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  1. Article ; Online: Combining fragment docking with graph theory to improve ligand docking for homology model structures.

    Sarfaraz, Sara / Muneer, Iqra / Liu, Haiyan

    Journal of computer-aided molecular design

    2020  Volume 34, Issue 12, Page(s) 1237–1259

    Abstract: Computational protein-ligand docking is well-known to be prone to inaccuracies in input receptor structures, and it is challenging to obtain good docking results with computationally predicted receptor structures (e.g. through homology modeling). Here we ...

    Abstract Computational protein-ligand docking is well-known to be prone to inaccuracies in input receptor structures, and it is challenging to obtain good docking results with computationally predicted receptor structures (e.g. through homology modeling). Here we introduce a fragment-based docking method and test if it reduces requirements on the accuracy of an input receptor structures relative to non-fragment docking approaches. In this method, small rigid fragments are docked first using AutoDock Vina to generate a large number of favorably docked poses spanning the receptor binding pocket. Then a graph theory maximum clique algorithm is applied to find combined sets of docked poses of different fragment types onto which the complete ligand can be properly aligned. On the basis of these alignments, possible binding poses of complete ligand are determined. This docking method is first tested for bound docking on a series of Cytochrome P450 (CYP450) enzyme-substrate complexes, in which experimentally determined receptor structures are used. For all complexes tested, ligand poses of less than 1 Å root mean square deviations (RMSD) from the actual binding positions can be recovered. Then the method is tested for unbound docking with modeled receptor structures for a number of protein-ligand complexes from different families including the very recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease. For all complexes, poses with RMSD less than 3 Å from actual binding positions can be recovered. Our results suggest that for docking with approximately modeled receptor structures, fragment-based methods can be more effective than common complete ligand docking approaches.
    MeSH term(s) ATPases Associated with Diverse Cellular Activities/chemistry ; ATPases Associated with Diverse Cellular Activities/metabolism ; Betacoronavirus/enzymology ; COVID-19 ; Coronavirus 3C Proteases ; Coronavirus Infections/drug therapy ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/drug effects ; Cysteine Endopeptidases/metabolism ; Cytochrome P-450 Enzyme System/chemistry ; Cytochrome P-450 Enzyme System/metabolism ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/metabolism ; Humans ; Ligands ; Models, Chemical ; Models, Molecular ; Molecular Chaperones/chemistry ; Molecular Chaperones/metabolism ; Molecular Docking Simulation ; Pandemics ; Peptide Fragments/chemistry ; Peptide Fragments/metabolism ; Pneumonia, Viral/drug therapy ; Protein Binding ; Protein Conformation ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/metabolism ; SARS-CoV-2 ; Transcription Factors/chemistry ; Transcription Factors/metabolism ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/drug effects ; Viral Nonstructural Proteins/metabolism
    Chemical Substances BRD2 protein, human ; DNA-Binding Proteins ; Ligands ; Molecular Chaperones ; Peptide Fragments ; Receptors, G-Protein-Coupled ; Transcription Factors ; Viral Nonstructural Proteins ; Cytochrome P-450 Enzyme System (9035-51-2) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28) ; ATAD2 protein, human (EC 3.6.1.3) ; ATPases Associated with Diverse Cellular Activities (EC 3.6.4.-)
    Keywords covid19
    Language English
    Publishing date 2020-10-09
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 808166-9
    ISSN 1573-4951 ; 0920-654X
    ISSN (online) 1573-4951
    ISSN 0920-654X
    DOI 10.1007/s10822-020-00345-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2625: Show issues Location:
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  2. Article ; Online: Repurposing FIASMAs against Acid Sphingomyelinase for COVID-19: A Computational Molecular Docking and Dynamic Simulation Approach.

    Naz, Aliza / Asif, Sumbul / Alwutayd, Khairiah Mubarak / Sarfaraz, Sara / Abbasi, Sumra Wajid / Abbasi, Asim / Alenazi, Abdulkareem M / Hasan, Mohamed E

    Molecules (Basel, Switzerland)

    2023  Volume 28, Issue 7

    Abstract: Over the past few years, COVID-19 has caused widespread suffering worldwide. There is great research potential in this domain and it is also necessary. The main objective of this study was to identify potential inhibitors against acid sphingomyelinase ( ... ...

    Abstract Over the past few years, COVID-19 has caused widespread suffering worldwide. There is great research potential in this domain and it is also necessary. The main objective of this study was to identify potential inhibitors against acid sphingomyelinase (ASM) in order to prevent coronavirus infection. Experimental studies revealed that SARS-CoV-2 causes activation of the acid sphingomyelinase/ceramide pathway, which in turn facilitates the viral entry into the cells. The objective was to inhibit acid sphingomyelinase activity in order to prevent the cells from SARS-CoV-2 infection. Previous studies have reported functional inhibitors against ASM (FIASMAs). These inhibitors can be exploited to block the entry of SARS-CoV-2 into the cells. To achieve our objective, a drug library containing 257 functional inhibitors of ASM was constructed. Computational molecular docking was applied to dock the library against the target protein (PDB: 5I81). The potential binding site of the target protein was identified through structural alignment with the known binding pocket of a protein with a similar function. AutoDock Vina was used to carry out the docking steps. The docking results were analyzed and the inhibitors were screened based on their binding affinity scores and ADME properties. Among the 257 functional inhibitors, Dutasteride, Cepharanthine, and Zafirlukast presented the lowest binding affinity scores of -9.7, -9.6, and -9.5 kcal/mol, respectively. Furthermore, computational ADME analysis of these results revealed Cepharanthine and Zafirlukast to have non-toxic properties. To further validate these findings, the top two inhibitors in complex with the target protein were subjected to molecular dynamic simulations at 100 ns. The molecular interactions and stability of these compounds revealed that these inhibitors could be a promising tool for inhibiting SARS-CoV-2 infection.
    MeSH term(s) Humans ; COVID-19 ; SARS-CoV-2 ; Molecular Docking Simulation ; Drug Repositioning ; Sphingomyelin Phosphodiesterase ; Protease Inhibitors/chemistry ; Molecular Dynamics Simulation ; Antiviral Agents/pharmacology
    Chemical Substances zafirlukast (XZ629S5L50) ; Sphingomyelin Phosphodiesterase (EC 3.1.4.12) ; Protease Inhibitors ; Antiviral Agents
    Language English
    Publishing date 2023-03-27
    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/molecules28072989
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    Zs.MO 81: Show issues

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  3. Article: Combining fragment docking with graph theory to improve ligand docking for homology model structures

    Sarfaraz, Sara / Muneer, Iqra / Liu, Haiyan

    J Comput Aided Mol Des

    Abstract: Computational protein-ligand docking is well-known to be prone to inaccuracies in input receptor structures, and it is challenging to obtain good docking results with computationally predicted receptor structures (e.g. through homology modeling). Here we ...

    Abstract Computational protein-ligand docking is well-known to be prone to inaccuracies in input receptor structures, and it is challenging to obtain good docking results with computationally predicted receptor structures (e.g. through homology modeling). Here we introduce a fragment-based docking method and test if it reduces requirements on the accuracy of an input receptor structures relative to non-fragment docking approaches. In this method, small rigid fragments are docked first using AutoDock Vina to generate a large number of favorably docked poses spanning the receptor binding pocket. Then a graph theory maximum clique algorithm is applied to find combined sets of docked poses of different fragment types onto which the complete ligand can be properly aligned. On the basis of these alignments, possible binding poses of complete ligand are determined. This docking method is first tested for bound docking on a series of Cytochrome P450 (CYP450) enzyme-substrate complexes, in which experimentally determined receptor structures are used. For all complexes tested, ligand poses of less than 1 Å root mean square deviations (RMSD) from the actual binding positions can be recovered. Then the method is tested for unbound docking with modeled receptor structures for a number of protein-ligand complexes from different families including the very recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease. For all complexes, poses with RMSD less than 3 Å from actual binding positions can be recovered. Our results suggest that for docking with approximately modeled receptor structures, fragment-based methods can be more effective than common complete ligand docking approaches.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #841071
    Database COVID19

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  4. Article ; Online: Comparative modeling and virtual screening for the identification of novel inhibitors for myo-inositol-1-phosphate synthase.

    Azam, Syed Sikander / Sarfaraz, Sara / Abro, Asma

    Molecular biology reports

    2014  Volume 41, Issue 8, Page(s) 5039–5052

    Abstract: Myo-inositol-1-phosphate (MIP) synthase is a key enzyme in the myo-inositol biosynthesis pathway. Disruption of the inositol signaling pathway is associated with bipolar disorders. Previous work suggested that MIP synthase could be an attractive target ... ...

    Abstract Myo-inositol-1-phosphate (MIP) synthase is a key enzyme in the myo-inositol biosynthesis pathway. Disruption of the inositol signaling pathway is associated with bipolar disorders. Previous work suggested that MIP synthase could be an attractive target for the development of anti-bipolar drugs. Inhibition of this enzyme could possibly help in reducing the risk of a disease in patients. With this objective, three dimensional structure of the protein was modeled followed by the active site prediction. For the first time, computational studies were carried out to obtain structural insights into the interactive behavior of this enzyme with ligands. Virtual screening was carried out using FILTER, ROCS and EON modules of the OpenEye scientific software. Natural products from the ZINC database were used for the screening process. Resulting compounds were docked into active site of the target protein using FRED (Fast Rigid Exhaustive Docking) and GOLD (Genetic Optimization for Ligand Docking) docking programs. The analysis indicated extensive hydrogen bonding network and hydrophobic interactions which play a significant role in ligand binding. Four compounds are shortlisted and their binding assay analysis is underway.
    MeSH term(s) Amino Acid Sequence ; Base Sequence ; Bipolar Disorder/enzymology ; Catalytic Domain/genetics ; Computer Simulation ; Crystallography, X-Ray ; Drug Discovery ; Humans ; Hydrogen Bonding ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Molecular Structure ; Myo-Inositol-1-Phosphate Synthase/antagonists & inhibitors ; Myo-Inositol-1-Phosphate Synthase/chemistry ; Protein Binding ; Protein Conformation ; Sequence Alignment
    Chemical Substances Ligands ; Myo-Inositol-1-Phosphate Synthase (EC 5.5.1.4)
    Language English
    Publishing date 2014-04-22
    Publishing country Netherlands
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186544-4
    ISSN 1573-4978 ; 0301-4851
    ISSN (online) 1573-4978
    ISSN 0301-4851
    DOI 10.1007/s11033-014-3370-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1140: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
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  5. Article ; Online: Targeted exome sequencing identified a novel frameshift variant in the PGAM2 gene causing glycogen storage disease type X.

    Nayab, Anam / Alam, Qamre / Alzahrani, Othman R / Khan, Ranjha / Sarfaraz, Sara / Albaz, Alrayan Abass / Rafeeq, Misbahuddin M / Sain, Ziaullah M / Waqas, Ahmed / Umair, Muhammad

    European journal of medical genetics

    2021  Volume 64, Issue 9, Page(s) 104283

    Abstract: Background: Phosphoglycerate mutase (PGAM) deficiency is associated with a rare glycogen storage disease (glycogenosis type X) in humans caused by pathogenic variants in the PGAM2 gene. Several genes causing autosomal forms of glycogen storage disease ( ... ...

    Abstract Background: Phosphoglycerate mutase (PGAM) deficiency is associated with a rare glycogen storage disease (glycogenosis type X) in humans caused by pathogenic variants in the PGAM2 gene. Several genes causing autosomal forms of glycogen storage disease (GSD) have been identified, involved in various forms of neuromuscular anomalies.
    Methods: Targeted whole exome sequencing (WES) was performed on the DNA of single affected individual (IV-1) followed by Sanger sequencing confirmation of the identified variant in all available members of the family.
    Results: In the present study, the affected individual, presenting mild features of glycogen storage disease type X. Targeted exome sequencing revealed a biallelic frameshift variant (c.687dupC; p. Met230Hisfs*6) in the PGAM2 gene located on chromosome 7p13.
    Conclusion: In short, we reported a novel homozygous frameshift variant as a cause of glycogen storage disease type X from Pakistani population. The work presented here proves significance of targeted WES in accurate diagnosis of known complex genetic disorders.
    MeSH term(s) Adolescent ; Frameshift Mutation ; Homozygote ; Humans ; Kidney Diseases/genetics ; Kidney Diseases/pathology ; Male ; Muscular Diseases/genetics ; Muscular Diseases/pathology ; Phosphoglycerate Mutase/chemistry ; Phosphoglycerate Mutase/deficiency ; Phosphoglycerate Mutase/genetics
    Chemical Substances Phosphoglycerate Mutase (EC 5.4.2.11)
    Language English
    Publishing date 2021-07-05
    Publishing country Netherlands
    Document type Case Reports ; Journal Article
    ZDB-ID 2184135-4
    ISSN 1878-0849 ; 1769-7212
    ISSN (online) 1878-0849
    ISSN 1769-7212
    DOI 10.1016/j.ejmg.2021.104283
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 84/9: Show issues Location:
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