Computational modelling of supramolecular human and animal structures: applications to enzymes relevant in comparative physiological studies

Currently, there is a need for improved drugs to treat diseases such as diabetes and cancer. This study used different computational methods to investigate a range of scientific problems that require rapid solutions to improve health and wellbeing. Ligand docking, in silico ADMET, protein-ligand binding affinity, density functional theory (DFT), and analytical techniques were applied to study the allosteric binding pocket of the GLP-1 receptor, the interactions between flavonoids and cytochrome P450s, the binding of phorbol diesters to the CYP19A1 enzyme and nuclear magnetic resonance (NMR) shielding. Findings from the study on ligand binding to the glucagon-like peptide-1 receptor GLP1-R) showed that the allosteric binding pocket of the GLP-1R is located near the transmembrane (TM) domain 6 of the receptor. This finding would enable the development of new allosteric modulators which can target the allosteric binding pocket of GLP-1R identified from this study. The next study which explored the binding of different ligands into cytochrome P450s showed that specific amino acid residues in the cytochrome P450s (CYP1A1 and CYP1B1) interact with different EROD flavonoids (Asp 313 and Phe 224 upon docking into CYP1A1 and Ala 330 upon docking into CYP1B1). The flavonoids isorhamnetin and pedalitin had the lowest binding energy upon docking into the crystal structures of 6DWM and 6IQ5. The results suggest the flavonoids isorhamnetin and pedalitin as potential precursors for natural productderived therapeutics. Additionally, the study also explored the interactions between phorbol diesters and CYP19A1. The results showed that the phorbol diesters had higher binding energy than commercial aromatase inhibitors. This suggests that phorbol diesters have the potential to modify the activity of the aromatase enzyme. A study investigating the lack of rotational invariance of some density functional theory (DFT) grids on DFT computed NMR spectra of a low vibrational frequency reaction showed that the lack of rotational invariance in some DFT grids does not impact DFT-calculated NMR spectra of low vibrational frequency reactions

G-Protein coupled receptors: structure and function in drug discovery

The G-protein coupled receptors (GPCRs) superfamily comprise similar proteins arranged into families or classes thus making it one of the largest in the mammalian genome. GPCRs take part in many vital physiological functions making them targets for numerous novel drugs. GPCRs share some distinctive features, such as the seven transmembrane domains, they also differ in the number of conserved residues in their transmembrane domain. Here we provide an introductory and accessible review detailing the computational advances in GPCR pharmacology and drug discovery. An overview is provided on family A-C GPCRs; their structural differences, GPCR signalling, allosteric binding and cooperativity. The dielectric constant (relative permittivity) of proteins is also discussed in the context of site-specific environmental effects

Differential spatial repositioning of activated genes in Biomphalaria glabrata snails infected with Schistosoma mansoni

Copyright @ 2014 Arican-Goktas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Schistosomiasis is an infectious disease infecting mammals as the definitive host and fresh water snails as the intermediate host. Understanding the molecular and biochemical relationship between the causative schistosome parasite and its hosts will be key to understanding and ultimately treating and/or eradicating the disease. There is increasing evidence that pathogens that have co-evolved with their hosts can manipulate their hosts' behaviour at various levels to augment an infection. Bacteria, for example, can induce beneficial chromatin remodelling of the host genome. We have previously shown in vitro that Biomphalaria glabrata embryonic cells co-cultured with schistosome miracidia display genes changing their nuclear location and becoming up-regulated. This also happens in vivo in live intact snails, where early exposure to miracidia also elicits non-random repositioning of genes. We reveal differences in the nuclear repositioning between the response of parasite susceptible snails as compared to resistant snails and with normal or live, attenuated parasites. Interestingly, the stress response gene heat shock protein (Hsp) 70 is only repositioned and then up-regulated in susceptible snails with the normal parasite. This movement and change in gene expression seems to be controlled by the parasite. Other differences in the behaviour of genes support the view that some genes are responding to tissue damage, for example the ferritin genes move and are up-regulated whether the snails are either susceptible or resistant and upon exposure to either normal or attenuated parasite. This is the first time host genome reorganisation has been seen in a parasitic host and only the second time for any pathogen. We believe that the parasite elicits a spatio-epigenetic reorganisation of the host genome to induce favourable gene expression for itself and this might represent a fundamental mechanism present in the human host infected with schistosome cercariae as well as in other host-pathogen relationships.NIH and Sandler Borroughs Wellcome Travel Fellowshi

The role of phorbol diesters in mediating human placental aromatase cytochrome P450 activity

Due to the aromatase enzyme’s involvement in estrogen biosynthesis, aromatase inhibitors have emerged as the preferred treatment for postmenopausal women with ER+ breast cancer. Using computational chemistry tools, we investigate how the human placental aromatase cytochrome P450 interacts with various phorbols with distinct chains at C-12, C-13, and C-20, as well as the well-known aromatase inhibitors anastrozole, exemestane, and letrozole. To identify phorbol-aromatase interactions, we performed a protein–ligand docking using the structures of our ligands and proteins using the Flare software (version 2.0, Cresset Software, Litlington, UK). These preliminary findings show that the phorbols considered (P-12,13-diAcPh, P-12,13-diiBu, P-12AcPh-13iBu, P-12Ang-13iBu, P-20Ac-12AcPh-13iBu and P-20Ac-12Ang-13iBu) had the highest binding energies in comparison with the commercially available aromatase inhibitors (anastrozole, letrozole, exemestane) used in this study. A subset of the previously described binding residues of testosterone (TST), the endogenous ligand, were also found to be responsible for the phorbol diesters’ binding to the aromatase enzyme, as demonstrated by the findings. This further suggests that the phorbol diesters can bind efficiently to CYP19A1 and may be able to alter its activity because they had higher binding energies than the commercially available drugs