Curcumin-based pyrazoline analogues as selective inhibitors of human monoamine oxidase A

Abstract

A series of 2-methoxy-4-(5-phenyl-4,5-dihydro-1-pyrazol-3-yl)phenol (pyrazoline) derivatives () have been synthesized and tested for human monoamine oxidase (hMAO) inhibitory activity. The most active derivative () behaved as a competitive hMAO-A inhibitor, with an inhibition constant value of 0.08 μM and a strong hMAO-A selectivity ((hMAO-B)/(hMAO-A) > 1751). In addition, exhibited little to no cytotoxic effects up to a 25 μM concentration and provided the best blood-brain barrier permeability among the derivatives synthesized. Molecular dynamics simulations revealed that a chlorine substituent at the-position of the phenyl ring in enabled a π-π stacking interaction with Tyr407 and Tyr444 that resulted in the formation of an "aromatic sandwich" structure. Consequently, this tight-binding aromatic cage culminated in a dramatically reduced active site volume that is believed to be the origin of the observed selectivity between the hMAO-A and hMAO-B isozymes. Removal of the chlorine from disrupted the favorable intermolecular interactions and resulted in a selectivity change towards hMAO-B.

Kobophenol A Inhibits Binding of Host ACE2 Receptor with Spike RBD Domain of SARS-CoV-2, a Lead Compound for Blocking COVID-19

“…Analysis was performed with the cpptraj and ptraj programs available in the AmberTools18 suite. 55 , 56 The first 100 ns of the data was discarded with an aim to ensure only an equilibrated trajectory analysis.…”

“…The MM/PBSA (Molecular Mechanics/Poisson–Boltzmann Surface Area) methodology began with reports from Kollman and co-workers, but more recent developmental efforts have provided an important tool for studying ligand binding on various biological systems. 35 It is one of the robust method that has been successfully applied to estimate the free energy of binding for inhibitors with small or large differences in the principle scaffold, 57 chiral compounds 55 and small peptides. 58 In this work, the binding affinity of Kobophenol A in the ACE2 pocket and the ACE2/spike interface was calculated using the MM/PBSA approach available within the Amber package ( eqs 1 - 6 ), where − E gas is the standard energy term in molecular mechanics for bonded and nonbonded integrations, and G pol and G np are the polar and nonpolar contribution states of the solvation free energy (Δ G solvation ), respectively.…”

Design and Synthesis of Piperazine‐Linked Imidazo[1,2‐a]pyridine Derivatives as Potent Anticancer Agents

“…In order to understand the binding mode analysis docking studies were carried out with available structure of tubulin binding site (PDB ID: 3E22) by using Autodock4.2 . All the synthesized compounds interacted with both α, β interface tubulin(PDB ID: 3E22) in the colchicine binding pocket ( α Asn101, α Ser178, α Val181, α Thr179, β Lys352, β Thr353, β Leu248, β Gln247).…”

Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (mpro): a molecular docking, molecular dynamics and structure-activity relationship studies

“…The different types of interactions are also given in the figure for both the compounds. Gangireddy et al, 2019;Munusamy et al, 2019;Nath et al, 2018;Nayak et al, 2015;Vishnu Nayak et al, 2013) software version 4.2 (Forli et al, 2012). After completing the molecular docking process, the generated DLG (.dlg) file was analyzed using AutoDock v4.2 tools for all the possible interaction and binding free energies following the methodology (Huey et al, 2007).…”