Identification of Novel Anticancer Agent by in silico Methods for Inhibition of KLK-12 Protein

A critical route for cancer metastases is pathological angiogenesis. The protein Kallikrein-12 (KLK-12) is a serine protease reported to be involved in a variety of biochemical processes that have a functional role in angiogenesis. The KLK-12 protein hydrolyzes the cysteine rich angiogenic inducer 61 (CYR61) protein and controls the bioavailability of angiogenesis-inducing growth factors. The work proposed involves the homology modeling of the KLK-12 protein, identify essential residues to be putatively linked to the natural substrate. Protein-protein docking is done to characterize Trp35, Gln36, Gly38, Trp82 and His107 residues of the active site, in addition to active site servers (active site prediction server and CASTp). Using Auto Dock Vina software, virtual screening studies were carried out to identify the substituted carboxamide scaffolds as a pharmacophore binding at the active site. Based on binding energy, ADME and visual inspection, an isochromene carboxamide moiety is identified as antiangiogenic and cancer antagonists.

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Functional Role of the Active Site Glutamate-368 in Rat Short Chain Acyl-CoA Dehydrogenase†

Biochemistry ◽

10.1021/bi961113r ◽

1996 ◽

Vol 35 (48) ◽

pp. 15356-15363 ◽

Cited By ~ 15

Author(s):

Kevin P. Battaile ◽

Al-Walid A. Mohsen ◽

Jerry Vockley

Keyword(s):

Active Site ◽

Functional Role ◽

Short Chain ◽

Chain Acyl

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Functional tyrosine residue in the active center of human dipeptidyl peptidase III

Biological Chemistry ◽

10.1515/bc.2008.021 ◽

2008 ◽

Vol 389 (2) ◽

pp. 163-167 ◽

Cited By ~ 14

Author(s):

Branka Salopek-Sondi ◽

Bojana Vukelić ◽

Jasminka Špoljarić ◽

Šumski Šimaga ◽

Dušica Vujaklija ◽

...

Keyword(s):

Oxidative Stress ◽

Transition State ◽

Active Site ◽

Functional Role ◽

Dipeptidyl Peptidase ◽

Site Directed Mutagenesis ◽

Directed Mutagenesis ◽

Tyrosine Residue ◽

Transition State Stabilization ◽

Endogenous Defense

Abstract Human dipeptidyl peptidase III (DPP III) is a member of the metallopeptidase family M49 with an implied role in the pain-modulatory system and endogenous defense against oxidative stress. Here, we report the heterologous expression of human DPP III and the site-directed mutagenesis results which demonstrate a functional role for Tyr318 at the active site of this enzyme. The substitution of Tyr318 to Phe decreased k cat by two orders of magnitude without altering the binding affinity of substrate, or of a competitive hydroxamate inhibitor designed to interact with S1 and S2 subsites. The results indicate that the conserved tyrosine could be involved in transition state stabilization during the catalytic action of M49 peptidases.

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Functional Role of the Conserved Active Site Proline of Triosephosphate Isomerase†,‡

Biochemistry ◽

10.1021/bi061683j ◽

2006 ◽

Vol 45 (51) ◽

pp. 15483-15494 ◽

Cited By ~ 30

Author(s):

Marco G. Casteleijn ◽

Markus Alahuhta ◽

Katrin Groebel ◽

Ibrahim El-Sayed ◽

Koen Augustyns ◽

...

Keyword(s):

Active Site ◽

Functional Role ◽

Triosephosphate Isomerase

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Functional role of a non-active site residue Trp23 on the enzyme activity of Escherichia coli thioesterase I/protease I/lysophospholipase L1

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics ◽

10.1016/j.bbapap.2009.06.008 ◽

2009 ◽

Vol 1794 (10) ◽

pp. 1467-1473 ◽

Cited By ~ 11

Author(s):

Li-Chiun Lee ◽

Yi-Li Chou ◽

Hong-Hwa Chen ◽

Ya-Lin Lee ◽

Jei-Fu Shaw

Keyword(s):

Escherichia Coli ◽

Enzyme Activity ◽

Active Site ◽

Functional Role ◽

Active Site Residue

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Organophosphate hydrolase interacts with ferric-enterobactin and promotes iron uptake in association with TonB dependent transport system.

Biochemical Journal ◽

10.1042/bcj20200299 ◽

2020 ◽

Author(s):

Hari Parapatla ◽

Ramurthy Gudla ◽

Guruprasad Varma Konduru ◽

Elsin Raju Devadasu ◽

Hampapathula Adimurthy Nagarajaram ◽

...

Keyword(s):

Binding Site ◽

Active Site ◽

Iron Uptake ◽

Docking Studies ◽

Protein Docking ◽

Catalytic Site ◽

Organophosphate Hydrolase ◽

E Coli ◽

Target Membrane ◽

Dependent Transport

Our previous studies have shown the existence of organophosphate hydrolase (OPH) as a part of the inner membrane associated TonB complex (ExbB/ExbD and TonB) of Sphingobium fuliginis. We now show its involvement in iron uptake by establishing direct interactions with ferric-enterobactin. The interactions between OPH and ferric-enterobactin were not affected even when the active site architecture is altered by substituting active site aspartate with either alanine or asparagine. Protein docking studies further substantiated these findings and predicted the existence of ferric-enterobactin binding site that is different from the catalytic site of OPH. A lysine residue (82 K) found at the predicted ferric-enterobactin binding site facilitated interactions between OPH and ferric-enterobactin. Substitution of lysine with alanine did not affect triesterase activity, but it abrogated OPH ability to interact with both ferric-enterobactin and ExbD, strengthening further the fact that the catalytic site is not the site for binding of these ligands. In the absence of interactions between OPHK82A and ExbD, OPHK82A failed to target membrane in E. coli cells. The Sphingobium fuliginis TonB dependent transport (SfTonBDT) system was reconstituted in E. coli GS027 cells generated by deleting the exbD and tonB genes. The E. coli GS030 cells having SfTonBDT system with OPH showed increased iron uptake. Such an increase was not seen in E. coli GS029, cells having SfTonBDT system generated either by omitting OPH or by including its variants, OPHD301A, OPHD301N suggesting a role for OPH in enhanced iron uptake.

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Analysis of whistles produced by the Tucuxi Dolphin Sotalia fluviatilis from Sepetiba Bay, Brazil

Anais da Academia Brasileira de Ciências ◽

10.1590/s0001-37652004000200029 ◽

2004 ◽

Vol 76 (2) ◽

pp. 381-385 ◽

Cited By ~ 18

Author(s):

Claudia Erber ◽

Sheila M. Simão

Keyword(s):

Functional Role ◽

Visual Inspection ◽

Sepetiba Bay ◽

Minimum Frequency ◽

Average Group ◽

Inflection Points ◽

Frequency Maximum ◽

Sotalia Fluviatilis ◽

Average Group Size

From July 2001 to June 2002, we recorded a total of 2h55min of Tucuxi Dolphin Sotalia fluviatilis vocalizations from Sepetiba Bay, Brazil (22º35'S-44º03'W). A total of 3350 whistles were analyzed quantitative and qualitatively and were divided into 124 types, by visual inspection of sonograms. The following parameters were measured: Initial Frequency, Final Frequency, Minimum Frequency, Maximum Frequency, Duration, Number of Inflections, Frequency at the Inflection Points, Frequency at 1/2, 1/4, and 3/4 of whistle duration, Presence of Frequency Modulation and Harmonics. Ascending type whistles (N=2719) were most common, representing 82% of the total. Dolphin behavior and average group size observed during recording influenced the whistle's quantitative and qualitative parameters. The results demonstrate the great diversity of whistles emitted and indicate a functional role of these vocalizations during the observed behaviors.

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