scholarly journals Proteolytic Emzymes. III. trans-4-Aminomethylcyclohexane-1-carboxylic Acid Derivatives as Substrates and an Active Site Titrant of Trypsin

1970 ◽  
Vol 18 (11) ◽  
pp. 2346-2348
Author(s):  
KAZUTAKA TANIZAWA ◽  
SHINICHI ISHII ◽  
YUICHI KANAOKA
Keyword(s):  
Carboxylic Acid ◽  
Active Site

scholarly journals Inhibition of Phosphodiesterase 5 Enzyme by Pterine- 6 Carboxylic Acid from Baphia nitida –Related to Erectile Dysfunction: Computational Kinetic

2020 ◽  
pp. 49-55
Author(s):  
Wopara, Iheanyichukwu ◽  
S. K. Mobisson ◽  
Egelege Aziemeola Pius ◽  
A. A. Uwakwe ◽  
M. O. Wegwu
Keyword(s):  
Erectile Dysfunction ◽  
Carboxylic Acid ◽  
Active Site ◽  
In Silico ◽  
Binding Pocket ◽  
Docking Studies ◽  
Drug Candidate ◽  
In Silico Docking ◽  
In Silico Studies ◽  
Phosphodiesterase 5

Treatment of erectile dysfunction is associated with inhibition of Phosphodiesterase 5 enzyme. This study deals with the evaluation of Pterin-6-carboxylic acid inhibitory activity on phosphodiesterase 5 (PDB ID: 4OEW) using in silico docking studies. Pterin-6-carboxylic acid from Baphia nitida was isolated using GC-MS and docked into PDE5 active site. The docking result showed that pterin-6-carboxylic acid bind to the active site of phosphodiesterase 5 with the binding energy value of -7.1 and 2.05A° - 2.23A° when compared with other compound found in the plant. Moreso, docking analysis with the ligand identified specific residues such as: Ile 778, Phe 820, Gln 817, Ser 815 and Gln 775 within the binding pocket which played an important role in the ligand binding affinity to the protein. Result from our In silico studies hypothesized that pterin-6-carboxylic acid can be an inhibitory agent for PDE5 protein which could be a potential drug candidate for the treatment of erectile dysfunction.

scholarly journals Structural and Binding Analysis of Pyrimidinol Carboxylic Acid andN-Hydroxy Quinazolinedione HIV-1 RNase H Inhibitors

2011 ◽  
Vol 55 (6) ◽  
pp. 2905-2915 ◽  
Author(s):  
Eric B. Lansdon ◽  
Qi Liu ◽  
Stephanie A. Leavitt ◽  
Mini Balakrishnan ◽  
Jason K. Perry ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Metal Ions ◽  
Active Site ◽  
Water Environment ◽  
Divalent Metal ◽  
Rnase H ◽  
Accurate Assessment ◽  
Divalent Metal Ions ◽  
Substrate State ◽  
Hiv 1

ABSTRACTHIV-1 RNase H breaks down the intermediate RNA-DNA hybrids during reverse transcription, requiring two divalent metal ions for activity. Pyrimidinol carboxylic acid andN-hydroxy quinazolinedione inhibitors were designed to coordinate the two metal ions in the active site of RNase H. High-resolution (1.4 Å to 2.1 Å) crystal structures were determined with the isolated RNase H domain and reverse transcriptase (RT), which permit accurate assessment of the metal and water environment at the active site. The geometry of the metal coordination suggests that the inhibitors mimic a substrate state prior to phosphodiester catalysis. Surface plasmon resonance studies confirm metal-dependent binding to RNase H and demonstrate that the inhibitors do not bind at the polymerase active site of RT. Additional evaluation of the RNase H site reveals an open protein surface with few additional interactions to optimize active-site inhibitors.

scholarly journals Tyrp1 Mutant Variants Associated with OCA3: Computational Characterization of Protein Stability and Ligand Binding

2021 ◽  
Vol 22 (19) ◽  
pp. 10203
Author(s):  
Milan H. Patel ◽  
Monika B. Dolinska ◽  
Yuri V. Sergeev
Keyword(s):  
Free Energy ◽  
Carboxylic Acid ◽  
Protein Stability ◽  
Active Site ◽  
Autosomal Recessive Disorder ◽  
Oculocutaneous Albinism ◽  
Acid Oxidase ◽  
Energy Landscapes ◽  
Docking Simulations ◽  
Free Energy Landscapes

Oculocutaneous albinism type 3 (OCA3) is an autosomal recessive disorder caused by mutations in the TYRP1 gene. Tyrosinase-related protein 1 (Tyrp1) is involved in eumelanin synthesis, catalyzing the oxidation of 5,6-dihydroxyindole-2-carboxylic acid oxidase (DHICA) to 5,6-indolequinone-2-carboxylic acid (IQCA). Here, for the first time, four OCA3-causing mutations of Tyrp1, C30R, H215Y, D308N, and R326H, were investigated computationally to understand Tyrp1 protein stability and catalytic activity. Using the Tyrp1 crystal structure (PDB:5M8L), global mutagenesis was conducted to evaluate mutant protein stability. Consistent with the foldability parameter, C30R and H215Y should exhibit greater instability, and two other mutants, D308N and R326H, are expected to keep a native conformation. SDS-PAGE and Western blot analysis of the purified recombinant proteins confirmed that the foldability parameter correctly predicted the effect of mutations critical for protein stability. Further, the mutant variant structures were built and simulated for 100 ns to generate free energy landscapes and perform docking experiments. Free energy landscapes formed by Y362, N378, and T391 indicate that the binding clefts of C30R and H215Y mutants are larger than the wild-type Tyrp1. In docking simulations, the hydrogen bond and salt bridge interactions that stabilize DHICA in the active site remain similar among Tyrp1, D308N, and R326H. However, the strengths of these interactions and stability of the docked ligand may decrease proportionally to mutation severity due to the larger and less well-defined natures of the binding clefts in mutants. Mutational perturbations in mutants that are not unfolded may result in allosteric alterations to the active site, reducing the stability of protein-ligand interactions.

scholarly journals Investigation of Carboxylic Acid Isosteres for Inhibition of the Human SIRT5 Lysine Deacylase Enzyme

2021 ◽  
Author(s):  
Nima Rajabi ◽  
Alexander L. Nielsen ◽  
Tobias N. Hansen ◽  
Huy T. Nguyen ◽  
Michael Bæk ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Posttranslational Modifications ◽  
Active Site ◽  
Drug Target ◽  
Mitochondrial Enzymes ◽  
Enzyme Active Site ◽  
High Affinity ◽  
Future Drug ◽  
Cell Inhibition ◽  
Sar Study

Sirtuin 5 (SIRT5) is a protein lysine deacylase enzyme that regulates diverse biology by hydrolyzing -N-carboxyacyllysine posttranslational modifications in the cell. Inhibition of SIRT5 has been linked to potential treatment of several cancers but potent compounds with activity in cells have been lacking. Here we developed mechanism-based inhibitors that incorporate isosteres of a carboxylic acid residue that is important for high-affinity binding to the enzyme active site. By masking of the tetrazole moiety of the most potent candidate from our initial SAR study, we achieved potent and cytoselective growth inhibition for the treatment of SIRT5-dependent leukemic cancer cell lines in culture. Thus, we provide an efficient, cellularly active small molecule that targets SIRT5, which can help elucidate its function and potential as a future drug target. This work shows that masked biosisosteres of carboxylic acids are viable chemical motifs for the development of inhibitors that target mitochondrial enzymes, which may have applications beyond the sirtuin field.

Active Site Inhibitors of HCV NS5B Polymerase. The Development and Pharmacophore of 2-Thienyl-5,6-dihydroxypyrimidine-4-carboxylic Acid.

ChemInform ◽  
2005 ◽  
Vol 36 (4) ◽  
Author(s):  
Ian Stansfield ◽  
Salvatore Avolio ◽  
Stefania Colarusso ◽  
Nadia Gennari ◽  
Frank Narjes ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Active Site ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

Active site inhibitors of HCV NS5B polymerase. The development and pharmacophore of 2-thienyl-5,6-dihydroxypyrimidine-4-carboxylic acid

2004 ◽  
Vol 14 (20) ◽  
pp. 5085-5088 ◽  
Author(s):  
Ian Stansfield ◽  
Salvatore Avolio ◽  
Stefania Colarusso ◽  
Nadia Gennari ◽  
Frank Narjes ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Active Site ◽  
Hcv Ns5b ◽  
Ns5b Polymerase
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