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

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

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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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
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Article: Dataset of AMBER force field parameters of drugs, natural products and steroids for simulations using GROMACS

Loschwitz, Jennifer / Jäckering, Anna / Keutmann, Monika / Olagunju, Maryam / Olubiyi, Olujide O. / Strodel, Birgit

Data in Brief. 2021 Apr., v. 35

2021

Abstract: We provide general AMBER force field (GAFF) parameters for 160 organic molecules including drugs, natural products, and steroids, which can be employed without further processing in molecular dynamics (MD) simulations using GROMACS. We determined these ... ...

Abstract	We provide general AMBER force field (GAFF) parameters for 160 organic molecules including drugs, natural products, and steroids, which can be employed without further processing in molecular dynamics (MD) simulations using GROMACS. We determined these parameters based on quantum mechanical (QM) calculations involving geometry optimization at the HF6-31G* level of theory. For each molecule we provide a coordinate file of the three-dimensional molecular structure, the topology and the parameter file. The applicability of these parameters was demonstrated by MD simulations of these molecules bound to the active site of the main protease of the coronavirus SARS-CoV-2, 3CLᵖʳᵒ, which is a main player during viral replication causing COVID-19.
Keywords	COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; active sites ; data collection ; geometry ; molecular dynamics ; proteinases ; quantum mechanics ; topology ; virus replication
Language	English
Dates of publication	2021-04
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	2786545-9
ISSN	2352-3409
ISSN	2352-3409
DOI	10.1016/j.dib.2021.106948
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Dataset of AMBER force field parameters of drugs, natural products and steroids for simulations using GROMACS.

Loschwitz, Jennifer / Jäckering, Anna / Keutmann, Monika / Olagunju, Maryam / Olubiyi, Olujide O / Strodel, Birgit

Data in brief

2021 Volume 35, Page(s) 106948

Abstract	We provide general AMBER force field (GAFF) parameters for 160 organic molecules including drugs, natural products, and steroids, which can be employed without further processing in molecular dynamics (MD) simulations using GROMACS. We determined these parameters based on quantum mechanical (QM) calculations involving geometry optimization at the HF6-31G* level of theory. For each molecule we provide a coordinate file of the three-dimensional molecular structure, the topology and the parameter file. The applicability of these parameters was demonstrated by MD simulations of these molecules bound to the active site of the main protease of the coronavirus SARS-CoV-2, 3CL
Language	English
Publishing date	2021-03-15
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2786545-9
ISSN	2352-3409 ; 2352-3409
ISSN (online)	2352-3409
ISSN	2352-3409
DOI	10.1016/j.dib.2021.106948
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2.

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

Molecules (Basel, Switzerland)

2020 Volume 25, Issue 14

Abstract: We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, ... ...

Abstract	We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CL
MeSH term(s)	Betacoronavirus/enzymology ; Binding Sites ; COVID-19 ; Computer Simulation ; Coronavirus 3C Proteases ; Coronavirus Infections/drug therapy ; Cysteine Endopeptidases ; Drug Design ; Drug Discovery ; Humans ; Inhibitory Concentration 50 ; Ligands ; Models, Molecular ; Molecular Structure ; Pandemics ; Pneumonia, Viral/drug therapy ; Protease Inhibitors/pharmacology ; SARS-CoV-2 ; Software ; Thermodynamics ; Viral Nonstructural Proteins/antagonists & inhibitors
Chemical Substances	Ligands ; Protease Inhibitors ; Viral Nonstructural Proteins ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
Keywords	covid19
Language	English
Publishing date	2020-07-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules25143193
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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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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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Article ; Online: Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay.

Loschwitz, Jennifer / Jäckering, Anna / Keutmann, Monika / Olagunju, Maryam / Eberle, Raphael J / Coronado, Monika Aparecida / Olubiyi, Olujide O / Strodel, Birgit

Bioorganic chemistry

2021 Volume 111, Page(s) 104862

Abstract: For the COVID-19 pandemic caused by SARS-CoV-2, there are currently no effective drugs or vaccines to treat this coronavirus infection. In this study, we focus on the main protease enzyme of SARS-CoV-2, ... ...

Abstract	For the COVID-19 pandemic caused by SARS-CoV-2, there are currently no effective drugs or vaccines to treat this coronavirus infection. In this study, we focus on the main protease enzyme of SARS-CoV-2, 3CL
MeSH term(s)	Antiviral Agents/metabolism ; Binding Sites ; Coronavirus 3C Proteases/antagonists & inhibitors ; Coronavirus 3C Proteases/metabolism ; Enzyme Assays ; Ligands ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protease Inhibitors/metabolism ; Protein Binding ; SARS-CoV-2/enzymology ; Small Molecule Libraries/metabolism
Chemical Substances	Antiviral Agents ; Ligands ; Protease Inhibitors ; Small Molecule Libraries ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
Language	English
Publishing date	2021-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120080-x
ISSN	1090-2120 ; 0045-2068
ISSN (online)	1090-2120
ISSN	0045-2068
DOI	10.1016/j.bioorg.2021.104862
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 4207: Show issues

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Article ; Online: High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2

Olubiyi, Olujide / Olagunju, Maryam / Keutmann, Monika / Loschwitz, Jennifer / Strodel, Birgit

Molecules 25(14), 3193 - (2020). doi:10.3390/molecules25143193

2020

Abstract: We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. From our screening of over ... ...

Abstract	We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CLpro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CLpro enzyme of the closely related SARS-CoV virus. The top-ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CLpro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CLpro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CLpro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.
Keywords	info:eu-repo/classification/ddc/540 ; covid19
Subject code	540
Language	English
Publisher	MDPI
Publishing country	de
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2

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

Molecules (Basel)

Abstract	We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CLpro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CLpro enzyme of the closely related SARS-CoV virus. The top-ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CLpro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CLpro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CLpro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #646769
Database	COVID19

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