In-silico lead identification of the pan-mutant IDH1 and IDH2 inhibitors to target glioblastoma.

Glioblastoma (GBM) is an aggressive malignant type of brain tumor. Targeting one single intracellular pathway might not alleviate the disease, rather it activates the other molecular pathways that lead to the worsening of the disease condition. Therefore, in this study, we attempted to target both isocitrate dehydrogenase 1 (IDH1) and IDH2, which are one of the most commonly mutated proteins in GBM and other cancer types. Here, standard precision and extra precision docking, IFD, MM-GBSA, QikProp, and molecular dynamics (MD) simulation were performed to identify the potential dual inhibitor for IDH1 and IDH2 from the enamine database containing 59,161 ligands. Upon docking the ligands with IDH1 (PDB: 6VEI) and IDH2 (PDB: 6VFZ), the top eight ligands were selected, based on the XP Glide score. These ligands produced favourable MMGBSA scores and ADME characteristics. Finally, the top four ligands 12953, 44825, 51295, and 53210 were subjected to MD analysis. Interestingly, 53210 showed maximum interaction with Gln 277 for 99% in IDH1 and Gln 316 for 100% in IDH2, which are the crucial amino acids for the inhibitory function of IDH1 and IDH2 to target GBM. Therefore, the present study attempts to identify the novel molecules which could possess a pan-inhibitory action on both IDH1 and IDH that could be crucial in the management of GBM. Yet further evaluation involving in vitro and in vivo studies is warranted to support the data in our current study.Communicated by Ramaswamy H. Sarma.

Current Drug Targets in Alzheimer's Associated Memory Impairment: A Comprehensive Review.

Alzheimer's disease (AD) is the most prevalent form of dementia among geriatrics. It is a progressive, degenerative neurologic disorder that causes memory and cognition loss. The accumulation of amyloid fibrils and neurofibrillary tangles in the brain of AD patients is a distinguishing feature of the disease. Therefore, most of the current therapeutic goals are targeting inhibition of beta-amyloid synthesis and aggregation as well as tau phosphorylation and aggregation. There is also a loss of the cholinergic neurons in the basal forebrain, and first-generation therapeutic agents were primarily focused on compensating for this loss of neurons. However, cholinesterase inhibitors can only alleviate cognitive symptoms of AD and cannot reduce the progression of the disease. Understanding the molecular and cellular changes associated with AD pathology has advanced significantly in recent decades. The etiology of AD is complex, with a substantial portion of sporadic AD emerging from unknown reasons and a lesser proportion of early-onset familial AD (FAD) caused by a mutation in several genes, such as the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes. Hence, efforts are being made to discover novel strategies for these targets for AD therapy. A new generation of AChE and BChE inhibitors is currently being explored and evaluated in human clinical trials for AD symptomatic treatment. Other approaches for slowing the progression of AD include serotonergic modulation, H3 receptor antagonism, phosphodiesterase, COX-2, and MAO-B inhibition. The present review provides an insight into the possible therapeutic strategies and their molecular mechanisms, enlightening the perception of classical and future treatment approaches.

Zinc as a plausible epigenetic modulator of glioblastoma multiforme.

Glioblastoma Multiforme (GBM) is an aggressive brain tumor (WHO grade 4 astrocytoma) with unknown causes and is associated with a reduced life expectancy. The available treatment options namely radiotherapy, surgery and chemotherapy have failed to improve life expectancy. Out of the various therapeutic approaches, epigenetic therapy is one of the most studied. Epigenetic therapy is involved in the effective treatment of GBM by inhibiting DNA methyltransferase, histone deacetylation and non-coding RNA. It also promotes the expression of the tumor suppressor gene and is involved in the suppression of the oncogene. Various targets are being studied to implement proper epigenetic regulation to control GBM effectively. Zinc is one of the micronutrients which is considered to maintain epigenetic regulation by promoting the proper DNA folding, protecting genetic material from the oxidative damage and controlling the enzyme activation involved in the epigenetic regulation. Here, we are discussing the importance of zinc in regulating the epigenetic modifications and assessing its role in glioblastoma research. The discussion also highlights the importance of artificial intelligence using epigenetics for envisaging the glioma progression, diagnosis and its management.