Metalloprotein Inhibitors

Martin, David P.; and, David T. Puerta; Cohen, Seth M.

doi:10.1002/9781118697191.ch14

Cited by 9 publications

(8 citation statements)

References 60 publications

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“…Metalloproteins which refer to proteins with one or more metal ions coordinated within its structure comprise almost half of the human proteome. Metalloproteins can carry out critical functions in human body ranging from catalyzing the reactions in respiration to scavenging free radicals. , Their extensive involvement in versatile biological processes also causes them to appear in various pathological conditions including neurodegeneration, cancer, inflammation, HIV infection, and hypertension. − Thus, discovery of novel inhibitors of metalloproteins carry paramount importance for treatment of these various pathologies. Undoubtedly, the modeler who aims to identify novel and/or more potent metalloprotein inhibitors needs to select the correct docking program which can account for the metal interactions.…”

Section: Introductionmentioning

confidence: 99%

Comparative Assessment of Seven Docking Programs on a Nonredundant Metalloprotein Subset of the PDBbind Refined

Çınaroğlu

Timuçin

2019

J. Chem. Inf. Model.

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Extensive usage of molecular docking for computer-aided drug discovery resulted in development of numerous programs with versatile scoring and posing algorithms. Selection of the docking program among these vast number of options is central to the outcome of drug discovery. To this end, comparative assessment studies of docking offer valuable insights into the selection of the optimal tool. Despite the availability of various docking assessment studies, the performance difference of docking programs has not been well addressed on metalloproteins which comprise a substantial portion of the human proteome and have been increasingly targeted for treatment of a wide variety of diseases. This study reports comparative assessment of seven docking programs on a diverse metalloprotein set which was compiled for this study. The refined set of the PDBbind (2017) was screened to gather 710 complexes with metal ion(s) closely located to the ligands (<4 Å). The redundancy was eliminated by clustering and overall 213 complexes were compiled as the nonredundant metalloprotein subset of the PDBbind refined. The scoring, ranking, and posing powers of seven noncommercial docking programs, namely, AutoDock4, AutoDock4Zn, AutoDock Vina, Quick Vina 2, LeDock, PLANTS, and UCSF DOCK6, were comprehensively evaluated on this nonredundant set. Results indicated that PLANTS (80%) followed by LeDock (77%), QVina (76%), and Vina (73%) had the most accurate posing algorithms while AutoDock4 (48%) and DOCK6 (56%) were the least successful in posing. Contrary to their moderate-to-high level of posing success, none of the programs was successful in scoring or ranking of the binding affinities (r 2 ≈ 0). Screening power was further evaluated by using active-decoy ligand sets for a large compilation of metalloprotein targets. PLANTS stood out among other programs to be able to enrich the active ligand for every target, underscoring its robustness for screening of metalloprotein inhibitors. This study provides useful information for drug discovery studies targeting metalloproteins.

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Section: Introductionmentioning

confidence: 99%

Comparative Assessment of Seven Docking Programs on a Nonredundant Metalloprotein Subset of the PDBbind Refined

Çınaroğlu

Timuçin

2019

J. Chem. Inf. Model.

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“…For the most part, metalloenzyme inhibitors contain pharmacophores that bind directly to the catalytic metal ion of the target. 8 Given the extensive structural optimization that goes into clinical candidates, it is surprising how little diversity there is in the metal-binding pharmacophores (MBPs) utilized in metalloenzyme inhibitor design; thiols, carboxylic acids, phosphates, and hydroxamic acids have historically dominated the chemical landscape for binding active site metal ions. However, this has begun to change as illustrated by the emergence of inhibitors targeting HIV1-IN that utilize innovative hetrocyclic MBPs as well as HDAC inhibitors containing the unconventional N -(2-aminophenyl)benzamide MBP.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Influence of the Protein Environment on Metal-Binding Pharmacophores

et al. 2014

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The binding of a series of metal-binding pharmacophores (MBPs) related to the ligand 1-hydroxypyridine-2-(1H)-thione (1,2-HOPTO) in the active site of human carbonic anhydrase II (hCAII) has been investigated. The presence and/or position of a single methyl substituent drastically alters inhibitor potency and can result in coordination modes not observed in small-molecule model complexes. It is shown that this unexpected binding mode is the result of a steric clash between the methyl group and a highly ordered water network in the active site that is further stabilized by the formation of a hydrogen bond and favorable hydrophobic contacts. The affinity of MBPs is dependent on a large number of factors including donor atom identity, orientation, electrostatics, and van der Waals interactions. These results suggest that metal coordination by metalloenzyme inhibitors is a malleable interaction and that it is thus more appropriate to consider the metal-binding motif of these inhibitors as a pharmacophore rather than a “chelator”. The rational design of inhibitors targeting metalloenzymes will benefit greatly from a deeper understanding of the interplay between the variety of forces governing the binding of MBPs to active site metal ions.

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“…The members of the compound library screened against the Rp MetAP enzyme were chosen based upon published inhibitory scaffolds and compounds possessing functional groups capable of binding to the metal cofactors. 27 Typically, MetAP inhibitors contain functional groups capable of potently coordinating the metal cofactors found within all species of MetAP. 20 These functional groups generally include carboxylic acid, 2,2′-bipyridyl, 1,2,4-triazolo, thiazolo, or oxamide derivatives.…”

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confidence: 99%

The identification of inhibitory compounds of Rickettsia prowazekii methionine aminopeptidase for antibacterial applications

Helgren

Seven

Chen

et al. 2018

Bioorganic & Medicinal Chemistry Letters

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Methionine aminopeptidase (MetAP) is a dinuclear metalloprotease responsible for the cleavage of methionine initiator residues from nascent proteins. MetAP activity is necessary for bacterial proliferation and is therefore a projected novel antibacterial target. A compound library consisting of 294 members containing metal-binding functional groups was screened against Rickettsia prowazekii MetAP to determine potential inhibitory motifs. The compounds were first screened against the target at a concentration of 10 µM and potential hits were determined to be those exhibiting greater than 50% inhibition of enzymatic activity. These hit compounds were then rescreened against the target in 8-point dose-response curves and 11 compounds were found to inhibit enzymatic activity with IC values of less than 10 µM. Finally, compounds (1-5) were docked against RpMetAP with AutoDock to determine potential binding mechanisms and the results were compared with crystal structures deposited within the PDB.

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Metalloprotein Inhibitors

Cited by 9 publications

References 60 publications

Comparative Assessment of Seven Docking Programs on a Nonredundant Metalloprotein Subset of the PDBbind Refined

Comparative Assessment of Seven Docking Programs on a Nonredundant Metalloprotein Subset of the PDBbind Refined

Exploring the Influence of the Protein Environment on Metal-Binding Pharmacophores

The identification of inhibitory compounds of Rickettsia prowazekii methionine aminopeptidase for antibacterial applications

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