J Biomol Struct Dyn. 2022 May 10:1-17. doi: 10.1080/07391102.2022.2074140. Online ahead of print.

ABSTRACT

5-fluorouracil and analogs are used in the treatment of many solid tumours. However, there are many cases of resistance and high toxicity associated with 5-fluorouracil chemotherapy. Repurposing FDA drugs against human thymidylate synthase revealed a number of FDA drugs that have a potential to be further developed for the treatment of various cancers for which 5-fluorouracil and analogs have been used for chemotherapy. Four FDA drugs prioritized for further validation included Erismodegib, Irinotecan, Conivaptan and Ergotamine. The role of water in mediating drug interactions and its contribution to the total binding energy was also shown. MM-PBSA calculations revealed that the binding affinity was the lowest for the hTS-Ergotamine complex (-66.702 ± 1.807 kJ/mol) suggesting moderate inhibition despite a large energetic contribution from van der Waal interactions (-190.889 ± 1.027 kJ/mol).Communicated by Ramaswamy H. Sarma.

PMID:35538714 | DOI:10.1080/07391102.2022.2074140

Drugs Today (Barc). 2022 May;58(5):241-247. doi: 10.1358/dot.2022.58.5.3381591.

ABSTRACT

Outpatient treatment options for mild to moderate COVID-19 are severely limited. While many therapeutic options have been proposed, very few have demonstrated the appropriate safety and efficacy to warrant approval by national or international regulatory bodies. Monoclonal antibodies have been shown to decrease hospitalization in high-risk patients, but use remains limited due to challenges associated with both production and administration, and other treatment options are urgently needed. The anti-inflammatory drug fluticasone propionate has recently emerged as a potential outpatient treatment option, especially for those with newly diagnosed disease. This manuscript reviews what is known about fluticasone and looks ahead to examine how the drug may be used in the future to address the COVID-19 pandemic.

PMID:35535815 | DOI:10.1358/dot.2022.58.5.3381591

Immunobiology. 2022 May 5;227(3):152224. doi: 10.1016/j.imbio.2022.152224. Online ahead of print.

ABSTRACT

The COVID-19 pandemic has set back progress made on antimicrobial resistance (AMR). Without urgent re-focus, we risk slowing down drug discovery and providing treatment for drug resistant Mycobacterium tuberculosis. Unique in its immune evasion, dormancy and resuscitation, the causal pathogens of tuberculosis (TB) have demonstrated resistance to antibiotics with efflux pumps and the ability to form biofilms. Repurposing drugs is a prospective avenue for finding new anti-TB drugs. There are many advantages to discovering novel targets of an existing drug, as the pharmacokinetic and pharmacodynamic properties have already been established, they are cost-efficient and can be commercially accelerated for the new development. One such group of drugs are non-steroidal anti-inflammatory drugs (NSAIDs) that are originally known for their ability to supress the host proinflammatory responses. In addition to their anti-inflammatory properties, some NSAIDs have been discovered to have antimicrobial modes of action. Of particular interest is Carprofen, identified to inhibit the efflux mechanism and disrupt biofilm formation in mycobacteria. Due to the complexities of host-pathogens interactions in the lung microbiome, inflammatory responses must carefully be controlled alongside the in vivo actions of the prospective anti-infectives. This critical review explores the potential dual role of a selection of NSAIDs, as an anti-inflammatory and anti-tubercular adjunct to reverse the tide of antimicrobial resistance in existing treatments.

PMID:35533535 | DOI:10.1016/j.imbio.2022.152224

Am J Cancer Res. 2022 Apr 15;12(4):1465-1483. eCollection 2022.

ABSTRACT

To evaluate the potential anticancer effects of 1175 FDA-approved drugs, cell viability screening was performed using 25 human cancer cell lines covering 14 human cancer types. Here, we focus on the action of paroxetine, which demonstrated greater toxicity toward human gastric adenocarcinoma cell-line AGS cells compared with the other FDA-approved drugs, exhibiting an IC50 value lower than 10 μM. Evaluation of the underlying novel mechanisms revealed that paroxetine can enhance DNA damage in gastric cancer cells and involves downregulation of Rad51, HR23B and ERCC1 expression and function, as well as nucleotide shortage. Enhancement of autophagy counteracted paroxetine-induced apoptosis but did not affect paroxetine-induced DNA damage. Paroxetine also enhanced ROS generation in AGS cells, but a ROS scavenger did not improve paroxetine-mediated DNA damage, apoptosis, or autophagy, suggesting ROS might play a minor role in paroxetine-induced cell toxicity. In contrast, paroxetine did not enhance DNA damage, apoptosis, or autophagy in another insensitive gastric adenocarcinoma cell-line MKN-45 cells. Interestingly, co-administration of paroxetine with conventional anticancer agents sensitized MKN-45 cells to these agents: co-treated cells showed increased apoptosis relative to MKN-45 cells treated with the anticancer agent alone. Unequivocally, these data suggest that for the first time that paroxetine triggers cytotoxicity and DNA damage in AGS cells at least partly by reducing the gene expression of Rad51, HR23B, and ERCC1. Our findings also suggest that paroxetine is a promising candidate anticancer agent and/or chemosensitizing agent for use in combination with other anticancer drugs in cancer therapy. The molecular mechanisms underlying the anticancer activity of co-treatment with paroxetine and chemotherapy appear to be complex and are worthy of further investigation.

PMID:35530295 | PMC:PMC9077064

Acta Pharm Sin B. 2022 Mar;12(3):1271-1287. doi: 10.1016/j.apsb.2021.09.007. Epub 2021 Sep 11.

ABSTRACT

As one of the hallmarks of cancer, metabolic reprogramming leads to cancer progression, and targeting glycolytic enzymes could be useful strategies for cancer therapy. By screening a small molecule library consisting of 1320 FDA-approved drugs, we found that penfluridol, an antipsychotic drug used to treat schizophrenia, could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma (ESCC). Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of penfluridol. By using drug affinity responsive target stability (DARTS) technology and proteomics, we identified phosphofructokinase, liver type (PFKL), a key enzyme in glycolysis, as a direct target of penfluridol. Penfluridol could not exhibit its anticancer property in PFKL-deficient cancer cells, illustrating that PFKL is essential for the bioactivity of penfluridol. High PFKL expression is correlated with advanced stages and poor survival of ESCC patients, and silencing of PFKL significantly suppressed tumor growth. Mechanistically, direct binding of penfluridol and PFKL inhibits glucose consumption, lactate and ATP production, leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent manner. Taken together, PFKL is a potential prognostic biomarker and therapeutic target in ESCC, and penfluridol may be a new therapeutic option for management of this lethal disease.

PMID:35530161 | PMC:PMC9069409 | DOI:10.1016/j.apsb.2021.09.007

F1000Res. 2022 Feb 25;11:237. doi: 10.12688/f1000research.108761.1. eCollection 2022.

ABSTRACT

B-Raf is a protein kinase participating to the regulation of many biological processes in cells. Recent studies have demonstrated that this protein is frequently overactivated in human cancers, especially when it bears activating mutations. In recent years, few ATP-competitive inhibitors of B-Raf have been marketed for the treatment of melanoma and are currently under clinical evaluation on a variety of other types of cancer. Although the introduction of drugs targeting B-Raf has provided significant advances in cancer treatment, responses to such ATP-competitive inhibitors remain limited, mainly due to selectivity issues, side effects, narrow therapeutic windows, and the insurgence of drug resistance. Impressive research efforts have been made so far towards the identification of novel ATP-competitive modulators with improved efficacy against cancers driven by mutant Raf monomers and dimers, some of them showing good premises. However, several limitations could still be envisioned for these compounds, according to recent literature data. Besides, increased attentions have recently arisen around approaches based on the design of allosteric modulators, polypharmacology, PROTACs and drug repurposing for the targeting of B-Raf proteins. The design of compounds acting through such innovative mechanisms is rather challenging. However, novel valuable therapeutic opportunities can be envisioned on these drugs, as they act through innovative mechanisms in which limitations typically observed for approved ATP-competitive B-Raf inhibitors are less prone to emerge. In this article, the most recent approaches adopted for the design of non-ATP competitive inhibitors targeting B-Raf are described, discussing also on the possibilities, ligands acting through such innovative mechanisms could provide for the obtainment of more effective therapies.

PMID:35529278 | PMC:PMC9043679 | DOI:10.12688/f1000research.108761.1

Curr Pharm Biotechnol. 2022 May 6. doi: 10.2174/1389201023666220507003726. Online ahead of print.

ABSTRACT

The advent and spread of novel coronavirus viruses (nCoV), has been presenting the planet with a new public health crisis since December 2019. Several cases of unexplained pneumonia occurred in Wuhan, Hubei Province, China, only a month before the Chinese Spring festival. After a diagnosis of broncho-alveolar fluid samples of people from the Wuhan Seafood Market, the new coronavirus was identified using next-generation sequence technology. This work aims to bring out information regarding COVID-19 under a common platform that will help the researchers to identify the vital therapeutic targets for SARS-CoV-2 and, also it will provide insights into some significant work performed in recent times by scientific communities around the globe. In this review, we have tried to explore multiple aspects related to COVID-19 that includes: Epidemiology, Etiology, COVID-19 variants, Vaccine candidates, Potential therapeutic targets, role of natural products, and computational studies in drug design and development, repurposing, analysis of crystal structures available for COVID-19 related protein structures. Druggable targets include all viral enzymes and proteins involved in viral replication and regulation of host cellular machines. The medical community is tracking several therapies to combat the infection by using various antiviral and immunomodulatory mechanisms. While some vaccines are approved in this world-wide health crisis, a more precise therapy or drug is formally recommended to be used against SARS-CoV-2 infection. Natural products other than synthetic drugs, have been tested by in silico analysis against COVID-19. However, important issues still need to be addressed regarding in vivo bioavailability and better efficacy.

PMID:35524656 | DOI:10.2174/1389201023666220507003726

Am J Physiol Endocrinol Metab. 2022 May 6. doi: 10.1152/ajpendo.00064.2022. Online ahead of print.

ABSTRACT

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic that has spread worldwide, resulting in over 6 million deaths as of March 2022. Older people have been disproportionately affected by the disease, as they have greater risk of hospitalization, are more vulnerable to severe infection, and have higher mortality than younger patients. Although effective vaccines have been rapidly developed and administered globally, several clinical trials are ongoing to repurpose existing drugs to combat severe infection. One such drug, rapamycin, is currently under study for this purpose, given its immunosuppressant effects that are mediated by its inhibition of the mechanistic target of rapamycin (mTOR), a master regulator of cell growth. Consistent with this premise, acute rapamycin administration in young healthy humans blocks or attenuates mTOR and its downstream effectors, leading to the inhibition of muscle protein synthesis (MPS). Skeletal muscle mass declines when MPS is chronically lower than muscle protein breakdown. This is consequential for older people who are more susceptible to anabolic resistance (i.e., the blunting of MPS) due to reduced activity, sedentariness, or bed rest such as that associated with COVID-19 hospitalization, and who have also demonstrated a delayed or blunted ability to regain inactivity-induced muscle loss. The lack of studies investigating rapamycin administration on skeletal muscle in older people, and the emergence of effective antiviral medications against severe infection, may indicate the reduced relevance of drug repurposing for present or future pandemics.

PMID:35521831 | DOI:10.1152/ajpendo.00064.2022

J Mass Spectrom Adv Clin Lab. 2022 Apr 26;24:57-64. doi: 10.1016/j.jmsacl.2022.04.002. eCollection 2022 Apr.

ABSTRACT

BACKGROUND: Utilising stable isotope labelled internal standards (SIL-IS) in quantitative LC-MS/MS drug analysis is the most widely used approach to normalise for variability during sample quantification processes. However, compounds containing atoms such as Sulphur, Chlorine or Bromine, could potentially cause cross-signal contribution to the SIL-IS from the naturally occurring isotopes, resulting in non-linear calibration curves. A simple, novel method of mitigating the effect is presented here. It entails monitoring of a less abundant SIL-IS isotope, as the precursor ion, of a mass that has no/minimal isotopic contribution from the analyte isotopes.

METHODS: Experiments were conducted on two LC-MS/MS analysers: Waters Xevo TQ-S and Shimadzu 8050. Flucloxacillin (FLX) was used as an example. Two transitions were selected for FLX (m/z 454 → 160 → 295) and one for each of the SIL-IS isotopes (m/z 458 → 160 for the isotope 457 g/mol and m/z 460 → 160 for the isotope 459 g/mol). Assay biases were assessed at three SIL-IS concentrations: 0.7, 7 and 14 mg/L for each isotope.

RESULTS: When using the SIL-IS isotope m/z 458 → 160 at a concentration of 0.7 mg/L, biases were up to 36.9 % on both instruments. Increasing the SIL-IS concentration to 14 mg/L, reduced the bias to 5.8 %. Using the less abundant isotope, m/z 460 → 160, resulted in biases of 13.9 % at an SIL-IS concentration of 0.7 mg/L.

CONCLUSIONS: Applying this method will mitigate cross-signal contribution from the analyte isotopes to the corresponding SIL-IS, minimise the use of SIL-IS, and, thereby, reduce overall cost.

PMID:35520954 | PMC:PMC9065310 | DOI:10.1016/j.jmsacl.2022.04.002

Adv Pharm Bull. 2022 Jan;12(1):34-44. doi: 10.34172/apb.2022.005. Epub 2021 Jan 30.

ABSTRACT

COVID -19 a global pandemic that has brought all the greater global countries to a hook. The novel coronavirus (SARS-CoV-2) outbreak was first reported in Wuhan, China which then started spreading to different countries around the world. ACE2 receptors are present in various organs but the overexpression of ACE2 at lung epithelia makes them more vulnerable to respiratory symptoms. SARS-CoV-2 binds to ACE2 receptors for entry into host cells which may serve as potential target for future therapy.Repurposing of drugs are the present strategy undertaken as the SARS-CoV-2 shows similar respiratory distress symptoms as in the case of SARS and MERS. At present the antiviral medications and vaccines are at the early stages and may take few months to years, to achieve their complete efficacy to solve the public crisis. The technological advancements have brought passive immunisation, which is an anecdotal success, but the ideal approach to future outbreaks of SARS-CoV-2 is done by vaccines that are under clinical trials. There are a large percentage of population under psychological crisis either due to the fear of infection or stress from the quarantine lives. High levels of viral loads at the initial stages cause higher chances of transmission hence immediate isolations and screening methods must be undertaken. This review mainly focuses on the treatment strategies followed with no definitive approval from authorities. This is an attempt to gather all the materialistic evidences available for now.

PMID:35517888 | PMC:PMC9012918 | DOI:10.34172/apb.2022.005

Brief Bioinform. 2022 May 4:bbac124. doi: 10.1093/bib/bbac124. Online ahead of print.

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spurred a boom in uncovering repurposable existing drugs. Drug repurposing is a strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication.

MOTIVATION: Current works of drug repurposing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are mostly limited to only focusing on chemical medicines, analysis of single drug targeting single SARS-CoV-2 protein, one-size-fits-all strategy using the same treatment (same drug) for different infected stages of SARS-CoV-2. To dilute these issues, we initially set the research focusing on herbal medicines. We then proposed a heterogeneous graph embedding method to signaled candidate repurposing herbs for each SARS-CoV-2 protein, and employed the variational graph convolutional network approach to recommend the precision herb combinations as the potential candidate treatments against the specific infected stage.

METHOD: We initially employed the virtual screening method to construct the 'Herb-Compound' and 'Compound-Protein' docking graph based on 480 herbal medicines, 12,735 associated chemical compounds and 24 SARS-CoV-2 proteins. Sequentially, the 'Herb-Compound-Protein' heterogeneous network was constructed by means of the metapath-based embedding approach. We then proposed the heterogeneous-information-network-based graph embedding method to generate the candidate ranking lists of herbs that target structural, nonstructural and accessory SARS-CoV-2 proteins, individually. To obtain precision synthetic effective treatments forvarious COVID-19 infected stages, we employed the variational graph convolutional network method to generate candidate herb combinations as the recommended therapeutic therapies.

RESULTS: There were 24 ranking lists, each containing top-10 herbs, targeting 24 SARS-CoV-2 proteins correspondingly, and 20 herb combinations were generated as the candidate-specific treatment to target the four infected stages. The code and supplementary materials are freely available at https://github.com/fanyang-AI/TCM-COVID19.

PMID:35514205 | DOI:10.1093/bib/bbac124

Virol Sin. 2022 May 2:S1995-820X(22)00079-7. doi: 10.1016/j.virs.2022.04.015. Online ahead of print.

ABSTRACT

Hantaviruses, such as Hantaan virus (HTNV) and Seoul virus, are the causative agents of Hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS), and are important zoonotic pathogens. China has the highest incidence of HFRS, which is mainly caused by HTNV and Seoul virus. No approved antiviral drugs are available for these hantaviral diseases. Here, a chemiluminescence-based high-throughput-screening (HTS) assay was developed and used to screen HTNV pseudovirus (HTNVpv) inhibitors in a library of 1813 approved drugs and 556 small-molecule compounds from traditional Chinese medicine sources. We identified six compounds with in vitro anti-HTNVpv activities in the low-micromolar range (EC50 values of 0.1-2.2 μmol/L; selectivity index of 40-900). Among the six selected compounds, cepharanthine not only showed good anti-HTNVpv activity in vitro but also inhibited HTNVpv-fluc infection in Balb/c mice 5 h after infection by 94% (180 mg/kg/d, P < 0.01), 93% (90 mg/kg/d, P < 0.01), or 92% (45 mg/kg/d, P < 0.01), respectively, in a bioluminescent imaging mouse model. A time-of-addition analysis suggested that the antiviral mechanism of cepharanthine involves the membrane fusion and entry phases. In this study, we have established a HTS method for antiviral drugs screening, and shown that cepharanthine is a candidate for HCPS and HFRS therapy. These findings may offer a starting point for the treatment of patients infected with hantaviruses.

PMID:35513270 | DOI:10.1016/j.virs.2022.04.015

Psychopharmacology (Berl). 2022 May 5. doi: 10.1007/s00213-022-06156-y. Online ahead of print.

ABSTRACT

RATIONALE: Clinical studies suggest that the highly lipophilic, anti-inflammatory molecule, simvastatin, might be an ideal candidate for drug repurposing in the treatment of depression. The neuropsychological effects of simvastatin are not known, but their ascertainment would have significant translational value about simvastatin's influence on mood and cognition.

OBJECTIVES: We aimed to investigate the effects of simvastatin on a battery of psychological tests and inflammatory markers in healthy volunteers.

METHODS: Fifty-three healthy subjects were randomly assigned to 7 days of either simvastatin (N = 27) or sucrose-based placebo (N = 26) given in a double-blind fashion. Then, participants were administered questionnaires measuring subjective rates of mood and anxiety, and a battery of tasks assessing emotional processing, reward learning, and verbal memory. Blood samples for C-reactive protein were also collected.

RESULTS: Compared to placebo, participants on simvastatin showed a higher number of positively valenced intrusions in the emotional recall task (F1,51 = 4.99, p = 0.03), but also an increase in anxiety scores (F1,51 = 5.37, p = 0.02). An exploratory analysis of the females' subgroup (N = 27) showed lower number of misclassifications as sad facial expression in the simvastatin arm (F1,25 = 6.60, p = 0.02). No further statistically significant changes could be observed on any of the other outcomes measured.

CONCLUSIONS: We found limited evidence that 7-day simvastatin use in healthy volunteer induces a positive emotional bias while also being associated with an increase in anxiety, potentially reflecting the early effects of antidepressants in clinical practice. Such effect might be more evident in female subjects. Different drug dosages, treatment lengths, and sample selection need consideration in further experimental medicine and clinical studies.

TRIAL REGISTRATION: Clinicaltrials.gov: NCT04652089.

PMID:35511258 | DOI:10.1007/s00213-022-06156-y

Future Microbiol. 2022 May 5. doi: 10.2217/fmb-2022-0083. Online ahead of print.

ABSTRACT

During the past few months, mucormycosis has been associated with SARS-CoV-2 infections. Molecular docking combined with molecular dynamics simulation is utilized to test nucleotide-based inhibitors against the RdRps of SARS-CoV-2 solved structure and Rhizopus oryzae RdRp model built in silico. The results reveal a comparable binding affinity of sofosbuvir, galidesivir, ribavirin and remdesivir compared with the physiological nucleotide triphosphates against R. oryzae RdRp as well as the SARS-CoV-2 RdRp as reported before. Additionally, other compounds such as setrobuvir, YAK, IDX-184 and modified GTP compounds 2, 3 and 4 show potential calculated average binding affinities against R. oryzae RdRp. The present in silico study suggests the dual inhibition potential of the recommended drugs and compounds against SARS-CoV-2 and R. oryzae RdRps.

PMID:35510477 | DOI:10.2217/fmb-2022-0083

Patterns (N Y). 2022 Mar 11;3(3):100466. doi: 10.1016/j.patter.2022.100466. eCollection 2022 Mar 11.

ABSTRACT

Senior researcher Vanessa Lage-Rupprecht and two collaborators talk about what data science means to them and illustrate how they managed to create a data and lab coexistence in their drug-repurposing project, which was recently published in Patterns. In this article, they have developed a drug-target-mechanism-oriented data model, Human Brain PHARMACOME, and have presented it as a resource to the community.

PMID:35510189 | PMC:PMC9058869 | DOI:10.1016/j.patter.2022.100466

Patterns (N Y). 2022 Jan 26;3(3):100433. doi: 10.1016/j.patter.2021.100433. eCollection 2022 Mar 11.

ABSTRACT

The high number of failed pre-clinical and clinical studies for compounds targeting Alzheimer disease (AD) has demonstrated that there is a need to reassess existing strategies. Here, we pursue a holistic, mechanism-centric drug repurposing approach combining computational analytics and experimental screening data. Based on this integrative workflow, we identified 77 druggable modifiers of tau phosphorylation (pTau). One of the upstream modulators of pTau, HDAC6, was screened with 5,632 drugs in a tau-specific assay, resulting in the identification of 20 repurposing candidates. Four compounds and their known targets were found to have a link to AD-specific genes. Our approach can be applied to a variety of AD-associated pathophysiological mechanisms to identify more repurposing candidates.

PMID:35510183 | PMC:PMC9058900 | DOI:10.1016/j.patter.2021.100433

Cell Rep. 2022 May 3;39(5):110764. doi: 10.1016/j.celrep.2022.110764.

ABSTRACT

Linear motifs have an integral role in dynamic cell functions, including cell signaling. However, due to their small size, low complexity, and frequent mutations, identifying novel functional motifs poses a challenge. Viruses rely extensively on the molecular mimicry of cellular linear motifs. In this study, we apply systematic motif prediction combined with functional filters to identify human linear motifs convergently evolved also in viral proteins. We observe an increase in the sensitivity of motif prediction and improved enrichment in known instances. We identify >7,300 non-redundant motif instances at various confidence levels, 99 of which are supported by all functional and structural filters. Overall, we provide a pipeline to improve the identification of functional linear motifs from interactomics datasets and a comprehensive catalog of putative human motifs that can contribute to our understanding of the human domain-linear motif code and the associated mechanisms of viral interference.

PMID:35508127 | DOI:10.1016/j.celrep.2022.110764

PLoS Comput Biol. 2022 May 4;18(5):e1009531. doi: 10.1371/journal.pcbi.1009531. Online ahead of print.

ABSTRACT

Schizophrenia is a debilitating psychiatric disorder, leading to both physical and social morbidity. Worldwide 1% of the population is struggling with the disease, with 100,000 new cases annually only in the United States. Despite its importance, the goal of finding effective treatments for schizophrenia remains a challenging task, and previous work conducted expensive large-scale phenotypic screens. This work investigates the benefits of Machine Learning for graphs to optimize drug phenotypic screens and predict compounds that mitigate abnormal brain reduction induced by excessive glial phagocytic activity in schizophrenia subjects. Given a compound and its concentration as input, we propose a method that predicts a score associated with three possible compound effects, i.e., reduce, increase, or not influence phagocytosis. We leverage a high-throughput screening to prove experimentally that our method achieves good generalization capabilities. The screening involves 2218 compounds at five different concentrations. Then, we analyze the usability of our approach in a practical setting, i.e., prioritizing the selection of compounds in the SWEETLEAD library. We provide a list of 64 compounds from the library that have the most potential clinical utility for glial phagocytosis mitigation. Lastly, we propose a novel approach to computationally validate their utility as possible therapies for schizophrenia.

PMID:35507580 | DOI:10.1371/journal.pcbi.1009531

Appl Biochem Biotechnol. 2022 May 4. doi: 10.1007/s12010-022-03928-2. Online ahead of print.

ABSTRACT

Furin, a pro-protein convertase, plays a significant role as a biological scissor in bacterial, viral, and even mammalian substrates which in turn decides the fate of many viral and bacterial infections along with the numerous ailments caused by cancer, diabetes, inflammations, and neurological disorders. In the wake of the current pandemic caused by the virus SARS-CoV-2, furin has become the center of attraction for researchers as the spike protein contains a polybasic furin cleavage site. In the present work, we have searched for novel inhibitors against this interesting human target from FDA-approved antiviral. To enhance the selection of new inhibitors, we employed Kohonen's artificial neural network-based self-organizing maps for ligand-based virtual screening. Promising results were obtained which can help in drug repurposing and network pharmacology studies can address the errors generated due to promiscuity/polypharmacology. We found 15 existing FDA antiviral drugs having the potential to inhibit furin. Among these, six compounds have targets on important human proteins (LDLR, FCGR1A, PCK1, TLR7, DNA, and PNP). The role of these 15 drugs inhibiting furin can be established by studying further on patients infected with number of viruses including SARS-CoV-2. Here we propose two promising candidate FDA drugs GS-441524 and Grazoprevir (MK-5172) for repurposing as inhibitors of furin. The best results were observed with GS-441524.

PMID:35507249 | DOI:10.1007/s12010-022-03928-2

Mol Divers. 2022 May 4. doi: 10.1007/s11030-022-10440-6. Online ahead of print.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been significantly paralyzing the societies, economies and health care systems around the globe. The mutations on the genome of SARS-CoV-2 led to the emergence of new variants, some of which are classified as "variant of concern" due to their increased transmissibility and better viral fitness. The Omicron variant, as the latest variant of concern, dominated the current COVID-19 cases all around the world. Unlike the previous variants of concern, the Omicron variant has 15 mutations on the receptor-binding domain of spike protein and the changes in the key amino acid residues of S protein can enhance the binding ability of the virus to hACE2, resulting in a significant increase in the infectivity of the Omicron variant. Therefore, there is still an urgent need for treatment and prevention of variants of concern, particularly for the Omicron variant. In this study, an in silico drug repurposing was conducted through the molecular docking of 2890 FDA-approved drugs against the mutant S protein of SARS-CoV-2 for Omicron variant. We discovered promising drug candidates for the inhibition of alarming Omicron variant such as quinestrol, adapalene, tamibarotene, and dihydrotachysterol. The stability of ligands complexed with the mutant S protein was confirmed using MD simulations. The lead compounds were further evaluated for their potential use and side effects based on the current literature. Particularly, adapalene, dihydrotachysterol, levocabastine and bexarotene came into prominence due to their non-interference with the normal physiological processes. Therefore, this study suggests that these approved drugs can be considered as drug candidates for further in vitro and in vivo studies to develop new treatment options for the Omicron variant of SARS-CoV-2.

PMID:35507211 | DOI:10.1007/s11030-022-10440-6