Molecular dynamics study of taxadiene synthase catalysis

Molecular dynamics (MD) simulations have been performed to study the dynamic behavior of noncovalent enzyme carbocation complexes involved in the cyclization of geranylgeranyl diphosphate to taxadiene catalyzed by taxadiene synthase (TXS). Taxadiene and the observed four side products originate from the deprotonation of carbocation intermediates. The MD simulations of the TXS carbocation complexes provide insights into potential deprotonation mechanisms of such carbocations. The MD results do not support a previous hypothesis that carbocation tumbling is a key factor in the deprotonation of the carbocations by pyrophosphate. Instead water bridges are identified which may allow the formation of side products via multiple proton transfer reactions. A novel reaction path for taxadiene formation is proposed on the basis of the simulations

The impact of macrocycle conformation on the taxadiene-forming carbocation cascade: insight gained from sobralene, a recently discovered verticillene isomer

This is an accepted manuscript of an article published by American Chemical Society in Journal of Organic Chemistry on 26/02/2020, available online: https://doi.org/10.1021/acs.joc.0c00369 The accepted version of the publication may differ from the final published version.Copyright © 2020 American Chemical Society. DFT calculations on the carbocation intermediates that connect the biosynthetic pathways leading to the sand fly pheromone sobralene and taxadiene have been made. Establishment of the conformation of the macrocyclic carbocation intermediate required to produce the (Z)-C8,C9 alkene bond in sobralene has identified new conformations of the verticillyl carbocation intermediates on the taxadiene biosynthetic pathway. These "sobralene-like" carbocation conformations provide an exothermic pathway to taxadiene and are validated by comparison to closely related structures (X-ray and NMR).The University of NottinghamPublished versio

Computational evaluation of 2-arylbenzofurans for their potential use against SARS-CoV-2: A DFT, molecular docking, molecular dynamics simulation study

Natural compounds obtained from various sources have been used in the treatment of many diseases for many years and are very important compounds for drug development studies. They can also be an option to treat COVID-19, which is affecting the whole world and not curable with medication, yet. In this study, two 2-arylbenzofuran derivatives from Sesbania cannabina which are newly entered the literature were investigated computationally with the assistance of computational techniques including DFT calculations, molecular docking calculation and molecular dynamics simulations. The study consists of four parts, in the first part of the study DFT calculations were performed on the 2-arylbenzofurans, and geometry optimizations, vibrational analyses, molecular electrostatic potential (MEP) map calculations, frontier molecular orbital (FMO) calculations and Mulliken charge analyses were carried out.In the second part, molecular docking calculations were performed to investigate the interactions between the molecules and two potential target, SARS-CoV-2 main protease (SARS-CoV-2 Mpro) and SARS-CoV-2 spike receptor binding domain – human angiotensin converting enzyme 2 complex (SARS-CoV-2 SRBD – hACE2). In the third part, MD simulations were performed on the top-scoring ligand – receptor complexes to investigate the stability of the complex and the interactions between ligands and receptors in more detail. Finally, drug-likeness analyses and ADME (adsorption, desorption, metabolism, excretion) predictions were performed on the investigated compounds. Results showed that investigated natural compounds effectively interacted with the target receptors and gave comparable results to the reference drug molecules

Computational evaluation of 2-arylbenzofurans for their potential use against SARS-CoV-2: A DFT, molecular docking, molecular dynamics simulation study

59-72Natural compounds obtained from various sources have been used in the treatment of many diseases for many years and are very important compounds for drug development studies. They can also be an option to treat COVID-19, which is affecting the whole world and not curable with medication, yet. In this study, two 2-arylbenzofuran derivatives from Sesbania cannabina which are newly entered the literature were investigated computationally with the assistance of computational techniques including DFT calculations, molecular docking calculation and molecular dynamics simulations. The study consists of four parts, in the first part of the study DFT calculations were performed on the 2-arylbenzofurans, and geometry optimizations, vibrational analyses, molecular electrostatic potential (MEP) map calculations, frontier molecular orbital (FMO) calculations and Mulliken charge analyses were carried out. In the second part, molecular docking calculations were performed to investigate the interactions between the molecules and two potential target, SARS-CoV-2 main protease (SARS-CoV-2 Mpro) and SARS-CoV-2 spike receptor binding domain – human angiotensin converting enzyme 2 complex (SARS-CoV-2 SRBD – hACE2). In the third part, MD simulations were performed on the top-scoring ligand – receptor complexes to investigate the stability of the complex and the interactions between ligands and receptors in more detail. Finally, drug-likeness analyses and ADME (adsorption, desorption, metabolism, excretion) predictions were performed on the investigated compounds. Results showed that investigated natural compounds effectively interacted with the target receptors and gave comparable results to the reference drug molecules