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Author: search.filters.author.Hassan, Md. Imtaiyaz

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    Molecular dynamics simulation of chitinase I from Thermomyces lanuginosus SSBP to ensure optimal activity
    (Taylor and Fancis Online, 2016-09-22) Khan, Faez Iqbal; Bisetty, Krishna; Gu, Ke-Ren; Singh, Suren; Permaul, Kugen; Hassan, Md. Imtaiyaz; Wei, Dong-Qing
    The fungal chitinase I obtained from Thermomyces lanuginosus SSBP, a thermophilic deuteromycete, has an optimum growth temperature and pH of 323.15 K and 6.5, respectively. This enzyme plays an important task in the defence mechanism of organisms against chitin-containing parasites by hydrolysing β-1, 4-linkages in chitin. It acts as both anti-fungal and biofouling agents, with some being thermostable and suitable for the industrial applications. Three-dimensional model of chitinase I enzyme was predicted and analysed using various bioinformatics tools. The structure of chitinase I exhibited a well-defined TIM barrel topology with an eight-stranded α/β domain. Structural analysis and folding studies at temperatures ranging from 300 to 375 K using 10 ns molecular dynamics simulations clearly showed the stability of the protein was evenly distributed even at higher temperatures, in accordance with the experimental results. We also carried out a number of 20 ns constant pH molecular dynamics simulations of chitinase I at a pH range 2–6 in a solvent. This work was aimed at establishing the optimum activity and stability profiles of chitinase I. We observed a strong conformational pH dependence of chitinase I and the enzyme retained their characteristic TIM barrel topology at low pH.
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    Chitinase from Thermomyces lanuginosus SSBP and its biotechnological applications
    (Springerlink, 2015) Khan, Faez Iqbal; Bisetty, Krishna; Singh, Suren; Permaul, Kugen; Hassan, Md. Imtaiyaz
    Chitinases are ubiquitous class of extracellu-lar enzymes, which have gained attention in the past few years due to their wide biotechnological applications. The effectiveness of conventional insecticides is increasingly compromised by the occurrence of resistance; thus, chi-tinase offers a potential alternative to the use of chemical fungicides. The thermostable enzymes from thermophilic microorganisms have numerous industrial, medical, envi-ronmental and biotechnological applications due to their high stability for temperature and pH. Thermomyces lanug-inosus produced a large number of chitinases, of which chi-tinase I and II are successfully cloned and purified recently. Molecular dynamic simulations revealed that the stability of these enzymes are maintained even at higher tempera-ture. In this review article we have focused on chitinases from different sources, mainly fungal chitinase of T. lanug-inosus and its industrial application.
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    PKR-inhibitor binds efficiently with human microtubule affinity-regulating kinase 4
    (Elsevier, 2015) Naz, Farha; Shahbaaz, Mohd; Khan, Shama; Bisetty, Krishna; Islam, Asimul; Ahmad, Faizan; Hassan, Md. Imtaiyaz
    MAP/microtubule affinity-regulating kinase 4 (MARK4) plays a central role in the cellular physiology, and it is inseparably linked with many human diseases including cancer, diet induced obesity, type2 diabetes and neurodegenerative disorders. Here, we studied the interaction of PKR-inhibitor with two variants of human MARK4. One variant is named as MARK4-F1 which has 59 N-terminal residues along with kinase domain while another variant is MARK4-F2 which has kinase domain only. Molecular-docking, molecular dynamics (MD) simulation and fluorescence-binding studies were undertaken to understand the role of N-terminal 59-residues in the binding of substrate/inhibitors. Molecular docking studies revealed that the PKR-inhibitor binds in the large hydrophobic cavity of the kinase domain of MARK4 through several hydrophobic and hydrogen-bonded interactions. Furthermore, MD simulation showed a stable param-eters for the complexes of both MARK4-F1 and MARK4-F2 to PKR-inhibitor with marginal difference in their binding affinities. A significant decrease in the fluorescence intensity of MARK4 was observed on successive addition of the PKR-inhibitor. Using fluorescence data we have calculated the binding-affinity and the number of binding site of PKR-inhibitor to the MARK4. A significantly high binding affinity was observed for the PKR-inhibitor to the MARK4 variants. However, there is no any significant difference in the binding affinity of PKR-inhibitor to the MARK4 variants was observed, indicating that 59 N-terminal residues of MARK4-F1 are not playing a crucial role in the ligand binding. The present study will pro-vide an insights into designing of new PKR-inhibitor derivative as potent and selective therapeutic agent against many life threatening diseases which are associated with MARK4.
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    Designing new kinase inhibitor derivatives as therapeutics against common complex diseases : structural basis of microtubule affinity-regulating kinase 4 (MARK4) inhibition
    (Mary Ann Liebert, Inc., 2015) Naz, Farha; Shahbaaz, Mohd; Bisetty, Krishna; Islam, Asimul; Ahmad, Faizan; Hassan, Md. Imtaiyaz
    Drug development for common complex diseases is in need of new molecular entities and actionable drug targets. MAP/microtubule affinity-regulating kinase 4 (MARK4) is associated with numerous diseases such as neurodegenerative disorders, obesity, cancer, and type 2 diabetes. Understanding the structural basis of ligands’ (inhibitors) and substrates’ binding to MARK4 is crucial to design new kinase inhibitors for therapeutic pur-poses. This study reports new observations on docking three well-known kinase inhibitors in the kinase domain of MARK4 variants and the calculated binding affinity. These variants of MARK4 are named as MARK4-F1 (59 N-terminal residues along with kinase domain) and MARK4-F2 (kinase domain of MARK4). We addi-tionally performed molecular dynamics (MD) simulation and fluorescence binding studies to calculate the actual binding affinity of kinase inhibitors, BX-912, BX-795, and OTSSP167 (hydrochloride) for the MARK4. Docking analyses revealed that ligands bind in the large hydrophobic cavity of the kinase domain of MARK4 through several hydrophobic and hydrogen-bonded interactions. Simulations suggested that OTSSP167 (hy-drochloride) is forming a stable complex, and hence the best inhibitor of MARK4. Intrinsic fluorescence of MARK4 was significantly quenched by addition of ligands, indicating their potential binding to MARK4. A lower KD value of MARK4 with OTSSP167 (hydrochloride) suggested that it is a better interacting partner than BX-912 and BX-795. These data form a basis for designing novel and potent OTSSP167 (hydrochloride) derivatives as therapeutic candidates against common complex diseases. The inhibitors designed as such might possibly suppress the growth of tumor-forming cells and be potentially applied for treatment of a wide range of human cancers as well.
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    In silico approaches for the identification of virulence candidates amongst hypothetical proteins of Mycoplasma pneumoniae 309
    (Elsevier, 2015) Shahbaaz, Mohd; Bisetty, Krishna; Ahmad, Faizan; Hassan, Md. Imtaiyaz
    Mycoplasma pneumoniae type 2a strain 309 is a simplest known bacterium and is the primary cause of community acquired pneumonia in the children. It mainly causes severe atypical pneumonia as well as several other non-pulmonary manifestations such as neurological, hepatic, hemolytic anemia, cardiacdiseases and polyarthritis. The size of M. pneumoniae genome (Accession number: NC_016807.1) is relatively smaller as compared to other bacteria and contains 707 functional proteins, in which 204 are classified as hypothetical proteins (HPs) because of the unavailability of experimentally validated functions. The functions of the HPs were predicted by integrating a variety of protein classification systems, motif discovery tools as well as methods that are based on characteristic features obtained from the protein sequence and metabolic pathways. The probable functions of 83HPs were predicted successfully. The accuracy of the diverse tools used in the adopted pipeline was evaluated on the basis of statistical techniques of Receiver Operating Characteristic (ROC), which indicated the reliability of the functional predictions. Furthermore, the virulent HPs present in the set of 83 functionally annotated proteins were predicted by using the Bioinformatics tools and the conformational behaviours of the proteins with highest virulence scores were studied by using the molecular dynamics (MD) simulations. This study will facilitate in the better understanding of various drug resistance and pathogenesis mechanisms present in the M. pneumoniae and can be utilized in designing of better therapeutic agents.
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    Towards new drug targets? Function prediction of putative proteins of Neisseria meningitidis MC58 and their virulence characterization
    (Mary Ann Liebert, Inc., 2015) Shahbaaz, Mohd; Bisetty, Krishna; Ahmad, Faizan; Hassan, Md. Imtaiyaz
    Neisseria meningitidis is a Gram-negative aerobic diplococcus, responsible for a variety of meningococcal dis-eases. The genome of N. meningitidis MC58 is comprised of 2114 genes that are translated into 1953 proteins. The 698 genes (*35%) encode hypothetical proteins (HPs), because no experimental evidence of their biological functions are available. Analyses of these proteins are important to understand their functions in the metabolic networks and may lead to the discovery of novel drug targets against the infections caused by N. meningitidis. This study aimed at the identification and categorization of each HP present in the genome of N. meningitidis MC58 using computational tools. Functions of 363 proteins were predicted with high accuracy among the annotated set of HPs investigated. The reliably predicted 363 HPs were further grouped into 41 different classes of proteins, based on their possible roles in cellular processes such as metabolism, transport, and replication. Our studies revealed that 22 HPs may be involved in the pathogenesis caused by this microorganism. The top two HPs with highest virulence scores were subjected to molecular dynamics (MD) simulations to better understand their conformational behavior in a water environment. We also compared the MD simulation results with other virulent proteins present in N. meningitidis. This study broadens our understanding of the mechanistic pathways of pathogenesis, drug resistance, tolerance, and adaptability for host immune responses to N. meningitidis.