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Comparative amino acid decomposition analysis of potent type I p38? inhibitors.

ABSTRACT: p38? is a member of mitogen-activated protein kinases (MAPK) considered as a prominent target in development of anti-inflammatory agents. Any abnormality in the phosphorylation process leads to the different human diseases such as cancer, diabetes and inflammatory diseases. Several small molecule p38? inhibitors have been developed up to now. In this regard, structural elucidation of p38 inhibitors needs to be done enabling us in rational lead development strategies.Various interactions of three potent inhibitors with p38? active site have been evaluated in terms of binding energies and bond lengths via density function theory and MD simulations.Our comparative study showed that both ab initio and MD simulation led to the relatively similar results in pharmacophore discrimination of p38? inhibitors.The results of the present study may find their usefulness in pharmacophore based modification of p38? inhibitors.

SUBMITTER: Ebadi A

PROVIDER: S-EPMC3680208 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Comparative amino acid decomposition analysis of potent type I p38α inhibitors.

Ebadi Ahmad A Razzaghi-Asl Nima N Khoshneviszadeh Mehdi M Khoshneviszadeh Mehdi M Miri Ramin R

Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences 20130529 1

<h4>Background and purpose of the study</h4>p38α is a member of mitogen-activated protein kinases (MAPK) considered as a prominent target in development of anti-inflammatory agents. Any abnormality in the phosphorylation process leads to the different human diseases such as cancer, diabetes and inflammatory diseases. Several small molecule p38α inhibitors have been developed up to now. In this regard, structural elucidation of p38 inhibitors needs to be done enabling us in rational lead developm ...[more]

PMID: 23714278

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Project description:Considering lack of validated therapeutic drugs or vaccines against contagious SARS-CoV2, various efforts have been focused on repurposing of existing drugs or identifying new agents. In an attempt to identify new and potential SARS-CoV2 inhibitors targeting specific enzyme of the pathogen, a few induced fit models of SARS-CoV2 main protease (Mpro) including N-aryl amide and aryl sulfonamide based fragments were subjected to a multi-step in silico strategy. Sub-structure query of co-crystallographic fragments provided numerous ZINC15 driven commercially available compounds that entered molecular docking stage to find binding interactions/modes inside Mpro active site. Docking results were reevaluated through time dependent stability of top-ranked ligand-protease complexes by molecular dynamics (MD) simulations within 50 ns. Relative contribution of interacted residues in binding to the most probable binding pose was estimated through amino acid decomposition analysis in B3LYP level of theory with Def2-TZVPP split basis set. In confirmation of docking results, MD simulations revealed less perceptible torsional distortions (more stable binding mode) in binding of ZINC_252512772 (ΔGb -9.18 kcal/mol) into Mpro active site. H-bond interactions and hydrophobic contacts were determinant forces in binding interactions of in silico hit. Quantum chemical calculations confirmed MD results and proved the pivotal role of a conserved residue (Glu166) in making permanent hydrogen bond (98% of MD simulations time) with ZINC_252512772. Drug-like physicochemical properties as well as desirable target binding interactions nominated ZINC_252512772 as a desirable in silico hit for further development toward SARS-CoV2 inhibitors. Highlights A few N-aryl amide/aryl sulfonamide based fragments were subjected to a multi-step in silico strategy to afford potential SARS-CoV2 Mpro inhibitors. MD simulations revealed less perceptible torsional distortions (more stable binding mode) in binding of ZINC_252512772 (ΔGb -9.18 kcal/mol) into Mpro active site. H-bond interactions and hydrophobic contacts were determinant forces in binding interactions of in silico hit. Quantum chemical calculations confirmed MD results and proved pivotal role of a conserved residue (Glu166) in making permanent hydrogen bond (98% of MD simulations time) with ZINC_252512772. Communicated by Ramaswamy H. Sarma.

Project description:BACKGROUND: Formation of alternative structures in mRNA in response to external stimuli, either direct or mediated by proteins or other RNAs, is a major mechanism of regulation of gene expression in bacteria. This mechanism has been studied in detail using experimental and computational approaches in proteobacteria and Firmicutes, but not in other groups of bacteria. RESULTS: Comparative analysis of amino acid biosynthesis operons in Actinobacteria resulted in identification of conserved regions upstream of several operons. Classical attenuators were predicted upstream of trp operons in Corynebacterium spp. and Streptomyces spp., and trpS and leuS genes in some Streptomyces spp. Candidate leader peptides with terminators were observed upstream of ilvB genes in Corynebacterium spp., Mycobacterium spp. and Streptomyces spp. Candidate leader peptides without obvious terminators were found upstream of cys operons in Mycobacterium spp. and several other species. A conserved pseudoknot (named LEU element) was identified upstream of leuA operons in most Actinobacteria. Finally, T-boxes likely involved in the regulation of translation initiation were observed upstream of ileS genes from several Actinobacteria. CONCLUSION: The metabolism of tryptophan, cysteine and leucine in Actinobacteria seems to be regulated on the RNA level. In some cases the mechanism is classical attenuation, but in many cases some components of attenuators are missing. The most interesting case seems to be the leuA operon preceded by the LEU element that may fold into a conserved pseudoknot or an alternative structure. A LEU element has been observed in a transposase gene from Bifidobacterium longum, but it is not conserved in genes encoding closely related transposases despite a very high level of protein similarity. One possibility is that the regulatory region of the leuA has been co-opted from some element involved in transposition. Analysis of phylogenetic patterns allowed for identification of ML1624 of M. leprae and its orthologs as the candidate regulatory proteins that may bind to the LEU element. T-boxes upstream of the ileS genes are unusual, as their regulatory mechanism seems to be inhibition of translation initiation via a hairpin sequestering the Shine-Dalgarno box.

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Comparative amino acid decomposition analysis of potent type I p38? inhibitors.

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Comparative amino acid decomposition analysis of potent type I p38α inhibitors.

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