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E-Pharmacophore mapping and docking studies on Vitamin D receptor (VDR).

ABSTRACT: Small structured chemical molecules are importance in the field of molecular medicine since their pharmacokinetic and pharmacodynamic properties are predictable and because of its ability to bind with target molecules and execute biological function. In this study, we engaged computer-aided methodology in combination with molecular docking and pharmacophore filtering to identify chemical compounds that can increase the synthesis of vitamin D receptor (VDR) since its lower expression leads to calcium phosphate metabolic disorders in Chronic Kidney Disease. Energy-optimized pharmacophore was mapped using available agonists for VDR. Based on the e-pharmacophore, we propose the pharmacophore features that should present in VDR agonists. The resulting pharmacophore model contains one hydrogen bond acceptor (A), one hydrogen bond donor (D) and two hydrophobic regions (H). Using these features pharmacophore had been made and screened against large public library of compounds (Asinex, TOSLab, Binding and Zinc database) to find potential lead compounds. The compounds which yield fitness score of more than 1.0 were further subjected to Glide HTVS, SP and XP. Glide docking results revealed five hits (BD_230, BD_12938, BD_18601, BD_19517 and BD_19584) were identified as potential lead molecules against calcium phosphate metabolic disorders.

SUBMITTER: Nagamani S

PROVIDER: S-EPMC3449383 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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E-Pharmacophore mapping and docking studies on Vitamin D receptor (VDR).

Nagamani Selvaraman S Kesavan Chandrasekhar C Muthusamy Karthikeyan K

Bioinformation 20120803 15

Small structured chemical molecules are importance in the field of molecular medicine since their pharmacokinetic and pharmacodynamic properties are predictable and because of its ability to bind with target molecules and execute biological function. In this study, we engaged computer-aided methodology in combination with molecular docking and pharmacophore filtering to identify chemical compounds that can increase the synthesis of vitamin D receptor (VDR) since its lower expression leads to cal ...[more]

PMID: 23055614

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Project description:The vitamin D receptor (VDR) regulates cell proliferation and differentiation including epidermal keratinocytes by modulating transcription of its target genes. We are investigating the role of VDR in epidermal stem cells and their progenies in the regeneration process of epidermis and hair in the skin. VDR null mice are utilized in which VDR is specifically deleted in keratin 14 (K14) expressing keratinocytes by Cre-lox strategy. The impact of VDR deletion was evaluated by comparison of VDR null mice with no cre littermate control mice. The VDR was abundantly expressed in potential epidermal stem cells including basal cells in interfollicular epidermis (IFE), and in CD34 expressing bulge keratinocytes in hair follicles. Gene expression profiles and subsequent pathway analysis of stem cell enriched keratinocyte populations revealed that the VDR deletion significantly suppressed β-catenin signaling as well as VDR signaling. The role of VDR in epidermal stem cells was studied during hair follicle cycling and wound healing processes. The epidermal stem cells were not appropriately stimulated by hair depilation, and did not reinitiate anagen in the hair follicles resulting in a failure of hair regrowth. In addition, the stem cells were not fully activated after full thickness wounds were generated in VDR null skin under a low calcium diet to suppress compensation pathways. Cell proliferation was not fully induced in potential stem cells located in both IFE and hair follicles near the wounding edges, and re-epithelialization rate was delayed in VDR null skin. Gene expression profiling of the wounded skin (3 days after injury) indicated that β-catenin signaling was not fully induced in VDR null skin comparable to that observed in β-catenin null mice. The β-catenin target genes including Axin2 and cell cycle regulators involved in epidermal stem cell function were not induced in the edges of the wound of VDR null skin. These results demonstrated that VDR plays an essential role in hair cycling and wound healing processes through regulation of β-catenin signaling in epidermal stem cells and their progenies. n=3 CON and KO (each sample contain RNA isolated from wounded or nonwounded skins excised from 3 mice)

Dataset Information

E-Pharmacophore mapping and docking studies on Vitamin D receptor (VDR).

Publications

E-Pharmacophore mapping and docking studies on Vitamin D receptor (VDR).

Similar Datasets

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