Biology subjects

Tastan Bishop, O.

Publications and source records attributed to Tastan Bishop, O..

7 recordsLinked to original sources

bioRxiv2018

Aminoacyl tRNA Synthetases as Malarial Drug Targets: A Comparative Bioinformatics Study

Treatment of parasitic diseases has been challenging due to the development of drug resistance by parasites, and thus there is need to identify new class of drugs and drug targets. Protein translation is important for survival of plasmodium and the pathway is present in all the life cycle stages of the plasmodium parasite. Aminoacyl tRNA synthetases are primary enzymes in protein translation as they catalyse the first reaction where an amino acid is added to the cognate tRNA. Currently, there is limited research on comparative studies of aminoacyl tRNA synthetases as potential drug targets. The aim of this study is to understand differences between plasmodium and human aminoacyl tRNA synthetases through bioinformatics analysis. Plasmodium falciparum, P. fragile, P. vivax, P. ovale, P. knowlesi, P. bergei, P. malariae and human aminoacyl tRNA synthetase sequences were retrieved from UniProt database and grouped into 20 families based on amino acid specificity. Despite functional and structural conservation, multiple sequence analysis, motif discovery, pairwise sequence identity calculations and molecular phylogenetic analysis showed striking differences between parasite and human proteins. Prediction of alternate binding sites revealed potential druggable sites in PfArgRS, PfMetRS and PfProRS at regions that were weakly conserved when compared to the human homologues. These differences provide a basis for further exploration of plasmodium aminoacyl tRNA synthetases as potential drug targets.

bioinformatics↗

bioRxiv2018

Modulation of Human Hsp90α Conformational Dynamics by Allosteric Ligand Interaction at the C-Terminal Domain

Recent years have seen heat shock protein 90 kDa (Hsp90) attract significant interest as a viable drug target, particularly for cancer. To date, designed inhibitors that target the ATPase domain demonstrate potent anti-proliferative effects, but have failed clinical trials due to high levels of associated toxicity. To circumvent this, the focus has shifted away from the ATPase domain. One option involves modulation of the protein through allosteric activation/inhibition. Here, we propose a novel approach: we use previously obtained information via residue perturbation scanning coupled with dynamic residue network analysis to identify allosteric drug targeting sites for inhibitor docking. We probe the open conformation of human Hsp90 for druggable sites that overlap with these allosteric control elements, and identify three putative natural compound allosteric modulators: Cephalostatin 17, 20(29)-Lupene-3{beta}-isoferulate and 3'-Bromorubrolide F. We assess the allosteric potential of these ligands by examining their effect on the conformational dynamics of the protein. We find evidence for the selective allosteric activation and inhibition of Hsp90s conformational transition toward the closed state in response to ligand binding and shed valuable insight to further the understanding of allosteric drug design and Hsp90s complex allosteric mechanism of action.

bioinformatics↗

bioRxiv2018

Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide-based inhibitor design

Falcipains are major cysteine proteases of Plasmodium falciparum essential in hemoglobin digestion. Several inhibitors blocking their activity have been identified, yet none of them has been approved for malaria treatment. For selective therapeutic targeting of these plasmodial proteases, identification of sequence and structure differences with homologous human cathepsins is necessary. The protein substrate processing activity of these proteases is tightly controlled in space and time via a prodomain segment occluding the active site making it inaccessible. Here, we utilised in silico approaches to determine sequence and structure variations between the prodomain regions of plasmodial proteins and human cathepsins. Hot spot residues, key for maintaining structural integrity of the prodomains as well as conferring their inhibitory activity, were identified via residue interaction analysis. Information gathered was used to design short peptides able to mimic the prodomain activity on plasmodial proteases whilst showing selectivity on human cathepsins. Inhibitory potency was highly dependent on peptide amino acid composition and length. Our current results show that despite the conserved structural and catalytic mechanism of human cathepsins and plasmodial proteases, significant differences between the two groups exist and may be valuable in the development of novel antimalarial peptide inhibitors.

bioinformatics↗

bioRxiv2018

Characterizing drug resistance using geometric ensembles from HIV protease dynamics

The use of antiretrovirals (ARVs) has drastically improved the life quality and expectancy of HIV patients since their introduction in health care. Several millions are still afflicted worldwide by HIV and ARV resistance is a constant concern for both healthcare practitioners and patients, as while treatment options are finite, the virus constantly adapts and selects for resistant viral strains under the pressure of drug treatment. The HIV protease is a crucial enzyme that processes viral polyproteins into their functional form, and has been a game changing drug target since the first application. Due to similarities in protease inhibitor designs, drug cross-resistance is not uncommon across ARVs of the same class. It is known that resistance against protease inhibitors is associated with a wider active site, but results from our large scale molecular dynamics analysis further show, for the first time, that there are regions of local expansions and compactions associated with high levels of resistance conserved across eight different protease inhibitors visible in their complexed form in closed receptor conformations. The method developed here is novel, supplementary to the methods of nonsynonymous mutation analysis, and should be applicable in analyzing the structural consequences of mutations in other contexts.

bioinformatics↗

bioRxiv2017

MODE-TASK: Large-scale protein motion tools

SummaryMODE-TASK, a novel software suite, comprises Principle Component Analysis, Multidimensional Scaling, and t-Distributed Stochastic Neighbor Embedding techniques using molecular dynamics trajectories. MODE-TASK also includes a Normal Mode Analysis tool based on Anisotropic Network Model so as to provide a variety of ways to analyse and compare large-scale motions of protein complexes for which long MD simulations are prohibitive.\n\nAvailability and ImplementationMODE-TASK has been open-sourced, and is available for download from https://github.com/RUBi-ZA/MODE-TASK, implemented in Python and C++.\n\nSupplementary informationDocumentation available at http://mode-task.readthedocs.io.

bioinformatics↗

bioRxiv2017

Allosteric Modulation of Conformational Dynamics in Human Hsp90?: A Computational Study

Central to Hsp90s biological function is its ability to interconvert between various conformational states. Drug targeting of Hsp90s regulatory mechanisms, including its modulation by co-chaperone association, presents as an attractive therapeutic strategy for Hsp90 associated pathologies. Here, we utilize homology modeling techniques to calculate full-length structures of human Hsp90 in closed and partially-open conformations. Atomistic simulations of these structures demonstrated that bound ATP stabilizes the dimer by tensing each protomer, while ADP and apo configurations relax the complex by increasing global flexibility. Dynamic residue network analysis revealed regions of the protein involved in intra-protein communication, and identified several overlapping key communication hubs that correlate with known functional sites. Perturbation response scanning analysis identified several potential residue sites capable of modulating conformational change in favour of interstate conversion. For the ATP-bound open conformation, these sites were found to overlap with known Aha1 and client binding sites, demonstrating how naturally occurring forces associated with co-factor binding could allosterically modulate conformational dynamics.

bioinformatics↗

bioRxiv2017

No evidence for association with APOL1 kidney disease risk alleles and Human African Trypanosomiasis in two Ugandan populations

BackgroundHuman African trypanosomiasis (HAT) manifests as an acute form caused by Trypanosoma brucei rhodesiense (Tbr) and a chronic form caused by Trypanosoma brucei gambiense (Tbg). Previous studies have suggested a host genetic role in infection outcomes, particularly for APOL1. We have undertaken a candidate gene association studies (CGAS) in a Ugandan Tbr and a Tbg HAT endemic area, to determine whether polymorphisms in IL10, IL8, IL4, HLAG, TNFA, TNX4LB, IL6, IFNG, MIF, APOL1, HLAA, IL1B, IL4R, IL12B, IL12R, HP, HPR, and CFH have a role in HAT.\n\nMethodology and resultsWe included 238 and 202 participants from the Busoga Tbr and Northwest Uganda Tbg endemic areas respectively. Single Nucleotide Polymorphism (SNP) genotype data were analysed in the CGAS. The study was powered to find odds ratios > 2 but association testing of the SNPs with HAT yielded no positive associations i.e. none significant after correction for multiple testing. However there was strong evidence for no association with Tbr HAT and APOL1 G2 of the size previously reported in the Kabermaido district.\n\nConclusions/significanceA recent study in the Soroti and Kaberamaido focus in Central Uganda found that the APOL1 G2 allele was strongly associated with protection against Tbr HAT (odds ratio = 0.2). However, in our study no effect of G2 on Tbr HAT was found, despite being well powered to find a similar sized effect. It is possible that the G2 allele is protective from Tbr in the Soroti/Kabermaido focus but not in the Iganga district of Busoga, which differ in ethnicity and infection history. Mechanisms underlying HAT infection outcome and virulence are complex and might differ between populations, and likely involve several host, parasite or even environmental factors.\n\nAuthor SummaryHuman African Trypanosomiasis (HAT) occurs in two distinct disease forms; the acute form and the chronic form which are caused by microscopically indistinguishable hemo-parasites, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense respectively. Uganda is the only country where both forms of the disease are found, though in geographically distinct areas. Recent studies have shown that host genetic factors play a role in HAT resistance and/or susceptibility, particularly by genes involved in the immune response. In this study, we identified single nucleotide polymorphisms in selected genes involved in immune responses and carried out a case-control candidate gene association study in Ugandan participants from the two endemic areas. We were unable to detect any polymorphisms that were robustly associated with either Tbr or Tbg HAT. However, our findings differ from recent studies carried out in the Tbr HAT another endemic area of Uganda that showed the APOL1 (Apolipoprotein 1) G2 allele to be protective against the disease which merits further investigation. Larger studies such as genome wide association studies (GWAS) by the TrypanoGEN network that has >3000 cases and controls covering seven countries (Cameroon, Cote dIvoire, DRC, Malawi, Uganda, Zambia) using the H3Africa customized chip reflective of African genetic diversity will present novel association targets.

genetics↗