👤 Avik Atta

Alzheimer's disease (AD) is a neurodegenerative condition characterized by significant synaptic loss and neuronal death in brain regions critical for cognitive functions. The disease is characterized by the formation of amyloid plaques, which are extracellular constructs consisting mainly of aggregated Aβ42. The latter is a peptide formed by the proteolytic cleavage of β-amyloid precursor protein (APP) by two enzymes, β- and γ-secretase. Therefore, inhibition of the aspartic protease β-secretase (BACE1) is considered a promising therapeutic approach for the treatment and prevention of Alzheimer's disease. Unfortunately, a limited number of β-secretase inhibitors have reached human trials and eventually failed due to inconclusive therapeutic and/or safety profiles. In this study, we developed drug-like molecules with a β-secretase inhibitory activity using a fragment growing strategy on isocytosine and acyl guanidine warheads. Our approach is based on optimizing the hydrophobic part of the molecules to obtain a conformationally restrained scaffold complementary to the hydrophobic pockets within the enzyme active site. We developed 32 compounds with promising Show less

Cytokines play a major role in the pathogenesis and progression of psoriasis. Interleukin (IL)-30 is a multifunctional cytokine. It binds to glycoprotein 130 (GP130) and inhibits the GP130 signaling pathways of psoriasis associated cytokines such as IL-6, IL-11, and IL-27. The study intended to assess associations of IL-30 and GP130 with the risk of psoriasis and Psoriasis Area Severity Index (PASI) score. Therefore, we measured the serum levels of IL-30 and GP130 in psoriasis patients and in a control group. An enzyme linked immunosorbent assay (ELISA) technique was used to measure IL-30 and GP130 levels in the serum of 43 patients and 43 normal controls. Statistical analysis of IL-30 and GP130 serum levels among patients and control groups and their correlation with PASI scores were performed. IL-30 serum levels showed a significant increase in patients with psoriasis compared with controls (p < 0.001) and a positive correlation with PASI scores. While serum levels of GP130 were not different in psoriatic patients and in the control group. Furthermore, the receiver operating characteristic (ROC) curve showed that IL-30 had diagnostic ability for prediction of psoriasis in comparison to controls, at cut of point of >14.34 showed a sensitivity of 97.7%, 100% specificity. In conclusion, IL-30 was elevated in psoriasis patients than controls, therefore, it can be considered a sensitive biomarker for diagnosis of psoriasis. Show less

The Central nervous system is blemished by the high incidence of neurodegenerative diseases, which is known to cause disfiguration of regeneration and repair of axonal growth. Recognition of proteins that act as agents of repressing such repair has become the norm to tackle these abominable conditions. One such protein is LINGO1 that act as a repressor for axonal growth. Being one of the critical causative agents of several neurodegenerative pathways. Consequently, its inhibition may tend to help the outcomes of regenerative technologies aiming to outweigh the symptoms of neurodegenerative diseases. For this objective, LINGO1 was targeted with pharmacophore analogs of Fasudil and Ibuprofen, as they are known to have a deterring effect against the concerned protein. 1-Tosyl-2-(chloromethyl)-2,3-dihydro-1H-indole was found showing the least binding score of - 6.8, with verified ADMET admissibility. The pharmacological activity of the said ligand was estimated with QSAR tool showing favourable electro-steric model. All this was finally collaborated with a molecular dynamics simulation study which exhibited a stable structure compatibility of the ligand with LINGO-1. Further, the efficacy of the compound can be evaluated through experimental studies for inferring its future potential and utilization as an effective means to tackle neuronal regeneration and remyleination. The online version contains supplementary material available at 10.1007/s13205-023-03789-4. Show less