Identification of Potent Caspase-3 Inhibitors for Treatment of Multi- Neurodegenerative Diseases Using Pharmacophore Modeling and Docking Approaches

Abstract

Neurodegenerative disorders are due to excessive neuronal apoptosis and the caspase-3 plays a key role in the apoptotic pathway. The caspase-3 inhibition may be a validated therapeutic approach for neurodegenerative disorders and an interesting target for molecular modeling studies using both Ligand and structure based approaches. In view of the above we have generated the Ligand based pharmacophore model using the Discovery studio 2.0 software. In addition to this a structure based approach has been used to validate the developed pharmacophoric features to gain a deeper insight into its molecular recognition process. This validated pharmacophore and the docking model was then implemented as a query for pharmacophore based virtual screening to prioritize the probable hits for the Caspase-3. Two ligands, ZINC12405015 and ZINC12405043 were finally selected on the basis of their fit values and docking scores. This study also reveals the important amino acids viz. His-121, Ser-205, Arg-207 which were found to be playing crucial role in the binding of the selected compounds within the active site of caspase-3.

Commonalities in Biological Pathways, Genetics, and Cellular Mechanism between Alzheimer Disease and Other Neurodegenerative Diseases: An In Silico-Updated Overview

“…Abnormalities in brain functions, such as memory, movement, and cognition, result in neurodegenerative disorders [4]. Various studies have reported that neurodegeneration is prompted rapidly by the combination of progressive neuronal loss and dysfunction [5, 6]. A common feature of many NDs is an extended time course until a sufficient amount of abnormal protein forms into aggregates, in addition to many symptoms over years with increasing disability [7].…”

Synthesis and characterisation of celastrol derivatives as potential anticancer agents

“…In all probability, compound 11 as a celastrol derivative could induce apoptosis by inducing the activation of caspases. The caspase-3 plays a key role in the apoptotic pathway 24 . To confirm this speculation, in this text, docking simulation was performed to position compound 11 into the caspase-3 (1GFW) active site to determine the probable binding model ( Figure 2 ).…”

Targeting Caspase 8: Using Structural and Ligand-Based Approaches to Identify Potential Leads for the Treatment of Multi-Neurodegenerative Diseases

“…Based on our previous studies on approaches to indirect drug design [32,33] and in the field of neurodegenerative disease [33] we decided to focus on caspase 8 inhibitors. Molecules reported in the literature were collated [26], but biological activity data did not exhibit the required 3 log unit variation necessary to develop a quantitative pharmacophore model using the Hypogen module in Catalyst software.…”