Discovery of novel benzophenone integrated derivatives as anti-Alzheimer’s agents targeting presenilin-1 and presenilin-2 inhibition: A computational approach

Abstract

The most commonly accepted hypothesis of Alzheimer’s disease (AD) is the amyloid hypothesis caused due to formation of accumulation of Aβ42 isoform, which leads to neurodegeneration. In this regard, presenilin-1 (PSEN-1) and -2 (PSEN-2) proteins play a crucial role by altering the amyloid precursor protein (APP) metabolism, affecting γ-secretase protease secretion, finally leading to the increased levels of Aβ. In the absence of reported commercial pharmacotherapeutic agents targeting presenilins, we aim to propose benzophenone integrated derivatives (BIDs) as the potential inhibitors of presenilin proteins through in silico approach. The study evaluates the interaction of BIDs through molecular docking simulations, molecular dynamics simulations, and binding free energy calculations. This is the first ever computational approach to discover the potential inhibitors of presenilin proteins. It also comprises druglikeliness and pharmacotherapeutic potential analysis of the compounds. Out of all the screened BIDs, BID-16 was found to be the lead compound against both the presenilin proteins. Based on these results, one can evaluate BID-16 as an anti-Alzheimer’s potential specifically targeting presenilin proteins in near future using in vitro and in vivo methods.

Phyto-Computational Intervention of Diabetes Mellitus at Multiple Stages Using Isoeugenol from Ocimum tenuiflorum: A Combination of Pharmacokinetics and Molecular Modelling Approaches

“…OB is one of the most significant pharmacokinetic features in addition ADME properties. Whereas, in the case of the TPSA, the compounds with <140 Å TPSA value were considered as more flexible and could interact better with the target protein [ 33 ]. As evident from Table 2 , the values of the selected properties were well within range, and the molecules showed excellent percentages of human oral absorption.…”

Discovery of Novel Coumarin Derivatives as Potential Dual Inhibitors against α-Glucosidase and α-Amylase for the Management of Post-Prandial Hyperglycemia via Molecular Modelling Approaches

“…∆G = ∆ EMM + ∆G Solvation − T∆S = ∆E (Bonded + non-bonded) + ∆G (Polar + non-polar) − T∆S (2) G Binding : binding free energy, G Complex : total free energy of the protein-ligand complex, G Protein and G Ligand : total free energies of the isolated protein and ligand in solvent, respectively, ∆G: standard free energy, ∆ EMM : average molecular mechanics potential energy in vacuum, G Solvation : solvation energy, ∆E: total energy of bonded as well as non-bonded interactions, ∆S: change in entropy of the system upon ligand binding, and T: temperature in Kelvin [27,28].…”

Synthesis, Characterization, Hirshfeld Surface Analysis, Crystal Structure and Molecular Modeling Studies of 1-(4-(Methoxy(phenyl)methyl)-2-methylphenoxy)butan-2-one Derivative as a Novel α-Glucosidase Inhibitor

“…This is an efficient and reliable free energy simulation method used to model molecular recognition, such as for protein-ligand binding interactions. A GROMACS program, g_mmpbsa [21] with the MmPbSaStat.py [22] script was exploited to evaluate the binding free energy for each protein-ligand complex. The g_mmpbsa program calculates binding free energy using three components: molecular mechanical energy, polar and apolar solvation energies, and molecular mechanical energy.…”