A new class of HIV-1 protease inhibitor: The crystallographic structure, inhibition and chemical synthesis of an aminimide peptide isostere

Rutenber, Earl; McPhee, Fiona; Kaplan, Alan P.; Gallion, Steven L.; Hogan, Joseph C.; Craik, Charles S.; Stroud, Rhonda M.

doi:10.1016/0968-0896(96)00147-2

Cited by 28 publications

(7 citation statements)

References 36 publications

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“…The 1XL2 structure contains a ligand based on a pyrrolidinemethaneamine scaffold that adopts a unique and unexpected binding mode (59). The other singleton, PDB ID 3AID, was based on an aminimide peptide isothere (60). In these two cases, the binding mode of the ligand places a phenyl group into a pocket that only these two ligands occupy (see Figure 2).…”

Section: Hiv Protease Binding Site Analysismentioning

confidence: 99%

Generation of Receptor Structural Ensembles for Virtual Screening Using Binding Site Shape Analysis and Clustering

2012

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Accounting for protein flexibility is an essential yet challenging component of structure-based virtual screening. Whereas an ideal approach would account for full protein and ligand flexibility during the virtual screening process, this is currently intractable using available computational resources. An alternative is ensemble docking, where calculations are performed on a set of individual rigid receptor conformations and the results combined. The primary challenge associated with this approach is the choice of receptor structures to use for the docking calculations. In this work, we show that selection of a small set of structures based on clustering on binding site volume overlaps provides an efficient and effective way to account for protein flexibility in virtual screening. We first apply the method to crystal structures of cyclin-dependent kinase 2 and HIV protease and show that virtual screening for ensembles of four cluster representative structures yields consistently high enrichments and diverse actives. We then apply the method to a structural ensemble of the androgen receptor generated with molecular dynamics and obtain results that are in agreement with those from the crystal structures of cyclin-dependent kinase 2 and HIV protease. This work provides a step forward in the incorporation of protein flexibility into structurebased virtual screening.Key words: binding site volume, clustering, docking, molecular dynamics Received 2 January 2012, revised 10 March 2012 and accepted for publication 9 April 2012 Virtual screening is an important part of computer-aided drug design, with many reviews (1-3) and successful applications reported (4-7) in the literature. Although ligand-based methods have been shown to yield high database enrichments in virtual screening (8-10), use of structural information, when available, provides the promise of high enrichments of hits that are not biased by knowledge of existing active compounds. Indeed, structure-based virtual screening has been applied successfully in many instances where novel compounds unrelated to existing known actives were found (11-16). However, docking tools have been most heavily validated in the context of a rigid receptor model for both pose prediction (17-22) and virtual screening (23,24), which helps reduce the conformational sampling space and makes the calculations more tractable from a computational perspective. Speed and throughput constraints are particularly important in virtual screening, considering that calculations are often performed on databases of millions of compounds and turnaround time is expected on the order of days to weeks for the computational approach to have a significant impact in the discovery process.Although successful efforts have been made to account for protein flexibility in pose prediction (25-28) and structure-based virtual screening (28-31), additional work is needed to develop a standardized protocol that can consistently add value over the standard rigid receptor approach. Rueda et al. (32) have focused on...

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Section: Hiv Protease Binding Site Analysismentioning

confidence: 99%

Generation of Receptor Structural Ensembles for Virtual Screening Using Binding Site Shape Analysis and Clustering

2012

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“…When the app's user interface has been explained, the students can work on the tasks mentioned above in groups of 2-3 students for about 15-20 min. Supplementary Video S1 shows a video sequence of a collaborative task on the molecule with the pdb code 3AID [23] to give an impression of how two overlaying representations are used to identify different aspects of protein structures. The whole procedure is visualized in Figure 3.…”

Section: Contents and Structure Of The Teaching Unitmentioning

confidence: 99%

Innovative Teacher Education with the Augmented Reality Device Microsoft HoloLens—Results of an Exploratory Study and Pedagogical Considerations

Wyss

Bührer

Furrer

et al. 2021

MTI

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Augmented Reality (AR) tools are increasingly finding their way into education settings. Although their use is still not widespread in educational contexts, the research literature indicates their potential and effectiveness. However, overall and specifically for the education sector there are still numerous research gaps. This study investigates how the use of head-mounted AR displays such as the Microsoft HoloLens can change learning and what needs to be considered from a didactic perspective. The researched sample consists of 18 student teachers with a nature and technology teaching profile of a German-speaking university of teacher education. The data collection included a written questionnaire, video recordings of a teaching unit with HoloLens examining molecular structures, and one-to-one semi-structured interviews. The results of questionnaires and interviews presented in this paper show that all students were highly motivated to work with this technology in teacher education. The usability of the HoloLens was rated very satisfactory, although many students expressed minor problems. Most students attributed a positive impact on learning to the AR device and stated that the usage of the devices increased their motivation for learning the topic. Overall, the results show that the use of AR in teacher education is considered very valuable and should be increasingly employed in the future.

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“…A novel aminimide transition‐state analogue has been identified and utilized as a general aspartyl protease pharmacophore 55. This isostere was designed to mimic the placement of hydrogen‐bonding atoms in the aspartyl protease active site, while being resistant to proteolysis.…”

Section: Protease Inhibitor Designmentioning

confidence: 99%

Combinatorial Strategies for Targeting Protein Families: Application to the Proteases

2002

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Tens of thousands of proteins have been identified as a result of recent large scale genomic and proteomic efforts. With this large influx of new proteins, the formidable task of elucidating their function begins. However, this task becomes more manageable if proteins are divided into families based upon sequence homology, thereby allowing tools for their systematic study to be developed based upon their common structural and mechanistic characteristics. Combinatorial chemistry is ideally suited for the systematic study of protein families because a large amount of diversity can be readily displayed about a common scaffold designed to target a given protein family. Targeted combinatorial libraries have been particularly effective for the study of a ubiquitous family of proteins, the proteases. Substrate-specificity profiles of many proteases have been determined by using combinatorial libraries of appropriately labeled peptides. This specificity information been utilized to identify the physiological protein substrates of these enzymes and has facilitated inhibitor design efforts. Furthermore, combinatorial libraries of small molecules prepared with mechanism-based scaffolds have resulted in the identification of potent, small-molecule inhibitors of numerous proteases. Cell-permeable small-molecule inhibitors identified by these methods have served as powerful chemical tools to study protease function in vitro and in vivo and have served as leads for the development of therapeutic agents.

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A new class of HIV-1 protease inhibitor: The crystallographic structure, inhibition and chemical synthesis of an aminimide peptide isostere

Cited by 28 publications

References 36 publications

Generation of Receptor Structural Ensembles for Virtual Screening Using Binding Site Shape Analysis and Clustering

Generation of Receptor Structural Ensembles for Virtual Screening Using Binding Site Shape Analysis and Clustering

Innovative Teacher Education with the Augmented Reality Device Microsoft HoloLens—Results of an Exploratory Study and Pedagogical Considerations

Combinatorial Strategies for Targeting Protein Families: Application to the Proteases

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