Diabetologia. 2022 Jun 23. doi: 10.1007/s00125-022-05739-w. Online ahead of print.

NO ABSTRACT

PMID:35736992 | DOI:10.1007/s00125-022-05739-w

Metabolites. 2022 May 30;12(6):496. doi: 10.3390/metabo12060496.

ABSTRACT

Genome-wide association studies (GWAS) with non-targeted metabolomics have identified many genetic loci of biomedical interest. However, metabolites with a high degree of missingness, such as drug metabolites and xenobiotics, are often excluded from such studies due to a lack of statistical power and higher uncertainty in their quantification. Here we propose ratios between related drug metabolites as GWAS phenotypes that can drastically increase power to detect genetic associations between pairs of biochemically related molecules. As a proof-of-concept we conducted a GWAS with 520 individuals from the Qatar Biobank for who at least five of the nine available acetaminophen metabolites have been detected. We identified compelling evidence for genetic variance in acetaminophen glucuronidation and methylation by UGT2A15 and COMT, respectively. Based on the metabolite ratio association profiles of these two loci we hypothesized the chemical structure of one of their products or substrates as being 3-methoxyacetaminophen, which we then confirmed experimentally. Taken together, our study suggests a novel approach to analyze metabolites with a high degree of missingness in a GWAS setting with ratios, and it also demonstrates how pharmacological pathways can be mapped out using non-targeted metabolomics measurements in large population-based studies.

PMID:35736429 | DOI:10.3390/metabo12060496

ESC Heart Fail. 2022 Jun 23. doi: 10.1002/ehf2.14026. Online ahead of print.

ABSTRACT

AIMS: The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme consisted of three parallel, randomized, double-blind clinical trials comparing candesartan with placebo in patients with heart failure (HF) categorized according to left ventricular ejection fraction and tolerability to an angiotensin-converting enzyme inhibitor. We conducted a pharmacogenomic study of the CHARM trials with the objective of identifying genetic predictors of HF progression and of the efficacy and safety of treatment with candesartan.

METHODS: We performed genome-wide association studies in 2727 patients of European ancestry from CHARM-Overall and stratified by CHARM study according to preserved and reduced ejection fraction and according to assignment to the interventional treatment with candesartan. We tested genetic association with the composite endpoint of cardiovascular death or hospitalization for heart failure for drug efficacy in candesartan-treated patients and for HF progression using patients from both candesartan and placebo arms. The safety endpoints for response to candesartan were hyperkalaemia, renal dysfunction, hypotension, and change in systolic blood pressure between baseline and 6 weeks of treatment. To support our observations, we conducted a genome-wide gene-level collapsing analysis from whole-exome sequencing data with the composite cardiovascular endpoint.

RESULTS: We found that the A allele (14% allele frequency) of the genetic variant rs66886237 at 8p21.3 near the gene GFRA2 was associated with the composite cardiovascular endpoint in 1029 HF patients with preserved ejection fraction from the CHARM-Preserved study (hazard ratio: 1.91, 95% confidence interval: 1.55-2.35; P = 1.7 × 10-9 ). The association was independent of candesartan treatment, and the genetic variant was not associated with the cardiovascular endpoint in patients with reduced ejection fraction. None of the genome-wide association studies for candesartan safety or efficacy conducted in patients treated with candesartan passed the significance threshold. We found no significant association from the gene-level collapsing analysis.

CONCLUSIONS: We have identified a candidate genetic variant potentially predictive of the progression of heart failure in patients with preserved ejection fraction. The findings require further replication, and we cannot exclude the possibility that the results may be chance findings.

PMID:35736394 | DOI:10.1002/ehf2.14026

Pharmacogenomics. 2022 Jun 23. doi: 10.2217/pgs-2022-0042. Online ahead of print.

ABSTRACT

Aim: This systematic review aimed to outline the outcome of OPRMI (A118G) variants on the effects of anesthetic and analgesic agents used in various procedures. Materials & methods: Literature was obtained from reliable, established databases and reference tracking. Efficacy and side/adverse effects of anesthetic and analgesic drugs intraoperatively or within 48 h postsurgery were the key outcome measures for all populations. Animal studies were excluded. Results: Twenty-nine studies were chosen for inclusion. In association with the efficacy and safety of anesthetic and analgesic agents, gene polymorphism in OPRM1 displayed a strong correlation in reduced analgesic effect and protection against adverse reactions. Conclusion: This systematic review summarized the correlation between genetic polymorphism in the OPRM1 gene and anesthetic/analgesic effects.

PMID:35735174 | DOI:10.2217/pgs-2022-0042

Tijdschr Psychiatr. 2022;64(5):312-316.

ABSTRACT

BACKGROUND: Medication side effects and limited efficacy are substantial problems in general and also in psychopharmaceuticals. Previous studies have shown that pharmacogenetic individual characteristics can be relevant.

AIM: To arrive at a responsible use of pharmacogenetics, exploiting its potential but also avoiding overdiagnosis.

METHOD: To provide an overview of the current status quo in the field of pharmacogenetics in psychiatry.

RESULTS: The Dutch Association for Psychiatrists (NVvP) authorized a guideline ‘Pharmacogenetics in Psychiatry’ that is summarized. Also the current international guidelines and clinical implementation of pharmacogenetics are discussed.

CONCLUSION: For the time being, pharmacogenetics seems to be indicated only when patients have already experienced problems with psychopharmaca use, such as side effects and/or inefficacy. If genotyping is requested then generally CYP2C19 and CYP2D6 can be useful, as dosage recommendations are available in case of genetic variants.

PMID:35735043

Expert Rev Mol Diagn. 2022 Jun 22. doi: 10.1080/14737159.2022.2093638. Online ahead of print.

ABSTRACT

INTRODUCTION: Non-steroidal anti-inflammatory drugs and opioids are widely prescribed for the treatment of mild to severe pain. Wide interindividual variability regarding the analgesic efficacy and adverse reactions to these drugs (ADRs) exist, although the mechanisms responsible for these ADRs are not well understood.

AREAS COVERED: We provide an overview of the clinical impact of variants in genes related to the pharmacokinetics and pharmacodynamics of painkillers, as well as those associated with the susceptibility to ADRs. Also, we discuss the current pharmacogenetic-guided treatment recommendations for the therapeutic use of non-steroidal anti-inflammatory drugs and opioids.

EXPERT OPINION: In the light of the data analyzed, common variants in genes involved in pharmacokinetics and pharmacodynamics processes may partially explain the lack of response to painkiller treatment and the occurrence of adverse drug reactions. The implementation of high-throughput sequencing technologies may help to unveil the role of rare variants as considerable contributors to explaining the interindividual variability in drug response. Furthermore, a consensus between the diverse pharmacogenetic guidelines is necessary to extend the implementation of pharmacogenetic-guided prescription in daily clinical practice. Additionally, the physiologically-based pharmacokinetics and pharmacodynamics modeling techniques may contribute to the improvement of these guidelines and facilitate clinicians drug dose adjustment.

PMID:35733288 | DOI:10.1080/14737159.2022.2093638

Am J Health Syst Pharm. 2022 Jun 22:zxac168. doi: 10.1093/ajhp/zxac168. Online ahead of print.

ABSTRACT

In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PMID:35732271 | DOI:10.1093/ajhp/zxac168

J Microbiol Methods. 2022 Jun 19:106524. doi: 10.1016/j.mimet.2022.106524. Online ahead of print.

ABSTRACT

The detection of Salmonella in food is based on the use of a selective enrichment broth such as Muller-Kauffman Tetrathionate-Novobiocin (MKTTn), in which tetrathionate plays a key role by providing Salmonella with a growth advantage. As sodium tetrathionate is unstable, it is generated in situ by the addition of iodine (Lugol's solution) before seeding. This step is cumbersome as the solution is easily spilled, compromising the performance of the medium and hindering the work of technicians. The aim of this study was to optimize MKTTn broth by generating tetrathionate ex situ through an external reaction between iodine and thiosulphate followed by lyophilization. Quality control procedures were performed to compare the modified and original media, testing pure productivity (enrichment with 50-120 CFU of Salmonella Thyphimurim ATCC 14028 and Salmonella Enteritidis ATCC 13076 and plating on Xylose Lysine Deoxycholate agar, XLD), mixed productivity (50-120 CFU of Salmonella strains and Pseudomonas aeruginosa and Escherichia coli at ≥104 CFU and XLD plating) and selectivity (≥104 CFU of P. aeruginosa and Enterococcus faecalis and plating on Tryptone Casein Soy agar, TSA). The modified MKTTn medium (S/L) performed comparably with the original medium in terms of growth of both Salmonella strains (>300 colonies in XLD), alone or with P. aeruginosa and E. coli. Quantitative assays showed no statistically significant differences in the number of colonies grown on XLD after 10-5 dilution (p = 0.7015 with S. Thyphimurim ATCC 14028 and p = 0.2387 with S. enteritidis ATCC 13076; ANOVA test). MKTTn medium (S/L) was also selective against E. coli (≤100 colonies) and E. faecalis (<10 colonies). These results suggest that adding tetrathionate as a lyophilisate (S/L) is a feasible alternative to the use of Lugol's solution for the preparation of MKTTn enrichment broth and does not affect the properties of the medium.

PMID:35732231 | DOI:10.1016/j.mimet.2022.106524

J Clin Pharm Ther. 2022 Jun 22. doi: 10.1111/jcpt.13716. Online ahead of print.

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: Red man syndrome (RMS) is a non-IgE-mediated anaphylactoid adverse event frequently witnessed after a rapid infusion of vancomycin. This study aims to unravel drugs and associated off-label targets that induce RMS by exploiting FDA Adverse Event Reporting System (FAERS) and Pharmacovigilance/Pharmacogenomics Insilico Pipeline (PHARMIP).

METHODS: The case/non-case retrospective observational study was conducted in the FAERS database. Reporting odds ratio (ROR) and proportional reporting ratio (PRR) data mining algorithms were used to evaluate the strength of the signal. The off-label targets of the drugs with potential signals were obtained using online servers by applying a similarity ensemble approach and a reverse pharmacophore database, which was further validated by molecular docking studies.

RESULTS AND DISCUSSION: Oritavancin exhibited a strong positive signal (PRR:1185.20 and ROR:1256), which suggests a higher risk for causing RMS. The literature search revealed the involvement of the MRGPRX2 gene in the development of RMS. PHARMIP study unearthed Carbonic anhydrase II (CA2) as the common off-label target among the drugs causing RMS. The results obtained from molecular docking studies reinforced the findings as mentioned earlier, wherein the highest docking score was disinterred for oritavancin (-9.4 for MRGPRX2 and - 8.7 for CA2).

WHAT IS NEW AND CONCLUSION: Many antibiotics and other classes of medications have been discovered in the quest for drugs that may induce RMS, although a causal relationship could not be established. The implication of MRGPX2 and CA2 in the initial stages of pathogenesis necessitates the development of inhibitors that could be used as potential therapeutic agents against RMS.

PMID:35730973 | DOI:10.1111/jcpt.13716

Pharmacogenomics. 2022 Jun 21. doi: 10.2217/pgs-2022-0020. Online ahead of print.

ABSTRACT

Background: Chronic shoulder pain/disability is a well-recognized side effect of treatment for breast cancer, with ∼40% of patients experiencing this, despite receiving pain management. To manage acute and chronic pain, several opioids are commonly prescribed. Pharmacogenomics have implicated genes within the opioid signaling pathway, including ABCB1 and OPRM1, to contribute to an individual's variable response to opioids. Aim: To evaluate ABCB1 (rs1045642 G>A, rs1128503 G>A) and OPRM1 (rs1799971 A>G, rs540825 T>A) single-nucleotide polymorphisms (SNPs) in chronic shoulder pain/disability in BCS. Materials and methods: TaqManTM assays were used to genotype ABCB1 and OPRM1 SNPs within the BCS (N = 252) cohort. The Shoulder Pain and Disability Index was used to evaluate pain and disability features associated with shoulder pathologies. Participants end scores for each feature (pain, disability and combined [pain and disability]) were categorized into no-low (>30%) and moderate-high (≥30%) scores. Statistical analysis was applied, and significance was accepted at p < 0.05. Results: 27.0, 19.0 and 22.0% of participants reported moderate-high pain, disability and combined (pain and disability) scores, respectively. ABCB1:rs1045642-(A/A) genotype was significantly associated with disability (p = 0.028: no-low [14.9%] vs mod-high [4.3%]) and combined (pain and disability) (p = 0.011: no-low [15.9%] vs mod-high [5.7%]). The ABCB1:rs1045642-(A) allele was significantly associated with disability (p = 0.015: no-low [37.9%] vs mod-high [23.9%]) and combined (pain and disability) (p = 0.003: no-low [38.5%] vs mod-high [23.6%]). The inferred ABCB1 (rs1045642 G>A-rs1128503 G>A): A-G (p = 0.029; odds ratio [OR]: 0.0; 95% CI: 0.0-0.0) and the OPRM1 (rs1799971 A>G - rs540825 T>A): G-T (p = 0.019; OR: 0.33; 95% CI: 0.14-0.75) haplotypes were associated with disability and pain, respectively. Gene-gene interactions showed the ABCB1 (rs1045642 G>A) - OPRM1 (rs540825 T>A) combinations, (A-T) (p = 0.019; OR: 0.62; 95% CI: 0.33-1.16) and (G-A) (p = 0.021; OR: 1.57; 95% CI: 0.30-3.10) were associated with disability. Conclusion: The study implicated ABCB1 with shoulder pain and disability; and haplotype analyses identified specific genetic intervals within ABCB1 and OPRM1 to associate with chronic shoulder pain and disability. Evidence suggests that potentially gene-gene interactions between ABCB1 and OPRM1 contribute to chronic shoulder pain and disability experienced in this SA cohort.

PMID:35727214 | DOI:10.2217/pgs-2022-0020

Kardiol Pol. 2022 Jun 21. Online ahead of print.

NO ABSTRACT

PMID:35726819

Expert Rev Neurother. 2022 Jun 21. doi: 10.1080/14737175.2022.2093107. Online ahead of print.

ABSTRACT

INTRODUCTION: : The therapeutic management of women with epilepsy (WWE) of childbearing age can be complicated by the need to balance maternal/fetal risks related to seizure occurrence during gestation with the potential teratogenic risks related to the use of anti-seizure medications (ASMs).

AREAS COVERED: : The authors review clinical evidence on seizure-related and ASM-related risks during pregnancy. Current regulatory indications are discussed, evaluating their impact on clinical practice, and ethical implications of pharmacological decisions are debated.

EXPERT OPINION: : If properly informed about the maternal/fetal risks carried by different pharmacological choices, WWE can become the final decision makers regarding their care in every phase of their life. Over the coming years, analysis of aggregated pregnancy registry data on the structural impact, on the fetus, of low doses of valproate and of newer ASMs, together with analysis of the main population study data on functional (cognitive and behavioral) outcomes, could lead to huge advances, making choosing an ASM a less complex process for the clinician and a less painful decision for the woman. Future objectives should include identification of the potential role of the pharmacogenomic profile of WWE in determining the risk of fetal malformations.

PMID:35726788 | DOI:10.1080/14737175.2022.2093107

Pharm Res. 2022 Jun 21. doi: 10.1007/s11095-022-03289-9. Online ahead of print.

ABSTRACT

PURPOSE: Venetoclax (VEN), an anti-tumor drug that is a substrate of cytochrome P450 3A enzyme (CYP3A4), is used to treat leukemia. Voriconazole (VCZ) is an antifungal medication that inhibits CYP3A4. The goal of this study is to predict the effect of VCZ on VEN exposure.

METHOD: Two physiological based pharmacokinetics (PBPK) models were developed for VCZ and VEN using the bottom-up and top-down method. VCZ model was also developed to describe the effect of CYP2C19 polymorphism on its pharmacokinetics (PK). The reversible inhibition constant (Ki) of VCZ for CYP3A4 was calibrated using drug-drug interaction (DDI) data of midazolam and VCZ. The clinical verified VCZ and VEN model were used to predict the DDI of VCZ and VEN at clinical dosing scenario.

RESULT: VCZ model predicted VCZ exposure in the subjects of different CYP2C19 genotype and DDI related fold changes of sensitive CYP3A substrate with acceptable prediction error. VEN model can capture PK of VEN with acceptable prediction error. The DDI PBPK model predicted that VCZ increased the exposure of VEN by 4.5-9.6 fold. The increase in VEN exposure by VCZ was influenced by subject's CYP2C19 genotype. According to the therapeutic window, VEN dose should be reduced to 100 mg when co-administered with VCZ.

CONCLUSION: The PBPK model developed here could support individual dose adjustment of VEN and DDI risk assessment. Predictions using the robust PBPK model confirmed that the 100 mg dose adjustment is still applicable in the presence of VCZ with high inter-individual viability.

PMID:35725843 | DOI:10.1007/s11095-022-03289-9

Pharmacogenomics J. 2022 Jun 20. doi: 10.1038/s41397-022-00283-7. Online ahead of print.

ABSTRACT

The heterogeneity of psychiatric disorders and the lack of reliable biomarkers for prediction and treatments follow-up pose difficulties towards recognition and understanding of the molecular basis of psychiatric diseases. However, several studies based on NGS approaches have shown that miRNAs could regulate gene expression during onset and disease progression and could serve as potential diagnostic and pharmacogenomics biomarkers during treatment. We provide herein a detailed overview of circulating miRNAs and their expression profiles as biomarkers in schizophrenia, bipolar disorder and major depressive disorder and their role in response to specific treatments. Bioinformatics analysis of miR-34a, miR-106, miR-134 and miR-132, which are common among SZ, BD and MDD patients, showed brain enrichment and involvement in the modulation of critical signaling pathways, which are often deregulated in psychiatric disorders. We propose that specific miRNAs support accurate diagnosis and effective precision treatment of psychiatric disorders.

PMID:35725816 | DOI:10.1038/s41397-022-00283-7

ARP Rheumatol. 2022 Feb 27. Online ahead of print.

ABSTRACT

BACKGROUND: Methotrexate (MTX) is an anti-folate drug with anti-proliferative and anti-inflammatory effects. MTX proved to be the most highly effective, fast-acting disease modifying anti-rheumatic drug (DMARD), being widely used for the treatment of rheumatoid arthritis (RA). This review aims to describe the main genetic variants identified concerning proteins that play a role in methotrexate's kinetics and efficiency profile.

METHODS: A literature review was conducted since January of 2000 until December 2020, by searching the PubMed and Embase bibliographic databases, employing the following MeSH terms: methotrexate, pharmacogenetics, pharmacokinetics, and rheumatoid arthritis. The search was limited to articles in English language. Two independent reviewers screened the titles and abstracts followed by a full-text review to assess papers regarding their eligibility. A total of 48 articles matched the research criteria and were analyzed.

RESULTS: Reduced folate carrier 1 (RFC1), a constitutively expressed folate transport protein that has high affinity for MTX is responsible, almost exclusively, for the transport of folate and MTX into the cell. The most studied variant of the gene is the 80G>A variant, mapped within exon 2, on chromosome 21. It seems to improve RA responses to MTX, clinical efficacy with long disease remission. ABC transporters are involved in the efflux of MTX from cells. An increased expression and function of these transporters should decrease MTX concentrations in target cells, resulting in lack of therapeutic response. ABCB1 3435 C/T is a high frequency polymorphism, significantly associated with RA good responses, symptom remission and reduced adverse events, due to MTX treatment. Thymidylate synthase (TYMS) is involved in thymidine synthesis. MTX decreases TYMS activity by inhibition and decreasing the access to tetrahydrofolate (THF) cofactors. The most common genetic variant of the TYMS gene consists of a 28 bp tandem repeat, with double and triple number of repeats (2R and 3R). The 3R allele genotype was associated with decreased efficacy and increased toxicity. The 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme is indirectly inhibited by MTX. The most common SNPs of the MTHFR gene are C677T and A1298C. Both are associated with a decreased efficacy and an increased toxicity of MTX.

CONCLUSION: MTX response is affected by many gene variants; the effect of each variant separately is likely to be small. Additionally, gene-gene interaction seems to enhance the potential role of linkage disequilibrium. This shows the emerging need for a better gene characterization and to improve the knowledge about variants distribution according to ethnicity, to explain different responses to MTX at an individual level.

PMID:35724450

Curr Issues Mol Biol. 2022 Jan 14;44(1):350-359. doi: 10.3390/cimb44010026.

ABSTRACT

CD147 (basigin, BSG) is a membrane-bound glycoprotein involved in energy metabolism that plays a role in cancer cell survival. Its soluble form is a promising marker of some diseases, but it is otherwise poorly studied. CD147 is overexpressed in multiple myeloma (MM) and is known to affect MM progression, while its genetic variants are associated with MM survival. In the present study, we aimed to assess serum soluble CD147 (sCD147) expression as a potential marker in MM. We found that sCD147 level was higher in MM patients compared to healthy individuals. It was also higher in patients with more advanced disease (ISS III) compared to both patients with less advanced MM and healthy individuals, while its level was observed to drop after positive response to treatment. Patients with high sCD147 were characterized by worse progression-free survival. sCD147 level did not directly correlate with bone marrow CD147 mRNA expression. In conclusion, this study suggests that serum sCD147 may be a prognostic marker in MM.

PMID:35723405 | DOI:10.3390/cimb44010026

Curr Issues Mol Biol. 2022 Apr 5;44(4):1552-1563. doi: 10.3390/cimb44040106.

ABSTRACT

Personalized treatments based on the genetic profiles of tumors can simultaneously optimize efficacy and minimize toxicity, which is beneficial for improving patient outcomes. This study aimed to integrate gene alterations associated with predictive and prognostic outcomes in patients with metastatic colorectal cancer (mCRC) with polymerase chain reaction (PCR) and in-house next-generation sequencing (NGS) to detect KRAS, NRAS, and BRAF mutations. In the present study, 41 patients with mCRC were assessed between August 2017 and June 2019 at a single institution. The overall concordance between NGS and PCR results for detecting KRAS, NRAS, and BRAF mutations was considerably high (87.8-92.7%), with only 15 discrepant results between PCR and NGS. Our companion diagnostic test analyzes KRAS, NRAS, and BRAF as a panel of CRC molecular targets; therefore, it has the advantages of requiring fewer specimens and being more time and cost efficient than conventional testing for separate analyses, allowing for the simultaneous analysis of multiple genes.

PMID:35723364 | DOI:10.3390/cimb44040106

Croat Med J. 2022 Jun 22;63(3):287-294.

ABSTRACT

In patients with COVID-19, thromboinflammation is one of the main causes of morbidity and mortality, which makes anticoagulation an integral part of treatment. However, pharmacodynamic and pharmacokinetic properties of direct oral anticoagulants (DOACs) limit the use of this class of anticoagulants in COVID-19 patients due to a significant interference with antiviral agents. DOACs use in COVID-19 hospitalized patients is currently not recommended. Furthermore, patients already on oral anticoagulant drugs should be switched to heparin at hospital admission. Nevertheless, outpatients with a confirmed diagnosis of COVID-19 are recommended to continue prior DOAC therapy. More studies are required to clarify the pathogenesis of COVID-19-induced derangement of the coagulation system in order to recommend an appropriate anticoagulant treatment.

PMID:35722697

Croat Med J. 2022 Jun 22;63(3):257-264.

ABSTRACT

AIM: To assess the prevalence of actionable pharmacogenetic interventions in patients who underwent pharmacogenetic testing with a multi-gene panel.

METHODS: We retrospectively reviewed single-center electronic health records. A total of 319 patients were enrolled who underwent pharmacogenomic testing with the RightMed test panel using TaqMan quantitative real-time PCR method and copy number variation analysis to determine the SNPs in the 27 target genes.

RESULTS: Actionable drug-gene pairs were found in 235 (73.7%) patients. Relevant guidelines on genotype-based prescribing were available for 133 (56.7%) patients at the time of testing. Based on the patients' genotype, 139 (43.6%) patients were using at least one drug with significant pharmacogenetic interactions.

CONCLUSION: Two out of three patients had at least one drug-gene pair in their therapy. Further studies should assess the clinical effectiveness of integrating pharmacogenomic data into patients' electronic health records.

PMID:35722694

ACS Omega. 2022 Jun 1;7(23):19243-19260. doi: 10.1021/acsomega.2c00518. eCollection 2022 Jun 14.

ABSTRACT

Novel drug development is a time-consuming process with relatively high debilitating costs. To overcome this problem, computational drug repositioning approaches are being used to predict the possible therapeutic scaffolds against different diseases. In the current study, computational drug repositioning approaches were employed to fetch the promising drugs from the pool of FDA-approved drugs against Ewing sarcoma. The binding interaction patterns and conformational behaviors of screened drugs within the active region of Ewing sarcoma protein (EWS) were confirmed through molecular docking profiles. Furthermore, pharmacogenomics analysis was employed to check the possible associations of selected drugs with Ewing sarcoma genes. Moreover, the stability behavior of selected docked complexes (drugs-EWS) was checked by molecular dynamics simulations. Taken together, astemizole, sulfinpyrazone, and pranlukast exhibited a result comparable to pazopanib and can be used as a possible therapeutic agent in the treatment of Ewing sarcoma.

PMID:35721972 | PMC:PMC9202290 | DOI:10.1021/acsomega.2c00518