Design of novel anti Alzheimer ligands based on contilisant structure by scaffold hopping method

Abstract

Alzheimer’s disease (AD) as a neurodegenerative disease is being increased among the aged population. Due to the multifaceted pathophysiological nature of AD, several efforts have been made for designing therapeutic agents with simultaneous modulation of multiple targets involved in AD. Cholinesterase enzymes and H3 receptors are the known targets which are implicated in AD. Reduced levels of acetylcholine trigger progressive loss of memory and cognition in AD. So inhibition of cholinesterase enzymes and antagonizing H3 receptors can enhance the acetylcholine level in synaptic transmission which ameliorate the symptoms of AD. Aim:The purpose of the current work was to identify novel multi-target directed ligands(MTDLs) as anti-Alzheimer agents using scaffold hopping method based on contilisant structure as lead compound. Materials and methods: In the current work, structure-based approaches were applied for design of MTDLs. To this end, contilisant was structurally modified using bioisosteric replacement tool implemented in Spark program. Designed structures were evaluated in terms of physicochemical, pharmacokinetic and drug-likeness properties. Then molecular docking experiment was conducted for prediction of binding mode of the selected ligands and the corresponding receptors. Finally, molecular dynamic simulation studies were performed for 50 ns with subsequent binding free energy calculation using Molecular Mechanics (MM)-Poisson-Boltzmann Surface Area (PBSA)/Generalized-Born Surface Area (GBSA) methodology.Results:Among the designed structures, we selected six compounds of which compound named C4 was the most appropriate candidate molecule in terms of predicted pharmacokinetic and drug-likeness features. Conclusion: The results of the current investigation can offer new scaffolds for the synthesis and biological evaluations of proposed compounds using in vitro and in vivo assessments.