Repurposing DrugBank compounds as potential Plasmodium falciparum class 1a aminoacyl tRNA synthetase multi-stage pan-inhibitors with a specific focus on mitomycin
- Authors: Olotu, Fisayo , Tchatat Tali, Mariscal Brice , Chepsiror, Curtis , Sheik Amamuddy, Olivier , Boyom,Fabrice Fekam , Tastan Bishop, Özlem
- Date: 2024
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/473661 , vital:77670 , https://hdl.handle.net/10520/EJC127052
- Description: Plasmodium falciparum aminoacyl tRNA synthetases (PfaaRSs) are potent antimalarial targets essential for proteome fidelity and overall parasite survival in every stage of the parasite's life cycle. So far, some of these proteins have been singly targeted yielding inhibitor compounds that have been limited by incidences of resistance which can be overcome via pan-inhibition strategies. Hence, herein, for the first time, we report the identification and in vitro antiplasmodial validation of Mitomycin (MMC) as a probable pan-inhibitor of class 1a (arginyl(A)-, cysteinyl(C), isoleucyl(I)-, leucyl(L), methionyl(M), and valyl(V)-) PfaaRSs which hypothetically may underlie its previously reported activity on the ribosomal RNA to inhibit protein translation and biosynthesis. We combined multiple in silico structure-based discovery strategies that first helped identify functional and druggable sites that were preferentially targeted by the compound in each of the plasmodial proteins: Ins1-Ins2 domain in Pf-ARS; anticodon binding domain in Pf-CRS; CP1-editing domain in Pf-IRS and Pf-MRS; C-terminal domain in Pf-LRS; and CP-core region in Pf-VRS. Molecular dynamics studies further revealed that MMC allosterically induced changes in the global structures of each protein. Likewise, prominent structural perturbations were caused by the compound across the functional domains of the proteins. More so, MMC induced systematic alterations in the binding of the catalytic nucleotide and amino acid substrates which culminated in the loss of key interactions with key active site residues and ultimate reduction in the nucleotide-binding affinities across all proteins, as deduced from the binding energy calculations. These altogether confirmed that MMC uniformly disrupted the structure of the target proteins and essential substrates. Further, MMC demonstrated IC50 5 μM against the Dd2 and 3D7 strains of parasite making it a good starting point for malarial drug development. We believe that findings from our study will be important in the current search for highly effective multi-stage antimalarial drugs.
- Full Text:
- Date Issued: 2024
Antiviral Mechanisms of N-Phenyl Benzamides on Coxsackie Virus A9
- Authors: Laajala, Mira , Kalander, Kerttu , Consalvi, Sara , Sheik Amamuddy, Olivier , Tastan Bishop, Özlem , Biava, Mariangela , Poce, Giovanna , Marjomäki, Varpu
- Date: 2023
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/474448 , vital:77708 , https://doi.org/10.3390/pharmaceutics15031028
- Description: Enteroviruses are one of the most abundant groups of viruses infecting humans, and yet there are no approved antivirals against them. To find effective antiviral compounds against enterovirus B group viruses, an in-house chemical library was screened. The most effective compounds against Coxsackieviruses B3 (CVB3) and A9 (CVA9) were CL212 and CL213, two N-phenyl benzamides. Both compounds were more effective against CVA9 and CL213 gave a better EC50 value of 1 µM with high a specificity index of 140. Both drugs were most effective when incubated directly with viruses suggesting that they mainly bound to the virions. A real-time uncoating assay showed that the compounds stabilized the virions and radioactive sucrose gradient as well as TEM confirmed that the viruses stayed intact. A docking assay, taking into account larger areas around the 2-and 3-fold axes of CVA9 and CVB3, suggested that the hydrophobic pocket gives the strongest binding to CVA9 but revealed another binding site around the 3-fold axis which could contribute to the binding of the compounds. Together, our data support a direct antiviral mechanism against the virus capsid and suggest that the compounds bind to the hydrophobic pocket and 3-fold axis area resulting in the stabilization of the virion
- Full Text:
- Date Issued: 2023
Deciphering Isoniazid Drug Resistance Mechanisms on Dimeric Mycobacterium tuberculosis KatG via Post-molecular Dynamics Analyses Including Combined Dynamic Residue Network Metrics
- Authors: Barozi, Victor , Musyoka, Thommas M , Sheik Amamuddy, Olivier , Tastan Bishop, Özlem
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/474493 , vital:77713 , https://doi.org/10.1021/acsomega.2c01036
- Description: Resistance mutations in Mycobacterium tuberculosis (Mtb) catalase peroxidase protein (KatG), an essential enzyme in isoniazid (INH) activation, reduce the sensitivity of Mtb to first-line drugs, hence presenting challenges in tuberculosis (TB) management. Thus, understanding the mutational imposed resistance mechanisms remains of utmost importance in the quest to reduce the TB burden. Herein, effects of 11 high confidence mutations in the KatG structure and residue network communication patterns were determined using extensive computational approaches. Combined traditional post-molecular dynamics analysis and comparative essential dynamics revealed that the mutant proteins have significant loop flexibility around the heme binding pocket and enhanced asymmetric protomer behavior with respect to wild-type (WT) protein. Heme contact analysis between WT and mutant proteins identified a reduction to no contact between heme and residue His270, a covalent bond vital for the heme-enabled KatG catalytic activity. Betweenness centrality calculations showed large hub ensembles with new hubs especially around the binding cavity and expanded to the dimerization domain via interface in the mutant systems, providing possible compensatory allosteric communication paths for the active site as a result of the mutations which may destabilize the heme binding pocket and the loops in its vicinity. Additionally, an interesting observation came from Eigencentrality hubs, most of which are located in the C-terminal domain, indicating relevance of the domain in the protease functionality. Overall, our results provide insight toward the mechanisms involved in KatG-INH resistance in addition to identifying key regions in the enzyme functionality, which can be used for future drug design.
- Full Text:
- Date Issued: 2022
Slipknot or Crystallographic Error: A Computational Analysis of the Plasmodium falciparum DHFR Structural Folds
- Authors: Tata, Rolland B , Alsulami, Ali F , Sheik Amamuddy, Olivier , Blundell, Tom L , Tastan Bishop, Özlem
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/476115 , vital:77883 , https://doi.org/10.3390/ijms23031514
- Description: The presence of protein structures with atypical folds in the Protein Data Bank (PDB) is rare and may result from naturally occurring knots or crystallographic errors. Proper characterisation of such folds is imperative to understanding the basis of naturally existing knots and correcting crystallographic errors. If left uncorrected, such errors can frustrate downstream experiments that depend on the structures containing them. An atypical fold has been identified in P. falciparum dihydrofolate reductase (PfDHFR) between residues 20–51 (loop 1) and residues 191–205 (loop 2). This enzyme is key to drug discovery efforts in the parasite, necessitating a thorough characterisation of these folds. Using multiple sequence alignments (MSA), a unique insert was identified in loop 1 that exacerbates the appearance of the atypical fold-giving it a slipknot-like topology. However, PfDHFR has not been deposited in the knotted proteins database, and processing its structure failed to identify any knots within its folds. The application of protein homology modelling and molecular dynamics simulations on the DHFR domain of P. falciparum and those of two other organisms (E. coli and M. tuberculosis) that were used as molecular replacement templates in solving the PfDHFR structure revealed plausible unentangled or open conformations of these loops. These results will serve as guides for crystallographic experiments to provide further insights into the atypical folds identified.
- Full Text:
- Date Issued: 2022
Allosteric pockets and dynamic residue network hubs of falcipain 2 in mutations including those linked to artemisinin resistance
- Authors: Okeke, Chiamaka J , Musyoka, Thommas M , Sheik Amamuddy, Olivier , Barozi, Victor , Tastan Bishop, Özlem
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/476585 , vital:77939 , xlink:href="https://doi.org/10.1016/j.csbj.2021.10.011"
- Description: Continually emerging resistant strains of malarial parasites to current drugs present challenges. Understanding the underlying resistance mechanisms, especially those linked to allostery is, thus, highly crucial for drug design. This forms the main concern of the paper through a case study of falcipain 2 (FP-2) and its mutations, some of which are linked to artemisinin (ART) drug resistance. Here, we applied a variety of in silico approaches and tools that we developed recently, together with existing computational tools. This included novel essential dynamics and dynamic residue network (DRN) analysis algorithms. We identified six pockets demonstrating dynamic differences in the presence of some mutations. We observed striking allosteric effects in two mutant proteins. In the presence of M245I, a cryptic pocket was detected via a unique mechanism in which Pocket 2 fused with Pocket 6. In the presence of the A353T mutation, which is located at Pocket 2, the pocket became the most rigid among all protein systems analyzed. Pocket 6 was also highly stable in all cases, except in the presence of M245I mutation. The effect of ART linked mutations was more subtle, and the changes were at residue level. Importantly, we identified an allosteric communication path formed by four unique averaged BC hubs going from the mutated residue to the catalytic site and passing through the interface of three identified pockets. Collectively, we established and demonstrated that we have robust tools and a pipeline that can be applicable to the analysis of mutations.
- Full Text:
- Date Issued: 2021
MDM-TASK-web: MD-TASK and MODE-TASK web server for analyzing protein dynamics
- Authors: Sheik Amamuddy, Olivier , Glenister, Michael , Tshabalala, Thulani , Tastan Bishop, Özlem
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/476574 , vital:77938 , xlink:href="https://doi.org/10.1016/j.csbj.2021.08.043"
- Description: The web server, MDM-TASK-web, combines the MD-TASK and MODE-TASK software suites, which are aimed at the coarse-grained analysis of static and all-atom MD-simulated proteins, using a variety of non-conventional approaches, such as dynamic residue network analysis, perturbation-response scanning, dynamic cross-correlation, essential dynamics and normal mode analysis. Altogether, these tools allow for the exploration of protein dynamics at various levels of detail, spanning single residue perturbations and weighted contact network representations, to global residue centrality measurements and the investigation of global protein motion. Typically, following molecular dynamic simulations designed to investigate intrinsic and extrinsic protein perturbations (for instance induced by allosteric and orthosteric ligands, protein binding, temperature, pH and mutations), this selection of tools can be used to further describe protein dynamics. This may lead to the discovery of key residues involved in biological processes, such as drug resistance. The server simplifies the set-up required for running these tools and visualizing their results. Several scripts from the tool suites were updated and new ones were also added and integrated with 2D/3D visualization via the web interface. An embedded work-flow, integrated documentation and visualization tools shorten the number of steps to follow, starting from calculations to result visualization. The Django-powered web server (available at https://mdmtaskweb.rubi.ru.ac.za/) is compatible with all major web browsers. All scripts implemented in the web platform are freely available at https://github.com/RUBi-ZA/MD-TASK/tree/mdm-task-web and https://github.com/RUBi-ZA/MODE-TASK/tree/mdm-task-web
- Full Text:
- Date Issued: 2021
Novel dynamic residue network analysis approaches to study allosteric modulation: SARS-CoV-2 Mpro and its evolutionary mutations as a case study
- Authors: Sheik Amamuddy, Olivier , Boateng, Rita A , Barozi, Victor , Nyamai, Dorothy W , Tastan Bishop, Özlem
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/476596 , vital:77940 , xlink:href="https://doi.org/10.1016/j.csbj.2021.11.016"
- Description: The rational search for allosteric modulators and the allosteric mechanisms of these modulators in the presence of mutations is a relatively unexplored field. Here, we established novel in silico approaches and applied them to SARS-CoV-2 main protease (Mpro) as a case study. First, we identified six potential allosteric modulators. Then, we focused on understanding the allosteric effects of these modulators on each of its protomers. We introduced a new combinatorial approach and dynamic residue network (DRN) analysis algorithms to examine patterns of change and conservation of critical nodes, according to five independent criteria of network centrality. We observed highly conserved network hubs for each averaged DRN metric on the basis of their existence in both protomers in the absence and presence of all ligands (persistent hubs). We also detected ligand specific signal changes. Using eigencentrality (EC) persistent hubs and ligand introduced hubs we identified a residue communication path connecting the allosteric binding site to the catalytic site. Finally, we examined the effects of the mutations on the behavior of the protein in the presence of selected potential allosteric modulators and investigated the ligand stability. One crucial outcome was to show that EC centrality hubs form an allosteric communication path between the allosteric ligand binding site to the active site going through the interface residues of domains I and II; and this path was either weakened or lost in the presence of some of the mutations. Overall, the results revealed crucial aspects that need to be considered in rational computational drug discovery.
- Full Text:
- Date Issued: 2021
Polyphenols Epigallocatechin Gallate and Resveratrol, and Polyphenol-Functionalized Nanoparticles Prevent Enterovirus Infection through Clustering and Stabilization of the Viruses
- Authors: Reshamwala, Dhanik , Sheik Amamuddy, Olivier , Laquintana, Valentino , Denora, Nunzio , Zacheo, Antonella , Lampinen, Vili , Hytonen, Vesa P , Tastan Bishop, Özlem , Krol, Silke , Marjomäki, Varpu
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/476607 , vital:77941 , xlink:href="https://doi.org/10.3390/pharmaceutics13081182"
- Description: To efficiently lower virus infectivity and combat virus epidemics or pandemics, it is important to discover broadly acting antivirals. Here, we investigated two naturally occurring polyphenols, Epigallocatechin gallate (EGCG) and Resveratrol (RES), and polyphenol-functionalized nanoparticles for their antiviral efficacy. Concentrations in the low micromolar range permanently inhibited the infectivity of high doses of enteroviruses (107 PFU/mL). Sucrose gradient separation of radiolabeled viruses, dynamic light scattering, transmission electron microscopic imaging and an in-house developed real-time fluorescence assay revealed that polyphenols prevented infection mainly through clustering of the virions into very stable assemblies. Clustering and stabilization were not compromised even in dilute virus solutions or after diluting the polyphenols-clustered virions by 50-fold. In addition, the polyphenols lowered virus binding on cells. In silico docking experiments of these molecules against 2- and 3-fold symmetry axes of the capsid, using an algorithm developed for this study, discovered five binding sites for polyphenols, out of which three were novel binding sites. Our results altogether suggest that polyphenols exert their antiviral effect through binding to multiple sites on the virion surface, leading to aggregation of the virions and preventing RNA release and reducing cell surface binding.
- Full Text:
- Date Issued: 2021
Determining the unbinding events and conserved motions associated with the pyrazinamide release due to resistance mutations of Mycobacterium tuberculosis pyrazinamidase:
- Authors: Sheik Amamuddy, Olivier , Musyoka, Thommas M , Boateng, Rita A , Zabo, Sophakama , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148869 , vital:38781 , https://doi.org/10.1016/j.csbj.2020.05.0099
- Description: Pyrazinamide (PZA) is the only first-line antitubercular drug active against latent Mycobacterium tuberculosis (Mtb). It is activated to pyrazinoic acid by the pncA-encoded pyrazinamidase enzyme (PZase). Despite the emergence of PZA drug resistance, the underlying mechanisms of resistance remain unclear. This study investigated part of these mechanisms by modelling a PZA-bound wild type and 82 mutant PZase structures before applying molecular dynamics (MD) with an accurate Fe2+ cofactor coordination geometry.
- Full Text:
- Date Issued: 2020
Impact of early pandemic stage mutations on molecular dynamics of SARS-CoV-2 Mpro:
- Authors: Sheik Amamuddy, Olivier , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162330 , vital:40835 , https://0-doi.org.wam.seals.ac.za/10.1021/acs.jcim.0c00634
- Description: A new coronavirus (SARS-CoV-2) is a global threat to world health and economy. Its dimeric main protease (Mpro), which is required for the proteolytic cleavage of viral precursor proteins, is a good candidate for drug development owing to its conservation and the absence of a human homolog. Improving our understanding of Mpro behavior can accelerate the discovery of effective therapies to reduce mortality. All-atom molecular dynamics (MD) simulations (100 ns) of 50 mutant Mpro dimers obtained from filtered sequences from the GISAID database were analyzed using root-mean-square deviation, root-mean-square fluctuation, Rg, averaged betweenness centrality, and geometry calculations.
- Full Text:
- Date Issued: 2020
Impact of emerging mutations on the dynamic properties the SARS-CoV-2 main protease: an in silico investigation
- Authors: Sheik Amamuddy, Olivier , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163035 , vital:41006 , doi: 10.1021/acs.jcim.0c00634
- Description: The new coronavirus (SARS-CoV-2) is a global threat to world health and its economy. Its main protease (Mpro), which functions as a dimer, cleaves viral precursor proteins in the process of viral maturation. It is a good candidate for drug development owing to its conservation and the absence of a human homolog. An improved understanding of the protein behaviour can accelerate the discovery of effective therapies in order to reduce mortality. 100 ns all-atom molecular dynamics simulations of 50 homology modelled mutant Mpro dimers were performed at pH 7 from filtered sequences obtained from the GISAID database. Protease dynamics were analysed using RMSD, RMSF, Rg, the averaged betweenness centrality and geometry calculations. Domains from each Mpro protomer were found to generally have independent motions, while the dimer-stabilising N-finger region was found to be flexible in most mutants.
- Full Text:
- Date Issued: 2020
Integrated computational approaches and tools for allosteric drug discovery:
- Authors: Sheik Amamuddy, Olivier , Veldman, Wade , Manyumwa, Colleen , Khairallah, Afrah , Agajanian, Steve , Oluyemi, Odeyemi , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163012 , vital:41004 , https://doi.org/10.3390/ijms21030847
- Description: Understanding molecular mechanisms underlying the complexity of allosteric regulation in proteins has attracted considerable attention in drug discovery due to the benefits and versatility of allosteric modulators in providing desirable selectivity against protein targets while minimizing toxicity and other side effects. The proliferation of novel computational approaches for predicting ligand–protein interactions and binding using dynamic and network-centric perspectives has led to new insights into allosteric mechanisms and facilitated computer-based discovery of allosteric drugs. Although no absolute method of experimental and in silico allosteric drug/site discovery exists, current methods are still being improved. As such, the critical analysis and integration of established approaches into robust, reproducible, and customizable computational pipelines with experimental feedback could make allosteric drug discovery more efficient and reliable. In this article, we review computational approaches for allosteric drug discovery and discuss how these tools can be utilized to develop consensus workflows for in silico identification of allosteric sites and modulators with some applications to pathogen resistance and precision medicine. The emerging realization that allosteric modulators can exploit distinct regulatory mechanisms and can provide access to targeted modulation of protein activities could open opportunities for probing biological processes and in silico design of drug combinations with improved therapeutic indices and a broad range of activities.
- Full Text:
- Date Issued: 2020
Computational analysis of missense mutations from the human Macrophage Migration Inhibitory Factor (MIF) protein by Molecular Dynamics Simulations and Dynamic Residue Network Analysis:
- Authors: Kimuda, Phillip M , Brown, David K , Sheik Amamuddy, Olivier , Ross, Caroline J , Matovu, Enock , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163238 , vital:41021 , https://doi.org/10.21955/aasopenres.1115054.1
- Description: Missense mutations are changes in the DNA that result in a change in the amino acid sequence. Depending on their location within the protein they can have a negative impact on how the protein functions. This is especially important for proteins involved in the body’s response to infection and diseases. Macrophage migration inhibitory factor (MIF) is one such protein that functions to recruit white blood cells to sites of inflammation.
- Full Text:
- Date Issued: 2019
Characterizing early drug resistance-related events using geometric ensembles from HIV protease dynamics:
- Authors: Sheik Amamuddy, Olivier , Bishop, Nigel T , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148126 , vital:38712 , DOI: 10.1038/s41598-018-36041-8
- Description: 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 via complex mutation patterns to select for resistant strains under the pressure of drug treatment. The HIV protease is a crucial enzyme for viral maturation 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.
- Full Text:
- Date Issued: 2018
MODE-TASK: Large-scale protein motion tools
- Authors: Ross, Caroline J , Nizami, B , Glenister, Michael , Sheik Amamuddy, Olivier , Atilgan, Ali R , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125206 , vital:35746 , http://dx.doi.org/10.1101/217505
- Description: Conventional analysis of molecular dynamics (MD) trajectories may not identify global motions of macromolecules. Normal Mode Analysis (NMA) and Principle Component Analysis (PCA) are two popular methods to quantify large-scale motions, and find the “essential motions”; and have been applied to problems such as drug resistant mutations (Nizami et al., 2016) and viral capsid expansion (Hsieh et al., 2016). MODE-TASK is an array of tools to analyse and compare protein dynamics obtained from MD simulations and/or coarse grained elastic network models. Users may perform standard PCA, kernel and incremental PCA (IPCA). Data reduction techniques (Multidimensional Scaling (MDS) and t-Distributed Stochastics Neighbor Embedding (t-SNE)) are implemented. Users may analyse normal modes by constructing elastic network models (ENMs) of a protein complex. A novel coarse graining approach extends its application to large biological assemblies.
- Full Text:
- Date Issued: 2018
Improving fold resistance prediction of HIV-1 against protease and reverse transcriptase inhibitors using artificial neural networks:
- Authors: Sheik Amamuddy, Olivier , Bishop, Nigel T , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148261 , vital:38724 , https://0-doi.org.wam.seals.ac.za/10.1186/s12859-017-1782-x
- Description: Drug resistance in HIV treatment is still a worldwide problem. Predicting resistance to antiretrovirals (ARVs) before starting any treatment is important. Prediction accuracy is essential, as low-accuracy predictions increase the risk of prescribing sub-optimal drug regimens leading to patients developing resistance sooner. Artificial Neural Networks (ANNs) are a powerful tool that would be able to assist in drug resistance prediction. In this study, we constrained the dataset to subtype B, sacrificing generalizability for a higher predictive performance, and demonstrated that the predictive quality of the ANN regression models have definite improvement for most ARVs.
- Full Text:
- Date Issued: 2017
MD-TASK: a software suite for analyzing molecular dynamics trajectories
- Authors: Brown, David K , Penkler, David L , Sheik Amamuddy, Olivier , Ross, Caroline J , Atilgan, Ali R , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125138 , vital:35735 , https://doi.10.1093/bioinformatics/btx349
- Description: Molecular dynamics (MD) determines the physical motions of atoms of a biological macromolecule in a cell-like environment and is an important method in structural bioinformatics. Traditionally, measurements such as root mean square deviation, root mean square fluctuation, radius of gyration, and various energy measures have been used to analyze MD simulations. Here, we present MD-TASK, a novel software suite that employs graph theory techniques, perturbation response scanning, and dynamic cross-correlation to provide unique ways for analyzing MD trajectories.
- Full Text:
- Date Issued: 2017
Structural analysis of proteases from South African HIV-1 (subtype C) patients undergoing Lopinavir treatment, using comparative modeling, ligand-docking and molecular dynamics
- Authors: Sheik Amamuddy, Olivier
- Date: 2017
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/4931 , vital:20744
- Description: HIV is regarded as one of the most devastating infectious diseases of the last few decades, and has a high prevalence in South Africa, subtype C being the most common. Palliative measures used to fight HIV involve the use various types of inhibitors, including the use of HIV protease inhibitors. Representatives from this class of inhibitors are gradually losing their efficacy due to development of resistance mutations from HIV-1. In this study, compounds from the South African Natural Compound Database (SANCDB) were screened against HIV-1 protease models generated from protease protein sequences belonging to 11 South African HIV patients before and after treatment with Lopinavir. The effect of Lopinavir on the alteration of drug-binding affinity before and after treatment is investigated by molecular docking of the protease against other FDA-approved drugs and detection of mutation types using the HIVdb tool. A network representation of hydrogen bonding between docked ligands and their receptor proteases has been developed and a profiling method of visualizing receptor-ligand docking energies at the local level is presented. Four potential HIV-1 protease inhibitors were identified from the list of 599 natural compounds on the basis of receptor conformation and binding free energy. Ligand stabilities were monitored by 20ns molecular dynamics runs using the GROMACS software.
- Full Text:
- Date Issued: 2017
Structure-based analysis of single nucleotide variants in the renin-angiotensinogen complex:
- Authors: Brown, David K , Sheik Amamuddy, Olivier , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/147994 , vital:38700 , https://doi.org/10.1016/j.gheart.2017.01.006
- Description: The renin-angiotensin system (RAS) plays an important role in regulating blood pressure and controlling sodium levels in the blood. Hyperactivity of this system has been linked to numerous conditions including hypertension, kidney disease, and congestive heart failure. Three classes of drugs have been developed to inhibit RAS. In this study, we provide a structure-based analysis of the effect of single nucleotide variants (SNVs) on the interaction between renin and angiotensinogen with the aim of revealing important residues and potentially damaging variants for further inhibitor design purposes.
- Full Text:
- Date Issued: 2017