Automated analysis of interatomic contacts in proteins.

Sobolev, V. M.; Sorokin, Anatoly; Prilusky, Jaime; Abola, Enrique E.; Edelman, Marvin

doi:10.1093/bioinformatics/15.4.327

Cited by 770 publications

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“…The relative distances between each Phe residue and the aromatic moieties of both enantiomers, together with the corresponding number of interactions, are shown in Table 2. 29 The sum of π-π interactions produced by the (S)-and (R)-enantiomers of 2 with both Phe residues was found to be almost the same in HDCA8. Overall, 13 interactions were detected in the case of (S)-2, and 11 were detected in the case of (R)-2, which may account for the slight difference shown by the enantiomers in binding this isoform [IC 50(R)/(S) = 3.3].…”

mentioning

confidence: 90%

Vorinostat-Like Molecules as Structural, Stereochemical, and Pharmacological Tools

Hanessian

Auzzas

Larsson

et al. 2010

ACS Med. Chem. Lett.

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The inhibitory activity of an ω-alkoxy analogue of the HDAC inhibitor, Vorinostat (SAHA), against the 11 isoforms of HDAC is described and evaluated with regard to structural biology information retrieved through computational methods. Preliminary absorption and metabolism studies were performed, which positioned this compound as a potential candidate for further preclinical studies and delineated measures for improving its pharmacokinetic profile.KEYWORDS HDAC promiscuous inhibitors, SAHA analogues, HDAC1-11 profile, class IIa-specific profile, absorption and metabolism I n spite of the significant progress made in HDAC research, 1-4 the quest for isoform-selective inhibitors continues to present a major challenge. [5][6][7] To date, detailed biostructural information is available only regarding a few among the known 11 metallo-enzymes. 1,[8][9][10][11] Consequently, the design of isoform-and class-selective inhibitors is somewhat arbitrary and derivative. 1,7,[12][13][14] In addition, complete data regarding the factual HDAC profile for most of the early discovered agents are not available, since the development of effective isozyme-based assays is relatively recent. [5][6][7][15][16][17][18] As a consequence of the complex, pleiotropic nature of cancer, promiscuous HDAC inhibitors such as Vorinostat (1) (SAHA, suberoylanilide hydroxamic acid) 19 (Figure 1) seem superior and as safe in the clinic as compared to the few class-specific agents available. [5][6][7]15 Ligand-based approaches are a first-choice solution to delineate the structural requirements for HDAC selectivity, especially with the emergence of ω-aryl alkanoyl hydroxamates such as Vorinostat as clinical candidates. 1,7,[12][13][14] In this regard, simple and readily accessible surrogates are worthy of study, provided that they bear pharmacophoric determinants as close as possible to a maximum common substructural consensus required to target the whole HDAC panel. The judicious inclusion of specific appendages capable of interacting with specific residues in the cap region of HDACs can provide valuable structural, functional, and stereochemical insight into the design of new inhibitors.In a previous study, we determined the optimal alkyl chain length for activity against a single isoform, HDAC2. 20 Designed for understanding the role of the chirality in simple ω-alkoxy analogues of Vorinostat, compound (R/S)-2 emerged as a promising lead for its preliminary cytotoxic activity against leukemia, colon, and lung tumor cell lines. Here, we describe the details for the improved and shortened synthesis of 2, together with the biostructural insights through molecular modeling and a preliminary study of its in vitro activity against an extended panel of HDACs.Although relatively simple in conception, the previous nine-step synthesis of racemic 2 20 was shortened and adapted to produce gram-scale material for pharmacological studies (Supporting Information) (Scheme 1). The required 8-carbon chain of (R/S)-2 was assembled by a cross metathesis reac...

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confidence: 90%

Vorinostat-Like Molecules as Structural, Stereochemical, and Pharmacological Tools

Hanessian

Auzzas

Larsson

et al. 2010

ACS Med. Chem. Lett.

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“…The predicted poses were analyzed with respect to the essential key interactions with the protein. [35]. Extended analysis of all heavy atom contacts was performed using the LPC CSU Server of the Weizmann Institute.…”

Section: Evaluation Of Docking Resultsmentioning

confidence: 99%

“…According to LPC analysis [35] both MOE and Glide recovered roughly 50 % of all heavy atoms contacts (below 4.5 Å) with a deviation of 0.6 Å or less in comparison with the reference structure.…”

Section: <Table 3>mentioning

confidence: 99%

“…Another interesting point is that in both docking studies the order of docking scores does not correlate with the order of RMSD values and hence the reproducibility of the reference structure. In addition LPC analysis [35] revealed that with respect to the X-ray structure MOE could recover 76 % and Glide 61 % of all heavy atom contacts (below 4.5 Å) with a deviation of 0.6 Å or less.…”

Section: <Table 2>mentioning

confidence: 99%

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Nucleotide docking: prediction of reactant state complexes for ribonuclease enzymes

Elsässer

Fels

2010

J Mol Model

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International audienceRibonuclease enzymes (RNases) play key roles in the maturation and metabolism of all RNA molecules. Computational simulations of the processes involved can help to elucidate the underlying enzymatic mechanism and is often employed in a synergistic approach together with biochemical experiments. Theoretical calculations require atomistic details regarding the starting geometries of the molecules involved, which, in the absence of crystallographic data, can only be achieved from computational docking studies. Fortunately, docking algorithms have improved tremendously in recent years, so that reliable structures of enzyme-ligand complexes can now be successfully obtained from computation. However, most docking programs are not particularly optimized for nucleotide docking. In order to assist our studies on the cleavage of RNA by the two most important ribonuclease enzymes, RNase A and RNase H, we evaluated four docking tools--MOE2009, Glide 5.5, QXP-Flo+0802, and Autodock 4.0--for their ability to simulate complexes between these enzymes and RNA oligomers. To validate our results, we analyzed the docking results with respect to the known key interactions between the protein and the nucleotide. In addition, we compared the predicted complexes with X-ray structures of the mutated enzyme as well as with structures obtained from previous calculations. In this manner, we were able to prepare the desired reaction state complex so that it could be used as the starting structure for further DFT/B3LYP QM/MM reaction mechanism studies

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“…The adenine nucleotide moiety of acetyl-CoA may also be recognized by region 137-373. The crystal structures of E. coli N-acetylglutamate kinase (NAGK) complexed with NAG and AMP (1GS5) and the histone acetyltransferase domain of P300/CBP Associating Factor (PCAF) containing CoA (1CM0) were examined, and 57 active site residues involved in binding CoA, NAG, or AMP were identified using the LPC server [22][23][24]. The sequences of human NAGS and these proteins were separately aligned to the hidden Markov models for the carbamate kinase-like fold and for the acylCoA N-acyltransferase fold.…”

Section: Protein Sequencementioning

confidence: 99%

Mammalian N-acetylglutamate synthase

Morizono

Caldovic

Shi

et al. 2004

Molecular Genetics and Metabolism

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N-Acetylglutamate synthase (NAGS, E.C. 2.3.1.1) is a mitochondrial enzyme that catalyzes the formation of N-acetylglutamate (NAG), an essential allosteric activator of carbamylphosphate synthetase I (CPSI). The mouse and human NAGS genes have been identified based on similarity to regions of NAGS from Neurospora crassa and cloned from liver cDNA libraries. These genes were shown to complement an argA-(NAGS) deficient Escherichia coli strain, and enzymatic activity of the proteins was confirmed by a new stable isotope dilution assay. The deduced amino acid sequence of mammalian NAGS contains a putative mitochondrial-targeting signal at the Nterminus. The mouse NAGS preprotein was overexpressed in insect cells to determine posttranslational modifications and two processed proteins with different N-terminal truncations have been identified. Sequence analysis using a hidden Markov model suggests that the vertebrate NAGS protein contains domains with a carbamate kinase fold and an acyl-CoA N-acyltransferase fold, and protein crystallization experiments are currently underway. Inherited NAGS deficiency results in hyperammonemia, presumably due to the loss of CPSI activity. We, and others, have recently identified mutations in families with neonatal and late-onset NAGS deficiency and the identification of the gene has now made carrier testing and prenatal diagnosis feasible. A structural analog of NAG, carbamylglutamate, has been shown to bind and activate CPSI, and several patients have been reported to respond favorably to this drug (Carbaglu®).

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Automated analysis of interatomic contacts in proteins.

Cited by 770 publications

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Vorinostat-Like Molecules as Structural, Stereochemical, and Pharmacological Tools

Vorinostat-Like Molecules as Structural, Stereochemical, and Pharmacological Tools

Nucleotide docking: prediction of reactant state complexes for ribonuclease enzymes

Mammalian N-acetylglutamate synthase

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