In Silico Drug Repurposing Against PSMB8 as a Potential Target for Acute Myeloid Leukemia Treatment.

PSMB8 emerges as a prominent gene associated with cancer survival, yet its potential therapeutic role in acute myeloid leukemia (AML) remains unexplored within the existing literature. The principal aim of this study is to systematically screen an expansive library of molecular entities, curated from various databases to identify the prospective inhibitory agents with an affinity for PSMB8. A comprehensive assortment of molecular compounds obtained from the ZINC15 database was subjected to molecular docking simulations with PSMB8 by using the AutoDock tool in PyRx (version 0.9.9) to elucidate binding affinities. Following the docking simulations, a select subset of molecules underwent further investigation through comprehensive ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis employing AdmetSar and SwissADME tools. Finally, RMSD, RMSF, Rg, and H bond analyses were conducted via GROMACS to determine the best conformationally dynamic molecule that represents the candidate agent for the study. Following rigorous evaluation, Adozelesin, Fiduxosin, and Rimegepant have been singled out based on considerations encompassing bioavailability scores, compliance with filter criteria, and acute oral toxicity levels. Additionally, ligand interaction analysis indicates that Adozelesin and Fiduxosin exhibit an augmented propensity for hydrogen bond formation, a factor recognized for its facilitative role in protein-ligand interactions. After final analyses, we report that Fiduxosin may offer a treatment possibility by reversing the low survival rates caused by PSMB8 high activation in AML. This study represents a strategic attempt to repurpose readily available pharmaceutical agents, potentially obviating the need for de novo drug development, and thereby offering promising avenues for therapeutic intervention in specific diseases.

Integrated systems biology analysis of acute lymphoblastic leukemia: unveiling molecular signatures and drug repurposing opportunities.

Acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by aberrant proliferation and accumulation of lymphoid precursor cells within the bone marrow. The tyrosine kinase inhibitor (TKI), imatinib mesylate, has played a significant role in the treatment of Philadelphia chromosome-positive ALL (Ph + ALL). However, the achievement of durable and sustained therapeutic success remains a challenge due to the development of TKI resistance during the clinical course.The primary objective of this investigation is to propose a novel and efficacious treatment approach through drug repositioning, targeting ALL and its Ph + subtype by identifying and addressing differentially expressed genes (DEGs). This study involves a comprehensive analysis of transcriptome datasets pertaining to ALL and Ph + ALL in order to identify DEGs associated with the progression of these diseases to identify possible repurposable drugs that target identified hub proteins.The outcomes of this research have unveiled 698 disease-related DEGs for ALL and 100 for Ph + ALL. Furthermore, a subset of drugs, specifically glipizide for Ph + ALL, and maytansine and isoprenaline for ALL, have been identified as potential candidates for therapeutic intervention. Subsequently, cytotoxicity assessments were performed to confirm the in vitro cytotoxic effects of these selected drugs on both ALL and Ph + ALL cell lines.In conclusion, this study offers a promising avenue for the management of ALL and Ph + ALL through drug repurposed drugs. Further investigations are necessary to elucidate the mechanisms underlying cell death, and clinical trials are recommended to validate the promising results obtained through drug repositioning strategies.

In silico drug screen reveals potential competitive MTHFR inhibitors for clinical repurposing.

MTHFR (Methylenetetrahydrofolate reductase) is a pivotal enzyme involved in one-carbon metabolism, which is critical for the proliferation of cancer cells. In line with this, published literature showed that MTHFR knockdown caused impaired growth of multiple types of cancer cells. Moreover, higher MTHFR expression levels were linked to shorter overall survival in hepatocellular carcinoma, adrenocortical carcinoma, and low-grade glioma, bringing the need to design MTHFR inhibitors as a possible treatment option. No competitive inhibitors of MTHFR have been reported as of today. This study aimed to identify potential competitive MTHFR inhibitor candidates using an in silico drug screen. A total of 30470 molecules containing biogenic compounds, FDA-approved drugs, and those in clinical trials were screened against the catalytic pocket of MTHFR in the presence and absence of cofactors. Binding energy and ADMET analysis revealed that Vilanterol (ß2-adrenergic agonist), Selexipag (prostacyclin receptor agonist), and Ramipril Diketopiperazine (ACE inhibitor) are potential competitive inhibitors of MTHFR. Molecular dynamics analyses and MM-PBSA calculations with these compounds particularly revealed the amino acids between 285-290 for ligand binding and highlighted Vilanterol as the strongest candidate for MTHFR inhibition. Our results could guide the development of novel MTHFR inhibitor compounds, which could be inspired by the drugs brought into the spotlight here. More importantly, these potential candidates could be quhickly tested as a repurposing strategy in pre-clinical and clinical studies of the cancers mentioned above.Communicated by Ramaswamy H. Sarma.

Enthesitis may be one of the signs of severe disease in familial Mediterranean fever.

OBJECTIVE: Familial Mediterranean fever (FMF) is an auto-inflammatory disease that is also characterized with some of the common musculoskeletal features of spondyloarthritis (SpA). Enthesitis is the hallmark of SpA. Recently, it was postulated that exertional leg pain is a possible sign of lower extremity enthesitis associated with FMF severity. In this study, we have evaluated the association between the enthesitis, enthesitis score and disease severity in FMF patients. METHODS: We enrolled 238 FMF patients that fulfilled the modified Tel-Hashomer criteria. We assessed the presence of enthesitis at the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) defined sites with standard palpation method. Then, FMF patients dichotomised two groups as enthesitis group and controls. Herein, we evaluated the enthesis extensity with MASES. FMF disease severity was determined via the international severity scoring system for FMF (ISSF). Firstly, we have compared demographic properties, disease-related features and ISSF scores of the groups. Then, we have correlated ISSF with MASES in enthesitis group. RESULTS: We showed that 54 (22.6%) of 238 patients had enthesitis. The demographic features were similar between the groups. The enthesitis group had higher ISSF scores (p < 0.001); higher frequency of fever (p = 0.004), exertional leg pain (p < 0.001), myalgia (p < 0.001) and arthritis (p = 0.01); and more intense, widespread, frequent and longer attacks compared with controls. Moreover, there was a weak correlation between ISSF and MASES in the patients with enthesitis. CONCLUSION: Enthesitis may be a sign of more severe FMF phenotype and frequently associated with other musculoskeletal manifestations resemble SpA. Key points •More than one-fifth of the patients with FMF would suffer from enthesitis. •The FMF patients with enthesitis had higher ISSF scores; higher frequency of fever, exertional leg pain, myalgia and arthritis; and more intense, widespread, frequent and longer attacks as compared with controls. •Enthesitis may be a sign of more severe FMF phenotype and frequently associated with other SpA-like musculoskeletal feature.