Comparative evaluation of commercially available homology modelling tools: A structural bioinformatics perspective

Dahiya, Sween; Gahlaut, Anjum; Kulharia, Mahesh

doi:10.1016/j.dit.2013.04.003

Cited by 3 publications

(2 citation statements)

References 21 publications

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“…A homology model of the scFv antibody was obtained using the macro incorporated within YASARA Structure ( Dahiya et al. 2013 ).…”

Section: Methodsmentioning

confidence: 99%

Identification of heparin-binding amino acid residues in antibody HS4C3 with the potential to design antibodies against heparan sulfate domains

Damen,

Bui,

van Wessel

et al. 2024

Glycobiology

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Heparan sulfate (HS) is a linear polysaccharide with high structural and functional diversity. Detection and localization of HS in tissues can be performed using single chain variable fragment (scFv) antibodies. Although several anti-HS antibodies recognizing different sulfation motifs have been identified, little is known about their interaction with HS. In this study the interaction between the scFv antibody HS4C3 and heparin was investigated. Heparin-binding lysine and arginine residues were identified using a protect and label methodology. Site-directed mutagenesis was applied to further identify critical heparin-binding lysine/arginine residues using immunohistochemical and biochemical assays. In addition, computational docking of a heparin tetrasaccharide towards a 3-D homology model of HS4C3 was applied to identify potential heparin-binding sites. Of the 12 lysine and 15 arginine residues within the HS4C3 antibody, 6 and 9, respectively, were identified as heparin-binding. Most of these residues are located within one of the complementarity determining regions (CDR) or in their proximity. All basic amino acid residues in the CDR3 region of the heavy chain were involved in binding. Computational docking showed a heparin tetrasaccharide close to these regions. Mutagenesis of heparin-binding residues reduced or altered reactivity towards HS and heparin. Identification of heparin-binding arginine and lysine residues in HS4C3 allows for better understanding of the interaction with HS and creates a framework to rationally design antibodies targeting specific HS motifs.

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“…A homology model of the scFv antibody was obtained using the macro incorporated within YASARA Structure ( Dahiya et al. 2013 ).…”

Section: Methodsmentioning

confidence: 99%

Identification of heparin-binding amino acid residues in antibody HS4C3 with the potential to design antibodies against heparan sulfate domains

Damen,

Bui,

van Wessel

et al. 2024

Glycobiology

View full text Add to dashboard Cite

show abstract

“…Five different structural descriptors are employed by QMEAN, which are (1) Interdiscip Sci Comput Life Sci distance-dependent pairwise potential, (2) solvation potential, (3) torsion angle potential, (4) secondary structure and solvent accessibility agreement, and (5) measures for the structural similarity between model and target [44]. Validation of many in silico predicted protein structures were also done with QMEAN for indicating the acceptability of the predicted model [45]. G-factor is log-odds score that measures stereochemical property of the models built to show how ''unusual'' a model is when comparing to native protein.…”

Section: Qmean G-factor and Final Potential Energymentioning

confidence: 99%

Targeting Heat Shock Proteins 60 and 70 of Toxoplasma gondii as a Potential Drug Target: In Silico Approach

Ashwinder

Kho

Chee

et al. 2015

Interdiscip Sci Comput Life Sci

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Heat shock proteins (Hsps) 60 and 70 are postulated as a potential drug target for toxoplasmosis due to its importance in the developmental and survival of Toxoplasma gondii (T. gondii). As of today, there have been no reports on three-dimensional (3D) structure of Hsp60 and Hsp70 deposited in the Brookhaven Protein Data Bank. Hence, this study was conducted to predict 3D structures for Hsp60 and Hsp70 in T. gondii by homology modeling. Selection of the best predicted model was done based on multiple scoring functions. In addition, virtual screening was performed to short-list chemical compounds from the National Cancer Institute (NCI) Diversity Set III in search of potential inhibitor against Hsp60 and Hsp70 in T. gondii. Prior to virtual screening, binding sites of Hsp60 and Hsp70 were predicted using various servers and were used as the center in docking studies. The Hsps were docked against known natural ligands to validate the method used in estimating free energy of binding (FEB) and possible interactions between ligand and protein. Virtual screening was performed with a total of 1560 compounds from the NCI Diversity Set III. The compounds were ranked subsequently according to their FEB. Molecular basis of interactions of the top five ranked compounds was investigated using Ligplot. The major interactions exhibited were hydrogen bonding and hydrophobic interactions in binding to Hsp60 and Hsp70. The results obtained provided information and guidelines for the development of inhibitors for Hsp60 and Hsp70 in T. gondii.

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An insight to the molecular interactions of the FDA approved HIV PR drugs against L38L↑N↑L PR mutant

Sanusi

Govender

Maguire

et al. 2018

J Comput Aided Mol Des

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The aspartate protease of the human immune deficiency type-1 virus (HIV-1) has become a crucial antiviral target in which many useful antiretroviral inhibitors have been developed. However, it seems the emergence of new HIV-1 PR mutations enhances drug resistance, hence, the available FDA approved drugs show less activity towards the protease. A mutation and insertion designated L38L↑N↑L PR was recently reported from subtype of C-SA HIV-1. An integrated two-layered ONIOM (QM:MM) method was employed in this study to examine the binding affinities of the nine HIV PR inhibitors against this mutant. The computed binding free energies as well as experimental data revealed a reduced inhibitory activity towards the L38L↑N↑L PR in comparison with subtype C-SA HIV-1 PR. This observation suggests that the insertion and mutations significantly affect the binding affinities or characteristics of the HIV PIs and/or parent PR. The same trend for the computational binding free energies was observed for eight of the nine inhibitors with respect to the experimental binding free energies. The outcome of this study shows that ONIOM method can be used as a reliable computational approach to rationalize lead compounds against specific targets. The nature of the intermolecular interactions in terms of the host-guest hydrogen bond interactions is discussed using the atoms in molecules (AIM) analysis. Natural bond orbital analysis was also used to determine the extent of charge transfer between the QM region of the L38L↑N↑L PR enzyme and FDA approved drugs. AIM analysis showed that the interaction between the QM region of the L38L↑N↑L PR and FDA approved drugs are electrostatic dominant, the bond stability computed from the NBO analysis supports the results from the AIM application. Future studies will focus on the improvement of the computational model by considering explicit water molecules in the active pocket. We believe that this approach has the potential to provide information that will aid in the design of much improved HIV-1 PR antiviral drugs.

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Comparative evaluation of commercially available homology modelling tools: A structural bioinformatics perspective

Cited by 3 publications

References 21 publications

Identification of heparin-binding amino acid residues in antibody HS4C3 with the potential to design antibodies against heparan sulfate domains

Identification of heparin-binding amino acid residues in antibody HS4C3 with the potential to design antibodies against heparan sulfate domains

Targeting Heat Shock Proteins 60 and 70 of Toxoplasma gondii as a Potential Drug Target: In Silico Approach

An insight to the molecular interactions of the FDA approved HIV PR drugs against L38L↑N↑L PR mutant

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