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Computational Approaches for Decoding Select Odorant-Olfactory Receptor Interactions Using Mini-Virtual Screening.

Harini K, Sowdhamini R - PLoS ONE (2015)

Bottom Line: Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences.This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity.A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors.

View Article: PubMed Central - PubMed

Affiliation: National Centre for Biological Sciences (TIFR), GKVK Campus, Bellary Road, Bangalore, India.

ABSTRACT
Olfactory receptors (ORs) belong to the class A G-Protein Coupled Receptor superfamily of proteins. Unlike G-Protein Coupled Receptors, ORs exhibit a combinatorial response to odors/ligands. ORs display an affinity towards a range of odor molecules rather than binding to a specific set of ligands and conversely a single odorant molecule may bind to a number of olfactory receptors with varying affinities. The diversity in odor recognition is linked to the highly variable transmembrane domains of these receptors. The purpose of this study is to decode the odor-olfactory receptor interactions using in silico docking studies. In this study, a ligand (odor molecules) dataset of 125 molecules was used to carry out in silico docking using the GLIDE docking tool (SCHRODINGER Inc Pvt LTD). Previous studies, with smaller datasets of ligands, have shown that orthologous olfactory receptors respond to similarly-tuned ligands, but are dramatically different in their efficacy and potency. Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences. This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity. A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors.

No MeSH data available.


The distribution of MOLPRINT2D features of the odorants.(a) shows the range of molecular weight of the odorants. Most of the odorants have a molecular weight between 100–150 Daltons. (b) shows the number of rotatable bonds present in the given set of odorants. The number of rotatable bonds varies from 1 to 11. (c) shows the number of aromatic rings present in the odorants. 80% of the odorants are aliphatic. (d) and (e) show the number of hydrogen bond acceptors and donor atoms respectively in the odorants. There are a maximum of 5 hydrogen bond acceptors and 3 hydrogen bond donor atom in the odorants.
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pone.0131077.g007: The distribution of MOLPRINT2D features of the odorants.(a) shows the range of molecular weight of the odorants. Most of the odorants have a molecular weight between 100–150 Daltons. (b) shows the number of rotatable bonds present in the given set of odorants. The number of rotatable bonds varies from 1 to 11. (c) shows the number of aromatic rings present in the odorants. 80% of the odorants are aliphatic. (d) and (e) show the number of hydrogen bond acceptors and donor atoms respectively in the odorants. There are a maximum of 5 hydrogen bond acceptors and 3 hydrogen bond donor atom in the odorants.

Mentions: The ligand dataset consists of 125 odorant molecules belonging to various chemical classes like alcohols, ketones, carboxylic acids, aldehydes and sulphur containing compounds (Fig 6). The ligands were clustered using the canvas module of Schrödinger software into 36 unique clusters. The clustering was analysed at merging distance ranging from 0.1 to 1.0 at regular intervals of 0.5 (Table 5). At each of the merging distances, the clusters were manually checked to confirm that ligands with similar features were clustered into a group. The clustering that resulted in maximum number of similar ligands in a given cluster was selected for further analysis. The merging distance of 0.85 yielded 36 clusters and was used for further studies. The cluster 33 had 55 aliphatic odorant members in it and it was further divided into 11 sub-clusters based on the number of carbon atoms. The number of ligands in each cluster is given in Table 6. Based on MOLPRINT2D, the ligands were classified based on their molecular weight, number of rotatable bonds, number of aromatic rings and number of hydrogen bond donors and acceptors. More than 60 of the ligands have a molecular weight between 100–150 Daltons. The ligands contain 1–11 rotatable bonds while 75% of the dataset contains aliphatic chains. Seventy odorants contain at least two hydrogen bond acceptor groups, while 80 ligands contain at least one hydrogen bond donor group (Fig 7). The ligand clusters were further used to compare odor-binding profiles of OR proteins under study. Binding of similar odorants or odorants belonging to the same clusters to a given OR will indicate common binding modes.


Computational Approaches for Decoding Select Odorant-Olfactory Receptor Interactions Using Mini-Virtual Screening.

Harini K, Sowdhamini R - PLoS ONE (2015)

The distribution of MOLPRINT2D features of the odorants.(a) shows the range of molecular weight of the odorants. Most of the odorants have a molecular weight between 100–150 Daltons. (b) shows the number of rotatable bonds present in the given set of odorants. The number of rotatable bonds varies from 1 to 11. (c) shows the number of aromatic rings present in the odorants. 80% of the odorants are aliphatic. (d) and (e) show the number of hydrogen bond acceptors and donor atoms respectively in the odorants. There are a maximum of 5 hydrogen bond acceptors and 3 hydrogen bond donor atom in the odorants.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4519343&req=5

pone.0131077.g007: The distribution of MOLPRINT2D features of the odorants.(a) shows the range of molecular weight of the odorants. Most of the odorants have a molecular weight between 100–150 Daltons. (b) shows the number of rotatable bonds present in the given set of odorants. The number of rotatable bonds varies from 1 to 11. (c) shows the number of aromatic rings present in the odorants. 80% of the odorants are aliphatic. (d) and (e) show the number of hydrogen bond acceptors and donor atoms respectively in the odorants. There are a maximum of 5 hydrogen bond acceptors and 3 hydrogen bond donor atom in the odorants.
Mentions: The ligand dataset consists of 125 odorant molecules belonging to various chemical classes like alcohols, ketones, carboxylic acids, aldehydes and sulphur containing compounds (Fig 6). The ligands were clustered using the canvas module of Schrödinger software into 36 unique clusters. The clustering was analysed at merging distance ranging from 0.1 to 1.0 at regular intervals of 0.5 (Table 5). At each of the merging distances, the clusters were manually checked to confirm that ligands with similar features were clustered into a group. The clustering that resulted in maximum number of similar ligands in a given cluster was selected for further analysis. The merging distance of 0.85 yielded 36 clusters and was used for further studies. The cluster 33 had 55 aliphatic odorant members in it and it was further divided into 11 sub-clusters based on the number of carbon atoms. The number of ligands in each cluster is given in Table 6. Based on MOLPRINT2D, the ligands were classified based on their molecular weight, number of rotatable bonds, number of aromatic rings and number of hydrogen bond donors and acceptors. More than 60 of the ligands have a molecular weight between 100–150 Daltons. The ligands contain 1–11 rotatable bonds while 75% of the dataset contains aliphatic chains. Seventy odorants contain at least two hydrogen bond acceptor groups, while 80 ligands contain at least one hydrogen bond donor group (Fig 7). The ligand clusters were further used to compare odor-binding profiles of OR proteins under study. Binding of similar odorants or odorants belonging to the same clusters to a given OR will indicate common binding modes.

Bottom Line: Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences.This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity.A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors.

View Article: PubMed Central - PubMed

Affiliation: National Centre for Biological Sciences (TIFR), GKVK Campus, Bellary Road, Bangalore, India.

ABSTRACT
Olfactory receptors (ORs) belong to the class A G-Protein Coupled Receptor superfamily of proteins. Unlike G-Protein Coupled Receptors, ORs exhibit a combinatorial response to odors/ligands. ORs display an affinity towards a range of odor molecules rather than binding to a specific set of ligands and conversely a single odorant molecule may bind to a number of olfactory receptors with varying affinities. The diversity in odor recognition is linked to the highly variable transmembrane domains of these receptors. The purpose of this study is to decode the odor-olfactory receptor interactions using in silico docking studies. In this study, a ligand (odor molecules) dataset of 125 molecules was used to carry out in silico docking using the GLIDE docking tool (SCHRODINGER Inc Pvt LTD). Previous studies, with smaller datasets of ligands, have shown that orthologous olfactory receptors respond to similarly-tuned ligands, but are dramatically different in their efficacy and potency. Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences. This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity. A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors.

No MeSH data available.