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Comparative Study to Predict Dipeptidyl Peptidase IV Inhibitory Activity of β-Amino Amide Scaffold.

Patil S, Sharma R, Abhishek A - Indian J Pharm Sci (2015 Mar-Apr)

Bottom Line: Comparative study was performed on 34 β-amino amide derivatives as dipeptidyl peptidase IV inhibitors in order to determine their structural requirement to enhance the antidiabetic activities.Hologram quantitative structure activity relationships models utilized specialized fragment fingerprints (hologram length 353) which showed good predictivity with cross-validated q(2) and conventional r(2) values of 0.971 and 0.971, respectively.Models were validated and optimized by a test set of eight compounds and gave satisfactory predictive ability.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Devi Ahilya Vishwavidyalaya, Takshshila Campus, Khandwa Road, Indore-452 001, India.

ABSTRACT
Comparative study was performed on 34 β-amino amide derivatives as dipeptidyl peptidase IV inhibitors in order to determine their structural requirement to enhance the antidiabetic activities. Hologram quantitative structure activity relationships models utilized specialized fragment fingerprints (hologram length 353) which showed good predictivity with cross-validated q(2) and conventional r(2) values of 0.971 and 0.971, respectively. Models were validated and optimized by a test set of eight compounds and gave satisfactory predictive ability. Hologram quantitative structure activity relationships maps were helpful in prediction of the structural features of the ligands to account for the activity in terms of positively and negatively contributing towards activity. The information obtained from maps could be effectively use as a guiding tool for further structure modifications and synthesis of new potent antidiabetic agents.

No MeSH data available.


The color encoded (A) and structural fragment contribution (B) for activity.The green and yellow color (represents positive contribution), white color (indicates intermediate or moderate contribution) while red and orange (negative contribution), suggested the structure fragment requirement for enhancing the binding affinity.
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Figure 5: The color encoded (A) and structural fragment contribution (B) for activity.The green and yellow color (represents positive contribution), white color (indicates intermediate or moderate contribution) while red and orange (negative contribution), suggested the structure fragment requirement for enhancing the binding affinity.

Mentions: We also observed important structural features such as regions with poor contributions (colored in orange and red) that can be identified as potential achieved targets for molecular modification and further creation of SAR studies (fig. 4). The color coding is based on the activity contribution of the individual atoms of the molecules. The individual atomic contribution of the most potent compounds is presented in fig. 4 where the bulky and electron donating group were attached to the β-amino amide ring define the antidiabetic activity, in addition to the well-known β-amino amide. In compound 1, triflouro phenyl ring is marked with yellow color at 3rd position indicates that positive contribution (no bulky group is required). In compound 3, diflouro phenyl ring attached with piperazine is covered with red color at 3rd position indicates negative contribution (electron donating group is required). In compound 4 the 4 hydroxyl ethyl phenyl ring attached with piperazine is marked with red color at 3rd position indicates negative contribution (that electron donating group is required). In compound 6 the bis phenyl ring attached with piperazine is marked with red color at different position indicates negative contribution (that electron donating group is required). In compound 7 the 2-cyano phenyl ring attached with piperazine is marked with green color at 1st and 4th position indicates positive contribution (that bulky group is required to increase the biological activity). The piperazine ring also contains the green color indicates positive contribution (requirement of bulky group). In compound 8 the 4-cyano phenyl ring attached with piperazine is marked with yellow color at 1st and 3rd position indicates positive contribution (no bulky group is essential to increase the biological activity). The piperazine ring also contains the yellow color indicates positive contribution (requirement of no bulky group). In compound 11 the piperazine is marked with yellow color at 1st and 5th position indicates positive contribution (that no bulky group is required to increase the biological activity). The piperazine ring also contains the green color at 2nd and 6th indicates positive contribution (necessity of bulky group). The amino ketone contains the yellow color indicates positive contribution (no bulky group attached on specified position). The compound 7 shows the positive contribution, compound 1, 8 and 11 indicates moderate contribution and compound 3, 4 and 6 shows negative contribution (fig. 4) for DPP IV inhibitory activity. The spectrum of colour coding on the fragment structure presented in the fig. 5.


Comparative Study to Predict Dipeptidyl Peptidase IV Inhibitory Activity of β-Amino Amide Scaffold.

Patil S, Sharma R, Abhishek A - Indian J Pharm Sci (2015 Mar-Apr)

The color encoded (A) and structural fragment contribution (B) for activity.The green and yellow color (represents positive contribution), white color (indicates intermediate or moderate contribution) while red and orange (negative contribution), suggested the structure fragment requirement for enhancing the binding affinity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 5: The color encoded (A) and structural fragment contribution (B) for activity.The green and yellow color (represents positive contribution), white color (indicates intermediate or moderate contribution) while red and orange (negative contribution), suggested the structure fragment requirement for enhancing the binding affinity.
Mentions: We also observed important structural features such as regions with poor contributions (colored in orange and red) that can be identified as potential achieved targets for molecular modification and further creation of SAR studies (fig. 4). The color coding is based on the activity contribution of the individual atoms of the molecules. The individual atomic contribution of the most potent compounds is presented in fig. 4 where the bulky and electron donating group were attached to the β-amino amide ring define the antidiabetic activity, in addition to the well-known β-amino amide. In compound 1, triflouro phenyl ring is marked with yellow color at 3rd position indicates that positive contribution (no bulky group is required). In compound 3, diflouro phenyl ring attached with piperazine is covered with red color at 3rd position indicates negative contribution (electron donating group is required). In compound 4 the 4 hydroxyl ethyl phenyl ring attached with piperazine is marked with red color at 3rd position indicates negative contribution (that electron donating group is required). In compound 6 the bis phenyl ring attached with piperazine is marked with red color at different position indicates negative contribution (that electron donating group is required). In compound 7 the 2-cyano phenyl ring attached with piperazine is marked with green color at 1st and 4th position indicates positive contribution (that bulky group is required to increase the biological activity). The piperazine ring also contains the green color indicates positive contribution (requirement of bulky group). In compound 8 the 4-cyano phenyl ring attached with piperazine is marked with yellow color at 1st and 3rd position indicates positive contribution (no bulky group is essential to increase the biological activity). The piperazine ring also contains the yellow color indicates positive contribution (requirement of no bulky group). In compound 11 the piperazine is marked with yellow color at 1st and 5th position indicates positive contribution (that no bulky group is required to increase the biological activity). The piperazine ring also contains the green color at 2nd and 6th indicates positive contribution (necessity of bulky group). The amino ketone contains the yellow color indicates positive contribution (no bulky group attached on specified position). The compound 7 shows the positive contribution, compound 1, 8 and 11 indicates moderate contribution and compound 3, 4 and 6 shows negative contribution (fig. 4) for DPP IV inhibitory activity. The spectrum of colour coding on the fragment structure presented in the fig. 5.

Bottom Line: Comparative study was performed on 34 β-amino amide derivatives as dipeptidyl peptidase IV inhibitors in order to determine their structural requirement to enhance the antidiabetic activities.Hologram quantitative structure activity relationships models utilized specialized fragment fingerprints (hologram length 353) which showed good predictivity with cross-validated q(2) and conventional r(2) values of 0.971 and 0.971, respectively.Models were validated and optimized by a test set of eight compounds and gave satisfactory predictive ability.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Devi Ahilya Vishwavidyalaya, Takshshila Campus, Khandwa Road, Indore-452 001, India.

ABSTRACT
Comparative study was performed on 34 β-amino amide derivatives as dipeptidyl peptidase IV inhibitors in order to determine their structural requirement to enhance the antidiabetic activities. Hologram quantitative structure activity relationships models utilized specialized fragment fingerprints (hologram length 353) which showed good predictivity with cross-validated q(2) and conventional r(2) values of 0.971 and 0.971, respectively. Models were validated and optimized by a test set of eight compounds and gave satisfactory predictive ability. Hologram quantitative structure activity relationships maps were helpful in prediction of the structural features of the ligands to account for the activity in terms of positively and negatively contributing towards activity. The information obtained from maps could be effectively use as a guiding tool for further structure modifications and synthesis of new potent antidiabetic agents.

No MeSH data available.