Analysis of the binding sites of vitamin D 1α-hydroxylase (CYP27B1) and vitamin D 24-hydroxylase (CYP24A1) for the design of selective CYP24A1 inhibitors: Homology modelling, molecular dynamics simulations and identification of key binding requirements

Abstract

A homology model of human CYP27B1 was built using MOE and was further optimised by molecular dynamics simulations of the hCYP27B1 homology model and a hCYP27B1-SDZ-88357 complex. Docking results from the hCYP27B1-SDZ-88357 complex showed amino acids Arg107, Asn387 and Asp320 have an important role in binding interaction, with Asp320 part of the important acid-alcohol pair situated in the I-helix with the conserved sequence (A/G) GX (E/D) (T/S), which assumes an essential role in the binding of an oxygen molecule for catalysis. Additional docking experiments with selective hCYP27B1 or hCYP24A1 inhibitors using both the hCYP27B1 model and a triple mutant hCYP24A1 model provided further support for the importance of H-bonding interactions with the three identified active site amino acids. To confirm the role of Arg107, Asn387 and Asp320 in the active site of hCYP27B1 compounds were designed that would form H-bonding interactions, as determined from docking experiments with the hCYP27B1 model. Subsequent synthesis and CYP24A1 and CYP27B1 enzyme assays of the designed compounds 1a and 1b showed a∼5-fold selectivity for CYP27B1 confirming the importance of Asp320 in particular and also Asn387 and Arg107 as important amino acids for CYP27B1 inhibitory activity.

Interactions between vitamin D binding protein variants and major dietary patterns on the odds of metabolic syndrome and its components in apparently healthy adults

“…Also, the genetic variants identified only account for a very small section of the variability in vitamin D status, and this study is consistent with other studies based on protein isoforms of this binding protein [61, 62]. Also, there is consistent support for one SNP in the enzyme that converts the storage form of the vitamin (25(OH)D) to the active ligand 1-25(OH)D (CYP27B1; rs10877012) [63], and one SNP in the vitamin D receptor gene ( VDR ; rs10735810) [64]. As mentioned above, genetic variants, through changes in vitamin D status, cause changes in health outcomes, including in the components of metabolic syndrome.…”

How does a Saccharomyces cerevisiae extract influence the components of isolated rotavirus particles from stool samples collected in a clinical setting from children?

“…In each target, water molecules & ions were observed. Moreover, hydrogens were added to the target ( Taban et al, 2017 ). The 2- dimensional structures of GC mass-identified compounds were downloaded from the open chemistry database PubChem ( https://pubchem.ncbi.nlm.nih.gov/ ).…”

Discovery and Anticancer Screening of Novel Oxindole-Based Derivative Bearing Pyridyl Group as Potent and Selective Dual FLT3/CDK2 Kinase Inhibitor

“…ylmethoxy) benzaldehyde (3b) White solid; 53% yield (110 mg); mp = 95-98 • C, reported mp: 93-95 • C; R f = 0.3 (pet.ether:EtOAc, 3:1)[34].4-(Pyridin-3-ylmethoxy) benzaldehyde (3c)Yellow solid; 53% yield (110 mg); mp = 75-78 • C, reported mp: 76-78 • C; R f = 0.3 (pet.ether:EtOAc, 3:1)[35].4-(Pyridin-4-ylmethoxy) benzaldehyde (3d)White solid; 53% yield (110 mg); mp = 99-103 • C, reported mp: 102-104 • C; R f = 0.3 (pet.ether:EtOAc, 3:1)[36].…”