Ligand Docking and Design in a Flexible Receptor Site

Alberts, Ian L.; Todorov, Nicolay P.; Källblad, Per; Dean, Philip M.

doi:10.1002/qsar.200430924

Cited by 10 publications

(11 citation statements)

References 31 publications

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“…In general, protein flexibility is still poorly simulated in many of the available docking packages. Accordingly, most publications on docking and virtual screening on metalloproteases currently concentrate on ensuring [39,41] or improving the accuracy of known ligand binding [151,155,156] and incorporating the protein flexibility into the equation [157], or the use of more pharmacophore-based approaches, such as for ADAM12 [158], Anthrax Lethal Factor [159], and botulinum neurotoxin A metalloprotease [156]. One report [160] of virtual screening-based discovery of novel angiotensinconverting enzyme 2 (ACE2) inhibitors from the NCI library of 140 000 compounds using DOCK 5.1 describes nine compounds chosen from the docking screen for in vitro assay.…”

Section: Metalloproteasesmentioning

confidence: 99%

Current Status of Virtual Screening as Analysed by Target Class

Stoermer

2006

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In silico virtual screening for drug discovery has become a hot topic in medicinal chemistry research during the last 5 years, growing from a largely academic pursuit concerned principally with validating the methods used, to a major early-stage technique for lead discovery in the pharmaceutical industry. In this review we highlight a few recent successes in ligand docking associated with virtual screening, paying particular attention to four major target classes of pharmaceutical interest (G Protein-Coupled receptors, nuclear hormone receptors, kinases, proteases). We also discuss some emerging trends in the field, some common limitations, and how they are being overcome.

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Section: Metalloproteasesmentioning

confidence: 99%

Current Status of Virtual Screening as Analysed by Target Class

Stoermer

2006

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“…SkelGen has been adapted to use several static receptors and flexible side chains through its Reflex method [16,17].…”

Section: Receptor Flexibilitymentioning

confidence: 99%

SkelGen

Todorov

2013

Methods and Principles in Medicinal Chemistry

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“…It has been demonstrated that incorporating protein structural flexibility is significant for both binding mode predictions and ligand generation [47]. In order to investigate whether the binding process of POM to N1 could be better described by induced-fit theory, we used the module Affinity to implement a flexible docking study on the configuration which had the highest score in the rigid docking.…”

Section: Flexible Affinity Of Pom/na Complexmentioning

confidence: 99%

Molecular simulation study of the binding mechanism of [α-PTi2W10O40]7− for its promising broad-spectrum inhibitory activity to FluV-A neuraminidase

Wang

2010

Chin. Sci. Bull.

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Polyoxometalate (POM) has promising antiviral activities. It shows broad-spectrum inhibiting ability, high efficiency, and low toxicity. Experimental assays show that titanium containing polyoxotungstates have anti-influenza-virus activity. In this paper, the binding mechanisms of five isomers of di-Ti-substituted polyoxotungstate, [α-1,2-PTi 2 W 10 O 40 ] 7-(α-1,2), [α-1,6-PTi 2 W 10 O 40 ] 7-(α-1,6), [α-1,5-PTi 2 W 10 O 40 ] 7-(α-1,5), [α-1,4-PTi 2 W 10 O 40 ] 7-(α-1,4) and [α-1,11-PTi 2 W 10 O 40 ] 7-(α-1,11), to five subtypes of influenza virus A neuraminidase (FluV-A NA) were investigated in the context of aqueous solution by using molecular docking and molecular dynamics studies. The results show that the isomer α-1,2 is superior to other isomers as a potential inhibitor to neuraminidase. The positively charged arginine residues around the active site of NA could be induced by negatively charged POM to adapt themselves and could form salt bridge interactions and hydrogen bond interactions with POM. The binding free energies of POM/NA complexes range from -5.36 to -8.31 kcal mol -1 . The electrostatic interactions are found to be the driving force during the binding process of POM to NA. The conformational analysis shows that POM tends to bind primarily with N1 and N8 at the edge of the active pocket, which causes the conformational change of the pincers structure comprising residue 347 and loop 150. Whereas, the active pockets of N2, N9 and N4 are found to be more spacious, which allows POM to enter into the active pockets directly and anchor there firmly. This study shows that negatively charged ligand as POM could induce the reorganization of the active site of NA and highlights POM as a promising inhibitor to NA despite the ever increasing mutants of NA.influenza virus A, neuraminidase, polyoxometalate, docking, molecular dynamics Citation:Wang J P, Hu D H, Su Z M. Molecular simulation study of the binding mechanism of [α-PTi 2 W 10 O 40 ] 7-for its promising broad-spectrum inhibitory activity to FluV-A neuraminidase.

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Ligand Docking and Design in a Flexible Receptor Site

Cited by 10 publications

References 31 publications

Current Status of Virtual Screening as Analysed by Target Class

Current Status of Virtual Screening as Analysed by Target Class

SkelGen

Molecular simulation study of the binding mechanism of [α-PTi2W10O40]7− for its promising broad-spectrum inhibitory activity to FluV-A neuraminidase

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