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  1. Article ; Online: Multiscale MD simulations of wild-type and sickle hemoglobin aggregation.

    Olagunju, Maryam O / Loschwitz, Jennifer / Olubiyi, Olujide O / Strodel, Birgit

    Proteins

    2022  Volume 90, Issue 11, Page(s) 1811–1824

    Abstract: Sickle cell disease is a hemoglobinopathy resulting from a point mutation from glutamate to valine at position six of the β-globin chains of hemoglobin. This mutation gives rise to pathological aggregation of the sickle hemoglobin and, as a result, ... ...

    Abstract Sickle cell disease is a hemoglobinopathy resulting from a point mutation from glutamate to valine at position six of the β-globin chains of hemoglobin. This mutation gives rise to pathological aggregation of the sickle hemoglobin and, as a result, impaired oxygen binding, misshapen and short-lived erythrocytes, and anemia. We aim to understand the structural effects caused by the single Glu6Val mutation leading to protein aggregation. To this end, we perform multiscale molecular dynamics simulations employing atomistic and coarse-grained models of both wild-type and sickle hemoglobin. We analyze the dynamics of hemoglobin monomers and dimers, study the aggregation of wild-type and sickle hemoglobin into decamers, and analyze the protein-protein interactions in the resulting aggregates. We find that the aggregation of sickle hemoglobin is driven by both hydrophobic and electrostatic protein-protein interactions involving the mutation site and surrounding residues, leading to an extended interaction area and thus stable aggregates. The wild-type protein can also self-assemble, which, however, results from isolated interprotein salt bridges that do not yield stable aggregates. This knowledge can be exploited for the development of sickle hemoglobin-aggregation inhibitors.
    MeSH term(s) Glutamates ; Hemoglobin, Sickle/genetics ; Hemoglobin, Sickle/metabolism ; Hemoglobins/chemistry ; Oxygen/metabolism ; Protein Aggregates ; Valine ; beta-Globins
    Chemical Substances Glutamates ; Hemoglobin, Sickle ; Hemoglobins ; Protein Aggregates ; beta-Globins ; Valine (HG18B9YRS7) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2022-05-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 806683-8
    ISSN 1097-0134 ; 0887-3585
    ISSN (online) 1097-0134
    ISSN 0887-3585
    DOI 10.1002/prot.26352
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease.

    Olubiyi, Olujide O / Olagunju, Maryam O / Strodel, Birgit

    Molecules (Basel, Switzerland)

    2019  Volume 24, Issue 24

    Abstract: Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the β-globin chain of hemoglobin. ...

    Abstract Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the β-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration. A third treatment was newly approved, while a monoclonal antibody preventing vaso-occlusive crises is also now available. The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30-40 years ago up to more promising 12- and 15-mers under consideration in recent years.
    MeSH term(s) Anemia, Sickle Cell/drug therapy ; Anemia, Sickle Cell/metabolism ; Anemia, Sickle Cell/pathology ; Antisickling Agents/chemistry ; Antisickling Agents/therapeutic use ; Drug Design ; Hemoglobin, Sickle/metabolism ; Humans ; Peptides/chemistry ; Peptides/therapeutic use
    Chemical Substances Antisickling Agents ; Hemoglobin, Sickle ; Peptides
    Language English
    Publishing date 2019-12-12
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules24244551
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 81: Show issues

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  3. Article ; Online: Computational Analysis of Physicochemical Factors Driving CYP2D6 Ligand Interaction.

    Olubiyi, Olujide O / Olagunju, Maryam O / Obisesan, Abiola O

    Current computer-aided drug design

    2017  Volume 13, Issue 1, Page(s) 39–47

    Abstract: Background: The metabolic action of CYP2D6 remains a crucial factor influencing the therapeutic outcomes for many drug molecules while others are either only slightly affected or not affected altogether.: Objective: This study seeks to understand, ... ...

    Abstract Background: The metabolic action of CYP2D6 remains a crucial factor influencing the therapeutic outcomes for many drug molecules while others are either only slightly affected or not affected altogether.
    Objective: This study seeks to understand, atomistic resolution, the structural and physicochemical factors influencing CYP2D6 metabolic discrimination.
    Method: Explicit solvent molecular dynamics simulations in GROMACS were employed to probe the conformational dynamics of CYP2D6 following which the most populated structures were employed for ligand interaction docking studies with AutoDock Vina using selected CYP2D6 drug substrates.
    Results: Using atomistic treatment at the molecular mechanics level and multiple CYP2D6 conformations for docking, two primary ligand binding subsites (subsites A and B) were identified within an otherwise extensive ligand recognition site. The studied drug molecules were found to display distinct preference for either of the two subsites. Correlation and center-of-mass distribution analysis showed subsite binding preference to depend significantly on CYP2D6 conformation, as well as molecular properties such as molecular size and number of hydrogen bond donor present in the drug molecule.
    Conclusion: CYP2D6 binding subsite A was found to be relatively selective for small molecular weight with higher polarity compared with subsite B which tends to favor larger molecular weight and relatively hydrophobic molecules such as tamoxifen and imipramine. Our simulations further suggest that the ability of the CYP2D6 binding site residues to sample different conformations may partly account for its ability to metabolize diverse drug classes.
    MeSH term(s) Binding Sites ; Cytochrome P-450 CYP2D6/chemistry ; Hydrogen Bonding ; Ligands ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Binding ; Protein Conformation
    Chemical Substances Ligands ; Cytochrome P-450 CYP2D6 (EC 1.14.14.1)
    Language English
    Publishing date 2017
    Publishing country United Arab Emirates
    Document type Journal Article
    ISSN 1875-6697
    ISSN (online) 1875-6697
    DOI 10.2174/1573409912666160909092600
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Structural Basis of Antisickling Effects of Selected FDA Approved Drugs: A Drug Repurposing Study.

    Olubiyi, Olujide O / Olagunju, Maryam O / Oni, James O / Olubiyi, Abidemi O

    Current computer-aided drug design

    2018  Volume 14, Issue 2, Page(s) 106–116

    Abstract: Introduction: Sickle cell disease is characterized by a point mutation involving substitution of glutamic acid at position 6 to valine. Encoded in this hydrophobic mutation is both an intrinsic capacity for the beta globin molecules to assemble into ... ...

    Abstract Introduction: Sickle cell disease is characterized by a point mutation involving substitution of glutamic acid at position 6 to valine. Encoded in this hydrophobic mutation is both an intrinsic capacity for the beta globin molecules to assemble into thermodynamically favoured polymeric states as well as a rational way of interrupting the aggregation.
    Methods: In this work, starting with a theoretical model that employs occlusive binding onto the beta globin aggregation surface and using a range of computational methods and an effective energy for screening, a number of FDA approved drugs with computed aggregation inhibitory activities were identified.
    Results and conclusion: The validity of the model was confirmed using sickling tests, after which pharmacophore models as well the structural basis for the observed antisickling effects were identified.
    MeSH term(s) Anemia, Sickle Cell/drug therapy ; Anemia, Sickle Cell/genetics ; Anemia, Sickle Cell/metabolism ; Antisickling Agents/chemistry ; Antisickling Agents/pharmacology ; Drug Approval ; Drug Repositioning/methods ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Point Mutation ; Protein Aggregates/drug effects ; United States ; United States Food and Drug Administration ; beta-Globins/genetics ; beta-Globins/metabolism
    Chemical Substances Antisickling Agents ; Protein Aggregates ; beta-Globins
    Language English
    Publishing date 2018-01-29
    Publishing country United Arab Emirates
    Document type Journal Article
    ISSN 1875-6697
    ISSN (online) 1875-6697
    DOI 10.2174/1573409914666180129163711
    Database MEDical Literature Analysis and Retrieval System OnLINE

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