 4HT and TAM induce estrogen antagonist effects when used at nanomolar concentrations, while pharmacological concentrations that are reached by TAM in clinical settings regulate the expression of VEGFα and other immune activation genes by ERα- and G protein-coupled receptor 1 (GPER1)-independent mechanisms that involve NRF2 through PI3K/Akt-dependent mechanisms. Importantly, we observed that SERMs potentiate cell phagocytosis and modify the effects of LPS on the expression of inflammatory cytokines, such as TNFα and IL1β, with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1β secretion through caspase-1 activation. Altogether, our data unravel a novel molecular mechanism and immune functions for TAM and 4HT, sustaining their repurposing in infective and other estrogen receptors-unrelated pathologies.

PMID:34653752 | DOI:10.1016/j.biopha.2021.112274

Eur J Pharmacol. 2021 Oct 12:174569. doi: 10.1016/j.ejphar.2021.174569. Online ahead of print.

ABSTRACT

Drug repurposing or studying existing drugs for potential therapeutic utility in newer indications has been identified as an attractive option for treating a number of diseases. Various strategies of drug repurposing include serendipitous observation of drug's unexpected effects, directing the failed investigational drugs to new indications and currently adopted systematic approach to identify, screen and develop existing drug molecules for new off-label indications. Drug repurposing is able to constructively overcome the bottleneck restraints encountered during traditional de novo drug development process in grounds of timelines, cost and resources. However, success rates of drug repurposing programs are not very impressive. Through a meticulous examination of some failed repurposing attempts we aimed to identify key factors leading to high attrition rate in such studies. Based on the fundamental elements of knowledge and evaluation, we have defined four pillars toward improving success rate in drug repurposing programs viz. sound knowledge of the repurposed drug's pharmacological characteristics (pillar 1: drug pharmacology); drug formulation considerations in new indication (pillar 2: drug formulation); evaluation in representative biological assays with translational potential (pillar 3: evaluation in biological assays); and robust clinical trial methodologies including biomarker driven approach to provide conclusive evidence of repurposed drug's efficacy in new indication (pillar 4: clinical evaluation). In addition to the pharmacological challenges, certain regulatory concerns, including lack of clear guidelines for evaluation and market exclusivity pose hurdles in the application of drug repurposing, which may however be overcome to a great extent by adopting some strategies as discussed in this review.

PMID:34653378 | DOI:10.1016/j.ejphar.2021.174569

Per Med. 2021 Oct 15. doi: 10.2217/pme-2021-0077. Online ahead of print.

ABSTRACT

SARS-CoV-2, a recently emerged zoonotic virus, has resulted in unstoppable high morbidity and mortality rates worldwide. However, due to a limited knowledge of the dynamics of the SARS-CoV-2 infection, it has been observed that the current COVID-2019 therapy has led to some clinical repercussions. We discuss the adverse effects of drugs for COVID-2019 primarily based on some clinical trials. As therapeutic efficacy and toxicity of therapy may vary due to different, genetic determinants, sex, age and the ethnic background of test subjects, hence biomarker-based personalized therapy could be more appropriate. We will share our thoughts on the current landscape of personalized therapy as a roadmap to fight against SARS-CoV-2 or another emerging pathogen.

PMID:34649460 | DOI:10.2217/pme-2021-0077

Curr Opin Struct Biol. 2021 Oct 11;72:114-126. doi: 10.1016/j.sbi.2021.09.003. Online ahead of print.

ABSTRACT

Drug discovery is the process of new drug identification. This process is driven by the increasing data from existing chemical libraries and data banks. The knowledge graph is introduced to the domain of drug discovery for imposing an explicit structure to integrate heterogeneous biomedical data. The graph can provide structured relations among multiple entities and unstructured semantic relations associated with entities. In this review, we summarize knowledge graph-based works that implement drug repurposing and adverse drug reaction prediction for drug discovery. As knowledge representation learning is a common way to explore knowledge graphs for prediction problems, we introduce several representative embedding models to provide a comprehensive understanding of knowledge representation learning.

PMID:34649044 | DOI:10.1016/j.sbi.2021.09.003

J Thorac Oncol. 2021 Oct 11:S1556-0864(21)03205-6. doi: 10.1016/j.jtho.2021.09.008. Online ahead of print.

ABSTRACT

INTRODUCTION: Mutations in BRAF occur in 2-4% of lung adenocarcinoma (LUAD) patients. Combination dabrafenib/trametinib or single-agent vemurafenib is approved only for patients with cancers driven by the V600E BRAF mutation. Targeted therapy is not currently available for patients harboring non-V600 BRAF mutations.

METHODS: An LUAD patient-derived xenograft (PDX) model (PHLC12) with wild-type and non-amplified epidermal growth factor receptor (EGFR) was tested for response to EGFR tyrosine kinase inhibitors (TKI). A cell line derived from this model (X12CL) was also used to evaluate drug sensitivity and to identify potential drivers by siRNA knockdown. Kinase assays were used to test direct targeting of the candidate driver by the EGFR TKIs. Structural modeling including, molecular dynamics (MD) simulations, and binding assays were conducted to explore the mechanism of off-target inhibition by EGFR TKIs on the model 12 driver.

RESULTS: Both PDX PHLC12 and the X12CL cell line were sensitive to multiple EGFR TKIs. The BRAFG469V mutation was found to be the only known oncogenic mutation in this model. siRNA knockdown of BRAF, but not the EGFR, killed X12CL, confirming BRAFG469V as the oncogenic driver. Kinase activity of the BRAF protein isolated from X12CL was inhibited by treatment with the EGFR TKIs gefitinib and osimertinib, and expression of BRAFG469V in non-EGFR-expressing NR6 cells promoted growth in low serum, which was also sensitive to EGFR TKIs. . Structural modeling, MD simulations, and in vitro binding assays support BRAFG469V being a direct target of the TKIs.

CONCLUSION: Clinically approved EGFR TKIs can be repurposed to treat NSCLC patients harboring the BRAFG469V mutation.

PMID:34648945 | DOI:10.1016/j.jtho.2021.09.008

Klin Mikrobiol Infekc Lek. 2020 Dec;26(4):138-139.

ABSTRACT

Antibiotics are considered to be one of the most important discoveries of medicine, which has significantly affected the mortality due to infectious diseases. Given their increasing use, certain problems arise over time, resulting from non-indicated and inadequate - administration of antibiotics. This results in increasing antibiotic resistance as well as a higher risk of side/adverse effects. Recently, these side effects of drugs have been used for indications other than those originally intended and approved. Such a process is called drug repositioning. Due to the recent increase in the cost of developing novel drugs and the high risk of failure in clinical trials, the pharmaceutical industry is trying to find new indications for existing drugs.

PMID:34648651

Curr Mol Pharmacol. 2021 Oct 13. doi: 10.2174/1874467214666211013122528. Online ahead of print.

ABSTRACT

BACKGROUND: The currently circulating novel SARS-CoV-2 coronavirus disease (COVID-19) has brought the whole world to a standstill. Recent studies have deciphered the viral genome structure, epidemiology and are in the process of unveiling multiple mechanisms of pathogenesis. Apart from atypical pneumonia and lung disease manifestations, this disease has also been found to be associated with neurological symptoms, which include dizziness, headache, stroke, or seizures, among others. However, a possible direct or indirect association between SARS-CoV-2 and seizures is still not clear. In any manner, it may be of interest to analyze the drugs being used for viral infection in the background of epilepsy or vice versa.

OBJECTIVE: To identify the most credible drug candidate for COVID-19 in persons with epilepsy or COVID-19 patients experiencing seizures.

METHODS: A literature search for original and review articles was performed, and further, the Comparative Toxicogenomics Database was used to unearth the most credible drug candidate.

RESULTS: Our search based on common mechanistic targets affecting SARS-CoV-2 and seizures revealed ivermectin, dexamethasone, anakinra, and tocilizumab for protection against both COVID-19 and seizures. Amongst the antiseizure medications, we found valproic acid as the most probable pharmacotherapy for COVID-19 patients experiencing seizures.

CONCLUSION: These findings would hopefully provide the basis for initiating further studies on the pathogenesis and drug targeting strategies for this emerging infection accompanied with seizures or in people with epilepsy.

PMID:34645381 | DOI:10.2174/1874467214666211013122528

Curr Mol Med. 2021 Oct 13. doi: 10.2174/1566524021666211013121831. Online ahead of print.

ABSTRACT

The coronavirus disease emerged in December 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome-related coronavirus 2 (SARS-CoV-2) and its rapid global spread has brought an international health emergency and urgent responses for seeking efficient prevention and therapeutic treatment. This has led to imperative needs for illustration of the molecular pathogenesis of SARS-CoV-2, identification of molecular targets or receptors, and development of antiviral drugs, antibodies, and vaccines. In this study, we investigated the current research progress in combating SARS-CoV-2 infection. Based on the published research findings, we first elucidated, at the molecular level, SARS-CoV-2 viral structures, potential viral host-cell-invasion and pathogenic mechanisms, main virus-induced immune responses, and emerging SARS-CoV-2 variants. We then focused on the main virus- and host-based potential targets, summarized and categorized effective inhibitory molecules based on drug development strategies for COVID-19, that can guide efforts for the identification of new drugs and treatment for this problematic disease. Current research and development of antibodies and vaccines were also introduced and discussed. We concluded that the main virus entry route- SARS-CoV-2 spike protein interaction with ACE2 receptors has played a key role in guiding the development of therapeutic treatments against COVID-19, four main therapeutic strategies may be considered in developing molecular therapeutics, and drug repurposing is likely to be an easy, fast and low-cost approach in such a short period of time with urgent need of antiviral drugs. Additionally, the quick development of antibody and vaccine candidates has yielded promising results, but the wide-scale deployment of safe and effective COVID-19 vaccines remains paramount in solving the pandemic crisis. As new variants of the virus begun to emerge, the efficacy of these vaccines and treatments must be closely evaluated. Finally, we discussed the possible challenges of developing molecular therapeutics for COVID-19 and suggested some potential future efforts. Despite the limited availability of literatures, our attempt in this work to provide a relatively comprehensive overview of current SARS-CoV-2 studies can be helpful for quickly acquiring the key information of COVID-19 and further promoting this important research to control and diminish the pandemic.

PMID:34645374 | DOI:10.2174/1566524021666211013121831

Sao Paulo Med J. 2021 Oct 11:S1516-31802021005024204. doi: 10.1590/1516-3180.2021.0120.R1.30062021. Online ahead of print.

ABSTRACT

BACKGROUND: Considering the disruptions imposed by lockdowns and social distancing recommendations, coupled with overwhelmed healthcare systems, researchers worldwide have been exploring drug repositioning strategies for treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

OBJECTIVE: To compile results from randomized clinical trials on the effect of dexamethasone, compared with standard treatment for management of SARS-CoV-2.

DESIGN AND SETTING: We conducted a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in a Brazilian public university.

METHODS: We sought to compile data from 6724 hospitalized patients with confirmed or suspected SARS-CoV-2 infection.

RESULTS: Treatment with dexamethasone significantly reduced mortality within 28 days (risk ratio, RR: 0.89; 95% confidence interval, CI: 0.82-0.97). Dexamethasone use was linked with being discharged alive within 28 days (odds ratio, OR: 1.20; 95% CI: 1.07-1.33).

CONCLUSIONS: This study suggests that dexamethasone may significantly improve the outcome among hospitalized patients with SARS-CoV-2 infection and associated severe respiratory complications. -Further studies need to consider both dose-dependent administration and outcomes in early and later stages of the disease.

PROSPERO PLATFORM: CRD42021229825.

PMID:34644768 | DOI:10.1590/1516-3180.2021.0120.R1.30062021

Parasitol Res. 2021 Oct 13. doi: 10.1007/s00436-021-07307-4. Online ahead of print.

ABSTRACT

Twenty diseases are recognized as neglected tropical diseases (NTDs) by World Health Assembly resolutions, including human filarial diseases. The end of NTDs is embedded within the Sustainable Development Goals for 2030, under target 3.3. Onchocerciasis afflicts approximately 20.9 million people worldwide with > 90% of those infected residing in Africa. Control programs have made tremendous efforts in the management of onchocerciasis by mass drug administration and aerial larviciding; however, disease elimination is not yet achieved. In the new WHO roadmap, it is recognized that new drugs or drug regimens that kill or permanently sterilize adult filarial worms would significantly improve elimination timelines and accelerate the achievement of the program goal of disease elimination. Drug development is, however, handicapped by high attrition rates, and many promising molecules fail in preclinical development or in subsequent toxicological, safety and efficacy testing; thus, research and development (R&D) costs are, in aggregate, very high. Drug discovery and development for NTDs is largely driven by unmet medical needs put forward by the global health community; the area is underfunded and since no high return on investment is possible, there is no dedicated drug development pipeline for human filariasis. Repurposing existing drugs is one approach to filling the drug development pipeline for human filariasis. The high cost and slow pace of discovery and development of new drugs has led to the repurposing of "old" drugs, as this is more cost-effective and allows development timelines to be shortened. However, even if a drug is marketed for a human or veterinary indication, the safety margin and dosing regimen will need to be re-evaluated to determine the risk in humans. Drug repurposing is a promising approach to enlarging the pool of active molecules in the drug development pipeline. Another consideration when providing new treatment options is the use of combinations, which is not addressed in this review. We here summarize recent advances in the late preclinical or early clinical stage in the search for a potent macrofilaricide, including drugs against the nematode and against its endosymbiont, Wolbachia pipientis.

PMID:34642800 | DOI:10.1007/s00436-021-07307-4

J Neurogastroenterol Motil. 2021 Oct 30;27(4):639-649. doi: 10.5056/jnm21018.

ABSTRACT

BACKGROUND/AIMS: The aim of this study is to identify the alteration in intestinal permeability with regard to the development of post-operative ileus (POI). Moreover, we investigated drug repositioning in the treatment of POI.

METHODS: An experimental POI model was developed using guinea pigs. To measure intestinal permeability, harvested intestinal membranes of the ileum and proximal colon was used in an Ussing chamber. To identify the mechanisms associated with altered permeability, we measured leukocyte count and expression of calprotectin, claudin-1, claudin-2, and mast cell tryptase. We compared control, POI, and drug groups (mosapride [0.3 mg/kg and 1 mg/kg, orally], glutamine [500 mg/kg, orally], or ketotifen [1 mg/kg, orally] with regard to these parameters.

RESULTS: Increased permeability after surgery significantly decreased after administration of mosapride, glutamine, or ketotifen. Leukocyte counts increased in the POI group and decreased significantly after administration of mosapride (0.3 mg/kg) in the ileum, and mosapride (0.3 mg/kg and 1 mg/kg), glutamine, or ketotifen in the proximal colon. Increased expression of calprotectin after surgery decreased after administration of mosapride (0.3 mg/kg), glutamine, or ketotifen in the ileum and proximal colon, and mosapride (1 mg/kg) in the ileum. The expression of claudin-1 decreased significantly and that of claudin-2 increased after operation. After administration of glutamine, the expression of both proteins was restored. Finally, mast cell tryptase levels increased in the POI group and decreased significantly after administration of ketotifen.

CONCLUSIONS: The alteration in intestinal permeability is one of the factors involved in the pathogenesis of POI. We repositioned 3 drugs (mosapride, glutamine, and ketotifen) as novel therapeutic agents for POI.

PMID:34642285 | DOI:10.5056/jnm21018

Int J Environ Res Public Health. 2021 Oct 4;18(19):10447. doi: 10.3390/ijerph181910447.

ABSTRACT

Off-label use of drugs is widely known as unapproved use of approved drugs, and it can be perceived as a relatively simple concept. Even though it has been in existence for many years, prescribing and dispensing of drugs in an off-label regimen is still a current issue, triggered especially by unmet clinical needs. Several therapeutic areas require off-label approaches; therefore, this practice is challenging for prescribing physicians. Meanwhile, the regulatory agencies are making efforts in order to ensure a safe practice. The present paper defines the off-label concept, and it describes its regulation, together with several complex aspects associated with clinical practices regarding rare diseases, oncology, pediatrics, psychiatry therapeutic areas, and the safety issues that arise. A systematic research of the literature was performed, using terms, such as "off-label", "prevalence", "rare diseases", "oncology", "psychiatry", "pediatrics", and "drug repurposing". There are several reasons for which off-label practice remains indispensable in the present; therefore, efforts are made worldwide, by the regulatory agencies and governmental bodies, to raise awareness and to ensure safe practice, while also encouraging further research.

PMID:34639747 | DOI:10.3390/ijerph181910447

Int J Mol Sci. 2021 Oct 2;22(19):10693. doi: 10.3390/ijms221910693.

ABSTRACT

Considering the current dramatic and fatal situation due to the high spreading of SARS-CoV-2 infection, there is an urgent unmet medical need to identify novel and effective approaches for prevention and treatment of Coronavirus disease (COVID 19) by re-evaluating and repurposing of known drugs. For this, tomatidine and patchouli alcohol have been selected as potential drugs for combating the virus. The hit compounds were subsequently docked into the active site and molecular docking analyses revealed that both drugs can bind the active site of SARS-CoV-2 3CLpro, PLpro, NSP15, COX-2 and PLA2 targets with a number of important binding interactions. To further validate the interactions of promising compound tomatidine, Molecular dynamics study of 100 ns was carried out towards 3CLpro, NSP15 and COX-2. This indicated that the protein-ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. Post dynamic MM-GBSA analysis of molecular dynamics data showed promising mean binding free energy 47.4633 ± 9.28, 51.8064 ± 8.91 and 54.8918 ± 7.55 kcal/mol, respectively. Likewise, in silico ADMET studies of the selected ligands showed excellent pharmacokinetic properties with good absorption, bioavailability and devoid of toxicity. Therefore, patchouli alcohol and especially, tomatidine may provide prospect treatment options against SARS-CoV-2 infection by potentially inhibiting virus duplication though more research is guaranteed and secured.

PMID:34639036 | DOI:10.3390/ijms221910693

Int J Mol Sci. 2021 Sep 22;22(19):10204. doi: 10.3390/ijms221910204.

ABSTRACT

Sepsis is the leading cause of death in intensive care units worldwide. Current treatments of sepsis are largely supportive and clinical trials using specific pharmacotherapy for sepsis have failed to improve outcomes. Here, we used the lipopolysaccharide (LPS)-stimulated mouse RAW264.7 cell line and AlphaLisa assay for TNFa as a readout to perform a supervised drug repurposing screen for sepsis treatment with compounds targeting epigenetic enzymes, including kinases. We identified the SCH772984 compound, an extracellular signal-regulated kinase (ERK) 1/2 inhibitor, as an effective blocker of TNFa production in vitro. RNA-Seq of the SCH772984-treated RAW264.7 cells at 1, 4, and 24 h time points of LPS challenge followed by functional annotation of differentially expressed genes highlighted the suppression of cellular pathways related to the immune system. SCH772984 treatment improved survival in the LPS-induced lethal endotoxemia and cecal ligation and puncture (CLP) mouse models of sepsis, and reduced plasma levels of Ccl2/Mcp1. Functional analyses of RNA-seq datasets for kidney, lung, liver, and heart tissues from SCH772984-treated animals collected at 6 h and 12 h post-CLP revealed a significant downregulation of pathways related to the immune response and platelets activation but upregulation of the extracellular matrix organization and retinoic acid signaling pathways. Thus, this study defined transcriptome signatures of SCH772984 action in vitro and in vivo, an agent that has the potential to improve sepsis outcome.

PMID:34638546 | DOI:10.3390/ijms221910204

Mol Divers. 2021 Oct 12. doi: 10.1007/s11030-021-10330-3. Online ahead of print.

ABSTRACT

Blocking the main replicating enzyme, 3 Chymotrypsin-like protease (3CLpro) is the most promising drug development strategy against the SARS-CoV-2 virus, responsible for the current COVID-19 pandemic. In the present work, 9101 drugs obtained from the drug bank database were screened against SARS-CoV-2 3CLpro prosing deep learning, molecular docking, and molecular dynamics simulation techniques. In the initial stage, 500 drug-screened by deep learning regression model and subjected to molecular docking that resulted in 10 screened compounds with strong binding affinity. Further, five compounds were checked for their binding potential by analyzing molecular dynamics simulation for 100 ns at 300 K. In the final stage, two compounds {4-[(2s,4e)-2-(1,3-Benzothiazol-2-Yl)-2-(1h-1,2,3-Benzotriazol-1-Yl)-5-Phenylpent-4-Enyl]Phenyl}(Difluoro)Methylphosphonic Acid and 1-(3-(2,4-dimethylthiazol-5-yl)-4-oxo-2,4-dihydroindeno[1,2-c]pyrazol-5-yl)-3-(4-methylpiperazin-1-yl)urea were screened as potential hits by analyzing several parameters like RMSD, Rg, RMSF, MMPBSA, and SASA. Thus, our study suggests two potential drugs that can be tested in the experimental conditions to evaluate the efficacy against SARS-CoV-2. Further, such drugs could be modified to develop more potent drugs against COVID-19.

PMID:34637068 | DOI:10.1007/s11030-021-10330-3

Curr Top Med Chem. 2021 Oct 12. doi: 10.2174/1568026621666211012110819. Online ahead of print.

ABSTRACT

Respiratory viruses continue to afflict mankind. Among them, pathogens such as coronaviruses [including the current pandemic agent known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] and the one causing influenza A (IAV) are highly contagious and deadly. These can evade the immune system defenses while causing a hyperinflammatory response that can damage different tissues/organs. Simultaneously targeting immunomodulatory proteins is a plausible antiviral strategy since it could lead to the discovery of indirect-acting pan-antiviral (IAPA) agents for the treatment of diseases caused by respiratory viruses. In this context, computational approaches, which are an essential part of the modern drug discovery campaigns, could accelerate the identification of multi-target immunomodulators. This perspective discusses the usefulness of computational multi-target drug discovery for the virtual screening (drug repurposing) of IAPA agents capable of boosting the immune system through the activation of the toll-like receptor 7 (TLR7) and/or the stimulator of interferon genes (STING) while inhibiting key pro-inflammatory proteins, such as caspase-1 and tumor necrosis factor-alpha (TNF-α).

PMID:34636311 | DOI:10.2174/1568026621666211012110819

In Silico Pharmacol. 2021 Sep 29;9(1):53. doi: 10.1007/s40203-021-00112-y. eCollection 2021.

ABSTRACT

Notch receptors play a significant role in the development and the regulation of cell-fate in several multicellular organisms. For normal differentiation, genomes are essential as their regular roles and play a role in cancer is dysregulated. Notch 3 has been shown to play a major role in lung cancer function and therefore, inhibition of notch 3 protein activation represents a clear plan for cancer treatment. This study accomplished a combined structure- and ligand-based pharmacophore hypothesis to explore novel notch 3 inhibitors. The analysis identified common lead molecule ZINC000013449462 that showed better XP GScore and binding energy score than the reference inhibitor DAPT. The identified lead compound that passed all the druggable characteristics exhibited stable binding. Furthermore, the lead molecule can also form hydrogen and salt bridge interactions with binding site residues Asp1621 and Arg1465 residues, respectively of the active pockets of notch 3 protein. In essence, the inhibitory activity of the hit was validated across 109 NSCLC cell lines by employing a deep neural network algorithm. Our study proposes that ZINC000013449462 would be a possible prototype molecule towards the notch 3 target and further examined by clinical studies to combat NSCLC.

PMID:34631360 | PMC:PMC8481405 | DOI:10.1007/s40203-021-00112-y

Appl Soft Comput. 2021 Oct 6:107945. doi: 10.1016/j.asoc.2021.107945. Online ahead of print.

ABSTRACT

The alarming pandemic situation of Coronavirus infectious disease COVID-19, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a critical threat to public health. The unexpected outbreak and unrealistic progression of COVID-19 havegenerated an utmost need torealize promising therapeutic strategiesto fight the pandemic. Drug repurposing-an efficientdrug discovery technique from approved drugs is an emerging tacticto face the immediate global challenge.It offers a time-efficient and cost-effective way to find potential therapeutic agents for the disease. Artificial Intelligence-empowered deep learning models enable the rapid identification of potentially repurposable drug candidates against diseases. This study presents a deep learning ensemble model to prioritize clinically validated anti-viral drugs for their potential efficacy against SARS-CoV-2. The method integrates the similarities of drug chemical structures and virus genome sequences to generate feature vectors. The best combination of features is retrieved by the convolutional neural network in a deep learning manner. The extracted deep features are classified by the extreme gradient boosting classifier to infer potential virus-drug associations. The method could achieve an AUC of 0.8897 with 0.8571 prediction accuracy and 0.8394 sensitivity under the fivefold cross-validation. The experimental results and case studies demonstrate the suggested deep learning ensemble system yields competitive results compared with the state-of-the-art approaches. The top-ranked drugs are released for further wet-lab researches.

PMID:34630000 | PMC:PMC8492370 | DOI:10.1016/j.asoc.2021.107945