Template-Based Protein Modeling: Recent Methodological Advances

Daga, Pankaj; Patel, Ronak Y.; Doerksen, Robert J.

doi:10.2174/156802610790232314

Cited by 39 publications

(33 citation statements)

References 151 publications

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“…The quality of comparative protein modeling is connected to the percent sequence identity of query and template sequences (Daga et al, 2010). The accurate homology models have nearly 1Å root mean square error (RMSE) for the atoms in the backbone.…”

Section: Discussionmentioning

confidence: 99%

Structural modeling and analysis of dengue-mediated inhibition of interferon signaling pathway

Aslam¹,

Ahmad²,

Ali³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Dengue virus (DENV) belongs to the family Flaviviridae and can cause major health problems worldwide, including dengue fever and dengue shock syndrome. DENV replicon in human cells inhibits interferon α and β with the help of its non-structural proteins. Nonstructural protein 5 (NS5) of DENV is responsible for the proteasomemediated degradation of signal transducer and activator of transcription B. Aslam et al. 4216©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 4215-4237 (2015) (STAT) 2 protein, which has been implicated in the development of resistance against interferon-mediated antiviral effect. This degradation of STAT2 primarily occurs with the help of E3 ubiquitin ligases. Seven in absentia homologue (SIAH) 2 is a host protein that can mediate the ubiquitination of proteins and is known for its interaction with NS5. In this study, comprehensive computational analysis was performed to characterize the protein-protein interactions between NS5, SIAH2, and STAT2 to gain insight into the residues and sites of interaction between these proteins. The objective of the study was to structurally characterize the NS5-STAT2, SIAH2-STAT2, and NS5-SIAH2 interactions along with the determination of the possible reaction pattern for the degradation of STAT2. Docking and physicochemical studies indicated that DENV NS5 may first interact with the host SIAH2, which can then proceed towards binding with STAT2 from the side of SIAH2. These implications are reported for the first time and require validation by wet-lab studies.

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Section: Discussionmentioning

confidence: 99%

Structural modeling and analysis of dengue-mediated inhibition of interferon signaling pathway

Aslam¹,

Ahmad²,

Ali³

et al. 2015

Genet. Mol. Res.

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“…6 Good sequence homology between HDP and HIV-1 RT has enabled several researchers to build 3D homology models of the structure of the HDP catalytic domain, [7][8][9] which were used to provide insights about the binding mode of various inhibitors and developing resistance. Das et al aligned the sequence of HDP to HIV-1 RT and used an HIV-1 RT X-ray structure 1RTD.pdb for building a tertiary structure of HDP, which was used to reveal the mechanism of HDP resistance to lamivudine and emtricitabine.…”

Section: Introductionmentioning

confidence: 99%

Computational model of hepatitis B virus DNA polymerase: Molecular dynamics and docking to understand resistant mutations

2010

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Hepatitis B virus (HBV) DNA polymerase (HDP) is a pharmacological target of intense interest. Of the seven agents approved in USA for the treatment of HBV infections, five are HDP inhibitors. However, resistance development against HDP inhibitors, such as lamivudine and adefovir, has severely hurt their efficacy to treat HBV. As a step toward understanding the mechanism of resistance development and for gaining detailed insights about the active site of the enzyme, we have built a homology model of HDP which is an advance over previously reported ones. Validation using various techniques, including PROSTAT, PROCHECK, and Verify-3D profile, proved the model to be stereochemically significant. The stability of the model was studied using a 5 ns molecular dynamics simulation. The model was found to be sufficiently stable after the initial 2.5 ns with overall root mean squared deviation (RMSD) of 4.13 Å . The homology model matched the results of experimental mutation studies of HDP reported in the literature, including those of antiviral-resistant mutations. Our model suggests the significant role of conserved residues, such as rtLys32, in binding of the inhibitors, contrary to previous studies. The model provides an explanation for the inactivity of some anti-HIV molecules which are inactive against HDP. Conformational changes which occurred in certain binding pocket amino acids helped to explain the better binding of some of the inhibitors in comparison to the substrates.

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“…Homology modeling is an established and widely documented process [7], a method based on the assumptions that proteins that possess similar sequences share similar threedimensional structures, and only a limited number of protein folds exist in nature [8,9]. Homology modeling has been stated as the best structure prediction method of homologous protein so far, and it was widely used in structure-based drug discovery projects [10].…”

Section: Homology Modelingmentioning

confidence: 99%

From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

Chen¹,

Morrow²,

Tran³

et al. 2012

curr drug metab

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As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting protein-ligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issues, may also cause failures. In this review, state-of-the-art techniques for protein modeling (e.g. structure prediction, modeling protein flexibility, etc.), hit identification/optimization (e.g. molecular docking, focused library design, fragment-based design, molecular dynamic, etc.), and polypharmacology design will be discussed. We will explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches. KeywordsStructure-based drug design; protein modeling; focused library design; pharmacophore; flexible docking; high-throughput virtual screening; de novo design; protein-protein interaction; polypharmacology Modern computational-aided drug design established a novel platform by which researchers perform in-depth in silico simulation prior to labor-extensive wet-lab validation [1]. It comprises of two major parts corresponding to the information of molecular source it utilizes: structure-based (or receptor-based) drug design and ligand-based drug design. Structure-based drug design, which relies on the knowledge of biological target structures, aims to discover small molecules/peptides leads with desired chemistry properties, and orchestrate the following experimental validation and lead optimization. Structure-based approach provides mechanism-based basis, where potential ligands are excavated using receptor-dependent parameters, while ligand-based approaches bypass the consideration of complex biomolecular "black box" in a living cell. This in silico method permeates all aspects of drug discovery today [2], and we expect it will draw more attentions with the unprecedented advances of computational power and modeling accuracy in this decade.* Corresponding author: Shuxing Zhang, Ph.D., The University of Texas M. D. Anderson Cancer Center, Department of Experimental Therapeutics, Unit 1950, 1901 East Rd., Houston, TX 77054, Telephone: (713)-745-2958 794-5577, shuzhang@mdanderson.org. Conflict of interestThe authors declare that they do not have competing interests. NIH Public Access Author ManuscriptCurr Pharm Des. Author manuscript; available in PMC 2013 November 07.Published in final edited form as:Curr Pharm Des. 2012 ; 18(9): 1217-1239. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn this review, we will overview the state-of-the-art structure-based drug discovery techniques ranging from receptor modeling to lead identification and optimization. In each topic, we will also highlight the fruitful successes as well as ch...

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Template-Based Protein Modeling: Recent Methodological Advances

Cited by 39 publications

References 151 publications

Structural modeling and analysis of dengue-mediated inhibition of interferon signaling pathway

Structural modeling and analysis of dengue-mediated inhibition of interferon signaling pathway

Computational model of hepatitis B virus DNA polymerase: Molecular dynamics and docking to understand resistant mutations

From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

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