Homology model of 1α,25-dihydroxyvitamin D3 24-hydroxylase cytochrome P450 24A1 (CYP24A1): Active site architecture and ligand binding

2007 ◽  
Vol 104 (1-2) ◽  
pp. 53-60 ◽  
Author(s):  
Mohamed Sayed Gomaa ◽  
Claire Simons ◽  
Andrea Brancale
Keyword(s):  
Cytochrome P450 ◽  
Ligand Binding ◽  
Active Site ◽  
Homology Model ◽  
Dihydroxyvitamin D3

Homology Model of Human Retinoic Acid Metabolising Enzyme Cytochrome P450 26A1 (CYP26A1): Active Site Architecture and Ligand Binding

2006 ◽  
Vol 21 (4) ◽  
pp. 361-369 ◽  
Author(s):  
Mohamed Sayed Gomaa ◽  
Sook Wah Yee ◽  
Ceri Elizabeth Milbourne ◽  
Maria Chiara Barbera ◽  
Claire Simons ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Retinoic Acid ◽  
Ligand Binding ◽  
Active Site ◽  
Homology Model

scholarly journals Evidence that serine 304 is not a key ligand-binding residue in the active site of cytochrome P450 2D6

2000 ◽  
Vol 345 (3) ◽  
pp. 565 ◽  
Author(s):  
S.Wynne ELLIS ◽  
Graham P. HAYHURST ◽  
Tracy LIGHTFOOT ◽  
Gillian SMITH ◽  
Jacky HARLOW ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Ligand Binding ◽  
Active Site ◽  
Cytochrome P450 2D6 ◽  
Binding Residue ◽  
P450 2D6

scholarly journals Computational Elucidation of Structural Basis for Ligand Binding withLeishmania donovaniAdenosine Kinase

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Rajiv K. Kar ◽  
Md. Yousuf Ansari ◽  
Priyanka Suryadevara ◽  
Bikash R. Sahoo ◽  
Ganesh C. Sahoo ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Active Site ◽  
Protein Complex ◽  
Leishmania Donovani ◽  
Homology Model ◽  
Adenosine Kinase ◽  
Dynamics Simulation ◽  
Structural Basis ◽  
Active Site Residues ◽  
Drug Candidates

Enzyme adenosine kinase is responsible for phosphorylation of adenosine to AMP and is crucial for parasites which are purine auxotrophs. The present study describes development of robust homology model ofLeishmania donovaniadenosine kinase to forecast interaction phenomenon with inhibitory molecules using structure-based drug designing strategy. Docking calculation using reported organic small molecules and natural products revealed key active site residues such as Arg131 and Asp16 for ligand binding, which is consistent with previous studies. Molecular dynamics simulation of ligand protein complex revealed the importance of hydrogen bonding with active site residues and solvent molecules, which may be crucial for successful development of drug candidates. Precise role of Phe168 residue in the active site was elucidated in this report that provided stability to ligand-protein complex via aromatic-πcontacts. Overall, the present study is believed to provide valuable information to design a new compound with improved activity for antileishmanial therapeutics development.

Influence of phenylalanine-481 substitutions on the catalytic activity of cytochrome P450 2D6

2001 ◽  
Vol 355 (2) ◽  
pp. 373-379 ◽  
Author(s):  
Graham P. HAYHURST ◽  
Jacky HARLOW ◽  
Joey CHOWDRY ◽  
Esme GROSS ◽  
Emma HILTON ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Ligand Binding ◽  
Active Site ◽  
Dominant Role ◽  
Yeast Cells ◽  
Primary Role ◽  
Cytochrome P450 2D6 ◽  
Wild Type ◽  
Binding Residue ◽  
P450 2D6

Homology models of the active site of cytochrome P450 2D6 (CYP2D6) have identified phenylalanine 481 (Phe481) as a putative ligand-binding residue, its aromatic side chain being potentially capable of participating in π-π interactions with the benzene ring of ligands. We have tested this hypothesis by replacing Phe481 with tyrosine (Phe481 → Tyr), a conservative substitution, and with leucine (Phe481 → Leu) or glycine (Phe481 → Gly), two non-aromatic residues, and have compared the properties of the wild-type and mutant enzymes in microsomes prepared from yeast cells expressing the appropriate cDNA-derived protein. The Phe481 → Tyr substitution did not alter the kinetics [Km (µM) and Vmax (pmol/min per pmol) respectively] of oxidation of S-metoprolol (27; 4.60), debrisoquine (46; 2.46) or dextromethorphan (2; 8.43) relative to the respective wild-type values [S-metoprolol (26; 3.48), debrisoquine (51; 3.20) and dextromethorphan (2; 8.16)]. The binding capacities [Ks (µM)] of a range of CYP2D6 ligands to the Phe481 → Tyr enzyme (S-metoprolol, 22.8; debrisoquine, 12.5; dextromethorphan, 2.3; quinidine, 0.13) were also similar to those for the wild-type enzyme (S-metoprolol, 10.9; debrisoquine, 8.9; dextromethorphan, 3.1; quinidine, 0.10). In contrast, the Phe481 → Leu and Phe481 → Gly substitutions increased significantly (3-16-fold) the Km values of oxidation of the three substrates [S-metoprolol (120-124µM), debrisoquine (152-184µM) and dextromethorphan (20-31µM)]. Similarly, the Ks values of the ligands to Phe481 → Leu and Phe481 → Gly mutants were also increased 3 to 10-fold (S-metoprolol, 33.2-41.9µM; debrisoquine, 85-90µM; dextromethorphan, 15.7-18.8µM; quinidine 0.35-0.53µM). However, contrary to a recent proposal that Phe481 has the dominant role in the binding of substrates that undergo CYP2D6-mediated N-dealkylation routes of metabolism, the Phe481 → Gly substitution did not substantially decrease the capacity of the enzyme to N-deisopropylate metoprolol (wild-type, 1.12pmol/min per pmol of P450; Phe481 → Gly, 0.71), whereas an Asp301 → Gly substitution decreased the N-dealkylation reaction by 95% of the wild-type rate. Overall, our results are consistent with the proposal that Phe481 is a ligand-binding residue in the active site of CYP2D6 and that the residue interacts with ligands via a π-π interaction between its phenyl ring and the aromatic moiety of the ligand. However, the relative importance of Phe481 in binding is ligand-dependent; furthermore, its importance is secondary to that of Asp301. Finally, contrary to predictions of a recent homology model, Phe481 does not seem to have a primary role in CYP2D6-mediated N-dealkylation.

scholarly journals Molecular Modeling of Cytochrome P450 1A1 using the newly Crystallized Template structure of CYP1A2-Human

2021 ◽  
Vol 1 (1) ◽  
pp. 31-40
Author(s):  
Rehan Zafar ◽  
Fahed Parvaiz ◽  
Babar Aslam ◽  
Umar Niazi
Keyword(s):  
Cytochrome P450 ◽  
Active Site ◽  
Homology Model ◽  
Docking Studies ◽  
Cytochrome P450 Enzyme ◽  
Analysis Model ◽  
Cytochrome P450 1A1 ◽  
Entry Site ◽  
Monooxygenase Activity ◽  
Xenobiotic Detoxification

Cytochrome P450 enzyme family plays significant roles in carcinogenesis and xenobiotic detoxification. CYP1A1 is the P450 family 1 enzyme preferably expressed extrahepatically and participates extensively in monooxygenase activity which can either change the substrate to normal or carcinogenic metabolites, having the ability to initiate oncogenesis in lung and breast. Variegated structural properties evident in the prosites of available Cytochrome P450 (CYP) structures show versatility among CYP catalyzed reactions. In order to understand the CYP1A1 functions, hypothesized homology model has been constructed and characterization of the active site was performed by identifying important residues using docking studies and pharmacophore analysis. Model of CYP-1A1- Human has been constructed using the available crystal structure of CYP-1A2- Human. Active site and entry site of CYP-1A1 was found to be more compact than CYP1A2. Difference of wildtype CYP1A1 against its polymorphisms shows the role of mutations in active site architecture, which explains that the M2 and M4 mutations in CYP1A1 have no possible significant roles in the substrate binding and orientation for detoxification or carcinogenic activation. Different ligands including A- naphthoflavone (ANF), Ethoxyresorufin, Theophylline, Tamoxifen, Ethanol, Phenacetin and Hesperetin were docked and reconfirm the ligand specific wet lab studies. 

The Molecular and Enzyme Kinetic Basis for Altered Activity of Three Cytochrome P450 2C19 Variants Found in the Chinese Population

2020 ◽  
Vol 13 (3) ◽  
pp. 233-244
Author(s):  
Amelia Nathania Dong ◽  
Nafees Ahemad ◽  
Yan Pan ◽  
Uma Devi Palanisamy ◽  
Beow Chin Yiap ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Molecular Docking ◽  
Active Site ◽  
Chinese Population ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
In Vitro Assays ◽  
Access Channel ◽  
Cytochrome P450 2C19

Background: There is a large inter-individual variation in cytochrome P450 2C19 (CYP2C19) activity. The variability can be caused by the genetic polymorphism of CYP2C19 gene. This study aimed to investigate the molecular and kinetics basis for activity changes in three alleles including CYP2C19*23, CYP2C19*24 and CYP2C19*25found in the Chinese population. Methods: The three variants expressed by bacteria were investigated using substrate (omeprazole and 3- cyano-7-ethoxycoumarin[CEC]) and inhibitor (ketoconazole, fluoxetine, sertraline and loratadine) probes in enzyme assays along with molecular docking. Results: All alleles exhibited very low enzyme activity and affinity towards omeprazole and CEC (6.1% or less in intrinsic clearance). The inhibition studies with the four inhibitors, however, suggested that mutations in different variants have a tendency to cause enhanced binding (reduced IC50 values). The enhanced binding could partially be explained by the lower polar solvent accessible surface area of the inhibitors relative to the substrates. Molecular docking indicated that G91R, R335Q and F448L, the unique mutations in the alleles, have caused slight alteration in the substrate access channel morphology and a more compact active site cavity hence affecting ligand access and binding. It is likely that these structural alterations in CYP2C19 proteins have caused ligand-specific alteration in catalytic and inhibitory specificities as observed in the in vitro assays. Conclusion: This study indicates that CYP2C19 variant selectivity for ligands was not solely governed by mutation-induced modifications in the active site architecture, but the intrinsic properties of the probe compounds also played a vital role.

scholarly journals Crystal Structure, Exogenous Ligand Binding, and Redox Properties of an Engineered Diiron Active Site in a Bacterial Hemerythrin

2013 ◽  
Vol 52 (22) ◽  
pp. 13014-13020 ◽  
Author(s):  
Yasunori Okamoto ◽  
Akira Onoda ◽  
Hiroshi Sugimoto ◽  
Yu Takano ◽  
Shun Hirota ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Ligand Binding ◽  
Active Site ◽  
Redox Properties ◽  
Exogenous Ligand
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