RESUMEN
Alzheimer's disease (AD) is a significant global healthcare challenge, particularly in the elderly population. This neurodegenerative disorder is characterized by impaired memory and progressive decline in cognitive function. BACE1, a transmembrane protein found in neurons, oligodendrocytes, and astrocytes, exhibits varying levels across different neural subtypes. Abnormal BACE1 activity in the brains of individuals with AD leads to the formation of beta-amyloid proteins. The complex interplay between myelin sheath formation, BACE1 activity, and beta-amyloid accumulation suggests a critical role in understanding the pathological mechanisms of AD. The primary objective of this study was to identify molecular inhibitors that target Aß. Structure-based virtual screening (SBVS) was employed using the MCULE database, which houses over 2 million chemical compounds. A total of 59 molecules were selected after the toxicity profiling. Subsequently, five compounds conforming to the Egan-Egg permeation predictive model of the ADME rules were selected and subjected to molecular docking using AutoDock Vina on the Mcule drug discovery platform. The top two ligands and the positive control, 5HA, were subjected to molecular dynamics simulation for five nanoseconds. Toxicity profiling, physiochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness, medicinal chemistry attributes, average potential energy, RMSD, RMSF, and Rg analyses were conducted to identify the ligand MCULE-9199128437-0-2 as a promising inhibitor of BACE1.
Asunto(s)
Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/química , Humanos , Ligandos , Descubrimiento de Drogas/métodos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/químicaRESUMEN
Cancer is regarded as one of the world's most serious health issues. Glucose regulated protein (GRP78) exhibits a vital role in the proliferation, invasion, and metastasis of numerous cancer cells. Based on that, this study screened the 390 natural compounds targeting the GRP78 catalytic site. Among them, corynanthin, toyocamycin, and nanaomycin were found to strongly bind with GRP78 and possess the binding affinities of -8.4, -8.9, and -8.7 kcal/mol, respectively. In addition, these compounds interacted with key residues of GRP78 and have several amino acid residues interaction in common with the cocrystal ligand (ATP). Based on physicochemical parameters and ADME evaluations, these compounds were found to have good drug-like properties. These compounds could be used as possible GRP78 inhibitors in the fight against cancers. Albeit, exhaustive experimental studies would be required to confirm the findings described here.
RESUMEN
AIM: We aimed to evaluate the levels of urine microalbumin, urine albumin creatinine ratio, plasma creatinine and glycosylated hemoglobin (HbA1c) among type 2 diabetic patients and assessed the correlation between microalbuminuria and plasma creatinine levels. MATERIALS AND METHODS: A retrospective chart review study was conducted at Department of Clinical Chemistry, King Abdulaziz Medical City in Riyadh, Saudi Arabia, during August to December 2014. The study included 100 male and female patients diagnosed with type 2 diabetes mellitus (DM) and excluding patients with type 1 DM. Medical history and biochemical laboratory data were obtained from medical records and from biochemistry laboratory database. RESULTS: Increase in mean level of plasma creatinine (138 µmol/L), urine microalbuminuria (240 mg/L), albumin creatinine ratio (82) and HbA1c (8.7%) was observed among type 2 DM patients. Moderate positive correlation was observed between microalbuminuria and urine albumin creatinine ratio (r = 0.509 P = 0.0006) and between urine albumin creatinine ratio and plasma creatinine (r = 0.553 P = 0.017). CONCLUSION: We concluded that type 2 DM patients who are at risk of developing renal impairment must be regularly monitored for microalbuminuria, urine albumin creatinine ratio, and HbA1c levels.