Am J Hum Genet. 2021 Aug 3:S0002-9297(21)00276-7. doi: 10.1016/j.ajhg.2021.07.008. Online ahead of print.

ABSTRACT

An individual's genetics can dramatically influence breast cancer (BC) risk. Although clinical measures for prevention do exist, non-invasive personalized measures for reducing BC risk are limited. Commonly used medications are a promising set of modifiable factors, but no previous study has explored whether a range of widely taken approved drugs modulate BC genetics. In this study, we describe a quantitative framework for exploring the interaction between the genetic susceptibility of BC and medication usage among UK Biobank women. We computed BC polygenic scores (PGSs) that summarize BC genetic risk and find that the PGS explains nearly three-times greater variation in disease risk within corticosteroid users compared to non-users. We map 35 genes significantly interacting with corticosteroid use (FDR < 0.1), highlighting the transcription factor NRF2 as a common regulator of gene-corticosteroid interactions in BC. Finally, we discover a regulatory variant strongly stratifying BC risk according to corticosteroid use. Within risk allele carriers, 18.2% of women taking corticosteroids developed BC, compared to 5.1% of the non-users (with an HR = 3.41 per-allele within corticosteroid users). In comparison, there are no differences in BC risk within the reference allele homozygotes. Overall, this work highlights the clinical relevance of gene-drug interactions in disease risk and provides a roadmap for repurposing biobanks in drug repositioning and precision medicine.

PMID:34363748 | DOI:10.1016/j.ajhg.2021.07.008

Acta Pharmacol Sin. 2021 Aug 6. doi: 10.1038/s41401-021-00724-2. Online ahead of print.

ABSTRACT

Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor, and 95% of patients die within 2 years after diagnosis. In this study, aiming to overcome chemoresistance to the first-line drug temozolomide (TMZ), we carried out research to discover a novel alternative drug targeting the oncogenic NFAT signaling pathway for GBM therapy. To accelerate the drug's clinical application, we took advantage of a drug repurposing strategy to identify novel NFAT signaling pathway inhibitors. After screening a set of 93 FDA-approved drugs with simple structures, we identified pimavanserin tartrate (PIM), an effective 5-HT2A receptor inverse agonist used for the treatment of Parkinson's disease-associated psychiatric symptoms, as having the most potent inhibitory activity against the NFAT signaling pathway. Further study revealed that PIM suppressed STIM1 puncta formation to inhibit store-operated calcium entry (SOCE) and subsequent NFAT activity. In cellula, PIM significantly suppressed the proliferation, migration, division, and motility of U87 glioblastoma cells, induced G1/S phase arrest and promoted apoptosis. In vivo, the growth of subcutaneous and orthotopic glioblastoma xenografts was markedly suppressed by PIM. Unbiased omics studies revealed the novel molecular mechanism of PIM's antitumor activity, which included suppression of the ATR/CDK2/E2F axis, MYC, and AuroraA/B signaling. Interestingly, the genes upregulated by PIM were largely associated with cholesterol homeostasis, which may contribute to PIM's side effects and should be given more attention. Our study identified store-operated calcium channels as novel targets of PIM and was the first to systematically highlight the therapeutic potential of pimavanserin tartrate for glioblastoma.

PMID:34363007 | DOI:10.1038/s41401-021-00724-2

Clin Cancer Res. 2021 Aug 6. doi: 10.1158/1078-0432.CCR-21-0560. Online ahead of print.

ABSTRACT

PURPOSE: The mainstay of treatment for basal cell carcinoma (BCC) is surgical excision, which can result in significant associated morbidity, particularly for patients with recurrent tumors. We previously conducted a drug repositioning screen using molecular data from human BCCs and identified histone deacetylase (HDAC) inhibitors as a potential treatment for BCC. Here we conduct the first proof-of-principle study of a topical pan-HDAC inhibitor, remetinostat, in human BCC.

PATIENTS AND METHODS: We conducted a phase II, open-label, single-arm, single-institution trial of a topical HDAC inhibitor. Participants with at least one BCC were recruited. All participants applied 1% remetinostat gel three times daily for 6 weeks, with measurements of tumor diameter conducted at baseline and week 8. Surgical excision of the remaining tumor was conducted at the end of the study and microscopic evaluation was performed.

RESULTS: Thirty-three per-protocol tumors from 25 participants were included in the analysis. The overall response rate, defined as the proportion of tumors achieving more than 30% decrease in the longest diameter from baseline to week 8, was 69.7% [90% confidence interval (CI), 54%-82.5%]. On pathologic examination, 54.8% of tumors demonstrated complete resolution. Pharmacodynamic analysis demonstrated similar levels of acetylated histone H3 in skin tissue before and after treatment, however, phosphorylation was increased. No systemic adverse events were reported.

CONCLUSIONS: The HDAC inhibitor remetinostat is a well-tolerated and effective topical treatment for reducing BCC disease burden in a clinically significant manner. This provides in-human validation of HDAC inhibitors as a therapy for BCC.

PMID:34362809 | DOI:10.1158/1078-0432.CCR-21-0560

Int J Mol Sci. 2021 Aug 2;22(15):8320. doi: 10.3390/ijms22158320.

ABSTRACT

A novel aptamer-based competitive drug screening platform for osteoporosis was devised in which fluorescence-labeled, sclerostin-specific aptamers compete with compounds from selected chemical libraries for the binding of immobilized recombinant human sclerostin to achieve high-throughput screening for potential small-molecule sclerostin inhibitors and to facilitate drug repurposing and drug discovery. Of the 96 selected inhibitors and FDA-approved drugs, six were shown to result in a significant decrease in the fluorescence intensity of the aptamer, suggesting a higher affinity toward sclerostin compared with that of the aptamer. The targets of these potential sclerostin inhibitors were correlated to lipid or bone metabolism, and several of the compounds have already been shown to be potential osteogenic activators, indicating that the aptamer-based competitive drug screening assay offered a potentially reliable strategy for the discovery of target-specific new drugs. The six potential sclerostin inhibitors suppressed the level of both intracellular and/or extracellular sclerostin in mouse osteocyte IDG-SW3 and increased alkaline phosphatase activity in IDG-SW3 cells, human bone marrow-derived mesenchymal stem cells and human fetal osteoblasts hFOB1.19. Potential small-molecule drug candidates obtained in this study are expected to provide new therapeutics for osteoporosis as well as insights into the structure-activity relationship of sclerostin inhibitors for rational drug design.

PMID:34361085 | DOI:10.3390/ijms22158320

Int J Mol Sci. 2021 Jul 30;22(15):8208. doi: 10.3390/ijms22158208.

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disease and accounts for most cases of dementia. The prevalence of AD has increased in the current rapidly aging society and contributes to a heavy burden on families and society. Despite the profound impact of AD, current treatments are unable to achieve satisfactory therapeutic effects or stop the progression of the disease. Finding novel treatments for AD has become urgent. In this paper, we reviewed novel therapeutic approaches in five categories: anti-amyloid therapy, anti-tau therapy, anti-neuroinflammatory therapy, neuroprotective agents including N-methyl-D-aspartate (NMDA) receptor modulators, and brain stimulation. The trend of therapeutic development is shifting from a single pathological target to a more complex mechanism, such as the neuroinflammatory and neurodegenerative processes. While drug repositioning may accelerate pharmacological development, non-pharmacological interventions, especially repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), also have the potential for clinical application. In the future, it is possible for physicians to choose appropriate interventions individually on the basis of precision medicine.

PMID:34360973 | DOI:10.3390/ijms22158208

Cancers (Basel). 2021 Jul 30;13(15):3845. doi: 10.3390/cancers13153845.

ABSTRACT

The increasing breadth of molecular targets, promise of immune-targeted therapies and repurposed agents have heightened interest in cancer prevention. While, to date, testing of oral cancer chemoprevention strategies has failed to deliver therapeutic agents for routine clinical practice, there remains an urgent need for further clinical research to overcome this hurdle. Patients at the greatest risk of disease stand to benefit the most from inclusion in clinical trials; therefore, there is a need to carefully define this population using validated clinical and molecular markers. Safety, tolerability and the efficacy of interventions is assessed through carefully selected endpoints. These endpoints may include pharmacodynamic, clinical, histological and on-target molecular modifications as an individual or as a composite endpoint. Early-phase trials provide an area of opportunity to explore novel and repurposed agents in the setting of oral cancer chemoprevention, eventually leading to phase III trials with clinical endpoints such as transformation and clinical outcome; these studies are large, lengthy and expensive and should be reserved for the most promising of agents. This paper will explore current evidence in oral cancer chemoprevention, drug repurposing, selection of appropriate endpoints for early-phase trials and novel therapeutic angles in oral cancer chemoprevention.

PMID:34359746 | DOI:10.3390/cancers13153845

Cancers (Basel). 2021 Jul 27;13(15):3778. doi: 10.3390/cancers13153778.

ABSTRACT

The overexpression of BRF2, a selective subunit of RNA polymerase III, has been shown to be crucial in the development of several types of cancers, including breast cancer and lung squamous cell carcinoma. Predominantly, BRF2 acts as a central redox-sensing transcription factor (TF) and is involved in rescuing oxidative stress (OS)-induced apoptosis. Here, we showed a novel link between BRF2 and the DNA damage response. Due to the lack of BRF2-specific inhibitors, through virtual screening and molecular dynamics simulation, we identified potential drug candidates that interfere with BRF2-TATA-binding Protein (TBP)-DNA complex interactions based on binding energy, intermolecular, and torsional energy parameters. We experimentally tested bexarotene as a potential BRF2 inhibitor. We found that bexarotene (Bex) treatment resulted in a dramatic decline in oxidative stress and Tert-butylhydroquinone (tBHQ)-induced levels of BRF2 and consequently led to a decrease in the cellular proliferation of cancer cells which may in part be due to the drug pretreatment-induced reduction of ROS generated by the oxidizing agent. Our data thus provide the first experimental evidence that BRF2 is a novel player in the DNA damage response pathway and that bexarotene can be used as a potential inhibitor to treat cancers with the specific elevation of oxidative stress.

PMID:34359683 | DOI:10.3390/cancers13153778

Comput Biol Med. 2021 Jul 31;136:104722. doi: 10.1016/j.compbiomed.2021.104722. Online ahead of print.

ABSTRACT

BACKGROUND: Mucormycosis, a fungal infection caused by Rhizopus species is on the rise in COVID-19 patients as a result of their suppressed immunity. The current therapies include systemic administration of Amphotericin B.

HYPOTHESIS AND METHOD: We screened several triazole broad-spectrum antifungal agents against the therapeutic target in mucormycosis using computational techniques like molecular docking and compared them with isavuconazole, an approved drug.

RESULT: The study concluded that 4 triazole drugs, pramiconazole, itraconazole, posaconazole and ketoconazole were strong candidates to be further evaluated and developed as a treatment for mucormycosis.

CONCLUSION: Novel topical and oral therapies could be developed from these drug leads.

PMID:34358995 | DOI:10.1016/j.compbiomed.2021.104722

Biomed Pharmacother. 2021 Jul 28;142:111954. doi: 10.1016/j.biopha.2021.111954. Online ahead of print.

ABSTRACT

The SARS-CoV-2 pandemic is a worldwide public health emergency. Despite the beginning of a vaccination campaign, the search for new drugs to appropriately treat COVID-19 patients remains a priority. Drug repurposing represents a faster and cheaper method than de novo drug discovery. In this study, we examined three different network-based approaches to identify potentially repurposable drugs to treat COVID-19. We analyzed transcriptomic data from whole blood cells of patients with COVID-19 and 21 other related conditions, as compared with those of healthy subjects. In addition to conventionally used drugs (e.g., anticoagulants, antihistaminics, anti-TNFα antibodies, corticosteroids), unconventional candidate compounds, such as SCN5A inhibitors and drugs active in the central nervous system, were identified. Clinical judgment and validation through clinical trials are always mandatory before use of the identified drugs in a clinical setting.

PMID:34358753 | PMC:PMC8316014 | DOI:10.1016/j.biopha.2021.111954

Pharmaceuticals (Basel). 2021 Jul 16;14(7):686. doi: 10.3390/ph14070686.

ABSTRACT

The intravascular parasitic worm Schistosoma mansoni is a causative agent of schistosomiasis, a disease of great global public health significance. Praziquantel is the only drug available to treat schistosomiasis and there is an urgent demand for new anthelmintic agents. Adopting a phenotypic drug screening strategy, here, we evaluated the antiparasitic properties of 46 commercially available cardiovascular drugs against S. mansoni. From these screenings, we found that amiodarone, telmisartan, propafenone, methyldopa, and doxazosin affected the viability of schistosomes in vitro, with effective concentrations of 50% (EC50) and 90% (EC90) values ranging from 8 to 50 µM. These results were further supported by scanning electron microscopy analysis. Subsequently, the most effective drug (amiodarone) was further tested in a murine model of schistosomiasis for both early and chronic S. mansoni infections using a single oral dose of 400 mg/kg or 100 mg/kg daily for five consecutive days. Amiodarone had a low efficacy in chronic infection, with the worm and egg burden reduction ranging from 10 to 30%. In contrast, amiodarone caused a significant reduction in worm and egg burden in early infection (>50%). Comparatively, treatment with amiodarone is more effective in early infection than praziquantel, demonstrating the potential role of this cardiovascular drug as an antischistosomal agent.

PMID:34358112 | DOI:10.3390/ph14070686

J Biomol Struct Dyn. 2021 Aug 6:1-16. doi: 10.1080/07391102.2021.1960608. Online ahead of print.

ABSTRACT

Drug repositioning has recently become one of the widely used drug design approaches in proposing alternative compounds with potentially fewer side effects. In this study, structure-based pharmacophore modelling and docking was used to screen existing drug molecules to bring forward potential modulators for ligand-binding domain of human glucocorticoid receptor (hGR). There exist several drug molecules targeting hGR, yet their apparent side effects still persist. Our goal was to disclose new compounds via screening existing drug compounds to bring forward fast and explicit solutions. The so-called shared pharmacophore model was created using the most persistent pharmacophore features shared by several crystal structures of the receptor. The shared model was first used to screen a small database of 75 agonists and 300 antagonists/decoys, and exhibited a successful outcome in its ability to distinguish agonists from antagonists/decoys. Then, it was used to screen a database of over 5000 molecules composed of FDA-approved, worldwide used and investigational drug compounds. A total of 110 compounds satisfying the pharmacophore requirements were subjected to different docking experiments for further assessment of their binding ability. In the final hit list of 54 compounds which fulfilled all scoring criteria, 19 of them were nonsteroidal and when further investigated, each presented a unique scaffold with little structural resemblance to any known nonsteroidal GR modulators. Independent 100 ns long MD simulations conducted on three selected drug candidates in complex with hGR displayed stable conformations incorporating several hydrogen bonds common to all three compounds and the reference molecule dexamethasone.Communicated by Ramaswamy H. Sarma.

PMID:34355665 | DOI:10.1080/07391102.2021.1960608

Front Microbiol. 2021 Jul 20;12:647693. doi: 10.3389/fmicb.2021.647693. eCollection 2021.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worldwide. Currently, many clinical trials in search of effective COVID-19 drugs are underway. Viral RNA-dependent RNA polymerase (RdRp) remains the target of choice for prophylactic or curative treatment of COVID-19. Nucleoside analogs are the most promising RdRp inhibitors and have shown effectiveness in vitro, as well as in clinical settings. One limitation of such RdRp inhibitors is the removal of incorporated nucleoside analogs by SARS-CoV-2 exonuclease (ExoN). Thus, ExoN proofreading activity accomplishes resistance to many of the RdRp inhibitors. We hypothesize that in the absence of highly efficient antivirals to treat COVID-19, combinatorial drug therapy with RdRp and ExoN inhibitors will be a promising strategy to combat the disease. To repurpose drugs for COVID-19 treatment, 10,397 conformers of 2,240 approved drugs were screened against the ExoN domain of nsp14 using AutoDock VINA. The molecular docking approach and detailed study of interactions helped us to identify dexamethasone metasulfobenzoate, conivaptan, hesperidin, and glycyrrhizic acid as potential inhibitors of ExoN activity. The results were further confirmed using molecular dynamics (MD) simulations and molecular mechanics combined with generalized Born model and solvent accessibility method (MM-GBSA) calculations. Furthermore, the binding free energy of conivaptan and hesperidin, estimated using MM-GBSA, was -85.86 ± 0.68 and 119.07 ± 0.69 kcal/mol, respectively. Based on docking, MD simulations and known antiviral activities, and conivaptan and hesperidin were identified as potential SARS-CoV-2 ExoN inhibitors. We recommend further investigation of this combinational therapy using RdRp inhibitors with a repurposed ExoN inhibitor as a potential COVID-19 treatment.

PMID:34354677 | PMC:PMC8329495 | DOI:10.3389/fmicb.2021.647693

Int J Psychiatry Clin Pract. 2021 Aug 4:1-13. doi: 10.1080/13651501.2021.1957117. Online ahead of print.

ABSTRACT

OBJECTIVE: The objective of this manuscript is to provide a comprehensive and critical overview of the current evidence on the association between Diabetes mellitus (DM) and mood disorders [i.e., Major depressive disorder (MDD) and bipolar disorder (BD)], and therapeutic opportunities.

METHODS: We searched in MEDLINE (via Ovid) for placebo-controlled clinical trials published in the last 20 years that assessed drug repurposing approaches for the treatment of DM or mood disorders.

RESULTS: We found seven studies that aimed to verify the effects of antidepressants in patients diagnosed with DM, and eight studies that tested the effect of antidiabetic drugs in patients diagnosed with MDD or BD. Most studies published in the last two decades did not report a positive effect of antidepressants on glycemic control in patients with DM. On the other hand, antidiabetic drugs seem to have a positive effect on the treatment of MDD and BD.

CONCLUSIONS: While effect of antidepressants on glycemic control in patients with DM is still controversial, the use of antidiabetic drugs may be a promising strategy for patients with MDD or BD. Prospective studies are still needed.Key pointsMood disorders in patients with DM affect glycemic control, potentially increasing mortality risk.The effect of antidepressants on glycemic control in patients with DM is still controversial. The coexistence of complicated DM and a mood disorders would require a careful, individualised, and comprehensive evaluation.Insulin resistance may increase the risk of depressive symptoms and is associated with worse outcomes in BD.The use antidiabetic drugs may be a promising strategy for patients with MDD or BD. However, prospective trials are needed to prove a potential antidepressant activity of antidiabetic drugs.

PMID:34348557 | DOI:10.1080/13651501.2021.1957117

J Biomol Struct Dyn. 2021 Aug 4:1-13. doi: 10.1080/07391102.2021.1958699. Online ahead of print.

ABSTRACT

Acinetobacter baumannii is an extremely dangerous multidrug-resistant (MDR) gram-negative pathogen which poses a serious life-threatening risk in immunocompromised patients. Phosphopantothenoyl cysteine synthetase (PPCS) catalyzes the formation of an amide bond between L-cysteine and phosphopantothenic acid (PPA) to form 4'- Phosphopantothenoylcysteine during Coenzyme A (CoA) biosynthesis. CoA is a crucial cofactor for cellular survival and inhibiting its synthesis will result in cell death. Bacterial PPCS differs from eukaryotic PPCS in a number of ways like it exists as a C-terminal domain of a PPCDC/PPCS fusion protein whereas eukaryotic PPCS exists as an independent protein. This difference makes it an attractive drug target. For which a conventional iterative approach of SBDD (structure-based drug design) was used, which began with three-dimensional structure prediction of AbPPCS using PHYRE 2.0. A database of FDA-approved compounds (Drug Bank) was then screened against the target of interest by means of docking score and glide energy, leading to the identification of 6 prominent drug candidates. The shortlisted 6 molecules were further subjected to all-atom MD simulation studies in explicit-solvent conditions (using AMBER force field). The MD simulation studies revealed that the ligands DB65103, DB449108 and DB443210, maintained several H-bonds with intense van der Waals contacts at the active site of the protein with high binding free energies: -11.42 kcal/mol, -10.49 kcal/mol and -10.98 kcal/mol, respectively, calculated via MM-PBSA method. Overall, binding of these compounds at the active site was found to be the most stable and robust highlighting the potential of these compounds to serve as antibacterials.Communicated by Ramaswamy H. Sarma.

PMID:34348086 | DOI:10.1080/07391102.2021.1958699

Aging Cell. 2021 Aug 4:e13441. doi: 10.1111/acel.13441. Online ahead of print.

ABSTRACT

The identification and validation of drugs that promote health during aging ("geroprotectors") are key to the retardation or prevention of chronic age-related diseases. Here, we found that most of the established pro-longevity compounds shown to extend lifespan in model organisms also alter extracellular matrix gene expression (i.e., matrisome) in human cell lines. To harness this observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a "youthful" matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for Caenorhabditis elegans longevity. With this reporter, we were able to eliminate false-positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach-employing extracellular matrix homeostasis-facilitates the discovery of pharmacological interventions promoting healthy aging.

PMID:34346557 | DOI:10.1111/acel.13441

J Gen Virol. 2021 Aug;102(8). doi: 10.1099/jgv.0.001627.

ABSTRACT

Human respiratory syncytial virus (hRSV) is a major cause of respiratory illness in young children and can cause severe infections in the elderly or in immunocompromised adults. To date, there is no vaccine to prevent hRSV infections, and disease management is limited to preventive care by palivizumab in infants and supportive care for adults. Intervention with small-molecule antivirals specific for hRSV represents a good alternative, but no such compounds are currently approved. The investigation of existing drugs for new therapeutic purposes (drug repositioning) can be a faster approach to address this issue. In this study, we show that chloroquine and pyrimethamine inhibit the replication of human respiratory syncytial virus A (long strain) and synergistically increase the anti-replicative effect of ribavirin in cellulo. Moreover, chloroquine, but not pyrimethamine, inhibits hRSV replication in the mouse model. Our results show that chloroquine can potentially be an interesting compound for treatment of hRSV infection in monotherapy or in combination with other antivirals.

PMID:34342560 | DOI:10.1099/jgv.0.001627

Elife. 2021 Aug 3;10:e65543. doi: 10.7554/eLife.65543.

ABSTRACT

The discovery of a drug requires over a decade of intensive research and financial investments - and still has a high risk of failure. To reduce this burden, we developed the NICEdrug.ch resource, which incorporates 250,000 bioactive molecules, and studied their enzymatic metabolic targets, fate, and toxicity. NICEdrug.ch includes a unique fingerprint that identifies reactive similarities between drug-drug and drug-metabolite pairs. We validated the application, scope, and performance of NICEdrug.ch over similar methods in the field on golden standard datasets describing drugs and metabolites sharing reactivity, drug toxicities, and drug targets. We use NICEdrug.ch to evaluate inhibition and toxicity by the anticancer drug 5-fluorouracil, and suggest avenues to alleviate its side effects. We propose shikimate 3-phosphate for targeting liver-stage malaria with minimal impact on the human host cell. Finally, NICEdrug.ch suggests over 1300 candidate drugs and food molecules to target COVID-19 and explains their inhibitory mechanism for further experimental screening. The NICEdrug.ch database is accessible online to systematically identify the reactivity of small molecules and druggable enzymes with practical applications in lead discovery and drug repurposing.

PMID:34340747 | DOI:10.7554/eLife.65543

Front Biosci (Landmark Ed). 2021 Jul 30;26(7):222-234. doi: 10.52586/4936.

ABSTRACT

Introduction: The prediction of interacting drug-target pairs plays an essential role in the field of drug repurposing, and drug discovery. Although biotechnology and chemical technology have made extraordinary progress, the process of dose-response experiments and clinical trials is still extremely complex, laborious, and costly. As a result, a robust computer-aided model is of an urgent need to predict drug-target interactions (DTIs). Methods: In this paper, we report a novel computational approach combining fuzzy local ternary pattern (FLTP), Position-Specific Scoring Matrix (PSSM), and rotation forest (RF) to identify DTIs. More specially, the target primary sequence is first numerically characterized into PSSM which records the biological evolution information. Afterward, the FLTP method is applied in extracting the highly representative descriptors of PSSM, and the combinations of FLTP descriptors and drug molecular fingerprints are regarded as the complete features of drug-target pairs. Results: Finally, the entire features are fed into rotation forests for inferring potential DTIs. The experiments of 5-fold cross-validation (CV) achieve mean accuracies of 89.08%, 86.14%, 82.41%, and 78.40% on Enzyme, Ion Channel, GPCRs, and Nuclear Receptor datasets. Discussion: For further validating the model performance, we performed experiments with the state-of-art support vector machine (SVM) and light gradient boosting machine (LGBM). The experimental results indicate the superiorities of the proposed model in effectively and reliably detect potential DTIs. There is an anticipation that the proposed model can establish a feasible and convenient tool to identify high-throughput identification of DTIs.

PMID:34340269 | DOI:10.52586/4936

Drug Discov Today. 2021 Jul 30:S1359-6446(21)00335-4. doi: 10.1016/j.drudis.2021.07.026. Online ahead of print.

ABSTRACT

The COVID-19 pandemic has caused millions of deaths and massive societal distress worldwide. Therapeutic solutions are urgently needed but de novo drug development remains a lengthy process. One promising alternative is computational drug repurposing, which enables the prioritization of existing compounds through fast in silico analyses. Recent efforts based on molecular docking, machine learning, and network analysis have produced actionable predictions. Some predicted drugs, targeting viral proteins and pathological host pathways are undergoing clinical trials. Here, we review this work, highlight drugs with high predicted efficacy and classify their mechanisms of action. We discuss the strengths and limitations of the published methodologies and outline possible future directions. Finally, we curate a list of COVID-19 data portals and other repositories that could be used to accelerate future research.

PMID:34339864 | DOI:10.1016/j.drudis.2021.07.026

BMC Biol. 2021 Aug 2;19(1):156. doi: 10.1186/s12915-021-01086-1.

ABSTRACT

BACKGROUND: The emergence and continued global spread of the current COVID-19 pandemic has highlighted the need for methods to identify novel or repurposed therapeutic drugs in a fast and effective way. Despite the availability of methods for the discovery of antiviral drugs, the majority tend to focus on the effects of such drugs on a given virus, its constituent proteins, or enzymatic activity, often neglecting the consequences on host cells. This may lead to partial assessment of the efficacy of the tested anti-viral compounds, as potential toxicity impacting the overall physiology of host cells may mask the effects of both viral infection and drug candidates. Here we present a method able to assess the general health of host cells based on morphological profiling, for untargeted phenotypic drug screening against viral infections.

RESULTS: We combine Cell Painting with antibody-based detection of viral infection in a single assay. We designed an image analysis pipeline for segmentation and classification of virus-infected and non-infected cells, followed by extraction of morphological properties. We show that this methodology can successfully capture virus-induced phenotypic signatures of MRC-5 human lung fibroblasts infected with human coronavirus 229E (CoV-229E). Moreover, we demonstrate that our method can be used in phenotypic drug screening using a panel of nine host- and virus-targeting antivirals. Treatment with effective antiviral compounds reversed the morphological profile of the host cells towards a non-infected state.

CONCLUSIONS: The phenomics approach presented here, which makes use of a modified Cell Painting protocol by incorporating an anti-virus antibody stain, can be used for the unbiased morphological profiling of virus infection on host cells. The method can identify antiviral reference compounds, as well as novel antivirals, demonstrating its suitability to be implemented as a strategy for antiviral drug repurposing and drug discovery.

PMID:34334126 | DOI:10.1186/s12915-021-01086-1