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CoMFA and CoMSIA 3D-QSAR analysis of DMDP derivatives as anti-cancer agents.

Srivastava V, Kumar A, Mishra BN, Siddiqi MI - Bioinformation (2008)

Bottom Line: Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (78 compounds) of 2, 4-diamino-5-methyl-5-deazapteridine (DMDP) derivatives as potent anticancer agents.Both models were validated by a test set of ten compounds producing very good predictive r(2) values of 0.935 and 0.842, respectively.This study suggests that the highly electropositive substituents with low steric tolerance are required at 5 position of the pteridine ring and bulky electronegatve substituents are required at the meta-position of the phenyl ring.

View Article: PubMed Central - PubMed

Affiliation: Department of biotechnology, Institute of engineering and technology, Sitapur road, Lucknow 21.

ABSTRACT
Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (78 compounds) of 2, 4-diamino-5-methyl-5-deazapteridine (DMDP) derivatives as potent anticancer agents. The best prediction were obtained with a CoMFA standard model (q(2) = 0.530, r(2) = 0.903) and with CoMSIA combined steric, electrostatic, hydrophobic and hydrogen bond donor fields (q(2) = 0.548, r(2) = 0.909). Both models were validated by a test set of ten compounds producing very good predictive r(2) values of 0.935 and 0.842, respectively. CoMFA and CoMSIA contour maps were then used to analyze the structural features of ligands to account for the activity in terms of positively contributing physiochemical properties such as steric, electrostatic, hydrophobic and hydrogen bond donor fields. The resulting contour maps produced by the best CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series of analogs. This study suggests that the highly electropositive substituents with low steric tolerance are required at 5 position of the pteridine ring and bulky electronegatve substituents are required at the meta-position of the phenyl ring. The information obtained from CoMFA and CoMSIA 3-D contour maps can be used for the design of deazapteridine-based analogs as anticancer agents.

No MeSH data available.


Related in: MedlinePlus

2(a) and 2(b) are steric and electrostatic contour maps of CoMFA and CoMSIA model for low active compound 29 and high active compound 63 respectively. The favorable steric areas (contribution level 80%) with more bulkiness are indicated by green isopleths and the dis-favorable steric areas (contribution level 20%) are shown by yellow isopleths. The favorable electrostatic areas (contribution level 80%) with positive charges are indicated by blue isopleths and the favorable electrostatic areas (contribution level 20%) with negative charges are shown by red isopleths. 2(c) and 2(d) are the hydrophobic contour maps and hydrogen-bond contour maps of CoMSIA model for high active compound 63, respectively. The favorable hydrophobic areas (contribution level 80%) indicated by yellow isopleths and the disfavorable hydrophobic areas (contribution level 20%) are shown by white isopleths. The hydrogen bond contour maps of CoMSIA model are also shown. Cyan isopleths contour maps (contribution level 80%) beyond the ligands where a hydrogen - bond donor group in the ligand will be favorable for biological activity and purple isopleths (contribution level 20%) represents hydrogen - bond acceptor in the ligands unfavorable for bioactivity.
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Figure 2: 2(a) and 2(b) are steric and electrostatic contour maps of CoMFA and CoMSIA model for low active compound 29 and high active compound 63 respectively. The favorable steric areas (contribution level 80%) with more bulkiness are indicated by green isopleths and the dis-favorable steric areas (contribution level 20%) are shown by yellow isopleths. The favorable electrostatic areas (contribution level 80%) with positive charges are indicated by blue isopleths and the favorable electrostatic areas (contribution level 20%) with negative charges are shown by red isopleths. 2(c) and 2(d) are the hydrophobic contour maps and hydrogen-bond contour maps of CoMSIA model for high active compound 63, respectively. The favorable hydrophobic areas (contribution level 80%) indicated by yellow isopleths and the disfavorable hydrophobic areas (contribution level 20%) are shown by white isopleths. The hydrogen bond contour maps of CoMSIA model are also shown. Cyan isopleths contour maps (contribution level 80%) beyond the ligands where a hydrogen - bond donor group in the ligand will be favorable for biological activity and purple isopleths (contribution level 20%) represents hydrogen - bond acceptor in the ligands unfavorable for bioactivity.

Mentions: Figure 2d displays the hydrogen bond donor contour maps represented by cyan and purple contours. Cyan contours indicate regions where hydrogen bond donor substituents on ligands are favored and purple contours represent areas where hydrogen bond donor properties on inhibitors are disfavored. However, in our CoMSIA analysis hydrogen bond donor field do not have effect on the variance. Therefore, we found only two cyan contours in the hydrogen bond donor maps near the NH2 group in deazaptredine ring of compound 63, indicating that hydrogen bond donor functionalities in this region will enhance the activity (Figure 2d). In summary, the CoMFA and CoMSIA models for anticancer activity indicated that highly electropositive substituents with low steric tolerance are required at position 5 of the pteridine ring and bulky electronegative substituents are required at meta position of the phenyl ring.


CoMFA and CoMSIA 3D-QSAR analysis of DMDP derivatives as anti-cancer agents.

Srivastava V, Kumar A, Mishra BN, Siddiqi MI - Bioinformation (2008)

2(a) and 2(b) are steric and electrostatic contour maps of CoMFA and CoMSIA model for low active compound 29 and high active compound 63 respectively. The favorable steric areas (contribution level 80%) with more bulkiness are indicated by green isopleths and the dis-favorable steric areas (contribution level 20%) are shown by yellow isopleths. The favorable electrostatic areas (contribution level 80%) with positive charges are indicated by blue isopleths and the favorable electrostatic areas (contribution level 20%) with negative charges are shown by red isopleths. 2(c) and 2(d) are the hydrophobic contour maps and hydrogen-bond contour maps of CoMSIA model for high active compound 63, respectively. The favorable hydrophobic areas (contribution level 80%) indicated by yellow isopleths and the disfavorable hydrophobic areas (contribution level 20%) are shown by white isopleths. The hydrogen bond contour maps of CoMSIA model are also shown. Cyan isopleths contour maps (contribution level 80%) beyond the ligands where a hydrogen - bond donor group in the ligand will be favorable for biological activity and purple isopleths (contribution level 20%) represents hydrogen - bond acceptor in the ligands unfavorable for bioactivity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: 2(a) and 2(b) are steric and electrostatic contour maps of CoMFA and CoMSIA model for low active compound 29 and high active compound 63 respectively. The favorable steric areas (contribution level 80%) with more bulkiness are indicated by green isopleths and the dis-favorable steric areas (contribution level 20%) are shown by yellow isopleths. The favorable electrostatic areas (contribution level 80%) with positive charges are indicated by blue isopleths and the favorable electrostatic areas (contribution level 20%) with negative charges are shown by red isopleths. 2(c) and 2(d) are the hydrophobic contour maps and hydrogen-bond contour maps of CoMSIA model for high active compound 63, respectively. The favorable hydrophobic areas (contribution level 80%) indicated by yellow isopleths and the disfavorable hydrophobic areas (contribution level 20%) are shown by white isopleths. The hydrogen bond contour maps of CoMSIA model are also shown. Cyan isopleths contour maps (contribution level 80%) beyond the ligands where a hydrogen - bond donor group in the ligand will be favorable for biological activity and purple isopleths (contribution level 20%) represents hydrogen - bond acceptor in the ligands unfavorable for bioactivity.
Mentions: Figure 2d displays the hydrogen bond donor contour maps represented by cyan and purple contours. Cyan contours indicate regions where hydrogen bond donor substituents on ligands are favored and purple contours represent areas where hydrogen bond donor properties on inhibitors are disfavored. However, in our CoMSIA analysis hydrogen bond donor field do not have effect on the variance. Therefore, we found only two cyan contours in the hydrogen bond donor maps near the NH2 group in deazaptredine ring of compound 63, indicating that hydrogen bond donor functionalities in this region will enhance the activity (Figure 2d). In summary, the CoMFA and CoMSIA models for anticancer activity indicated that highly electropositive substituents with low steric tolerance are required at position 5 of the pteridine ring and bulky electronegative substituents are required at meta position of the phenyl ring.

Bottom Line: Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (78 compounds) of 2, 4-diamino-5-methyl-5-deazapteridine (DMDP) derivatives as potent anticancer agents.Both models were validated by a test set of ten compounds producing very good predictive r(2) values of 0.935 and 0.842, respectively.This study suggests that the highly electropositive substituents with low steric tolerance are required at 5 position of the pteridine ring and bulky electronegatve substituents are required at the meta-position of the phenyl ring.

View Article: PubMed Central - PubMed

Affiliation: Department of biotechnology, Institute of engineering and technology, Sitapur road, Lucknow 21.

ABSTRACT
Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (78 compounds) of 2, 4-diamino-5-methyl-5-deazapteridine (DMDP) derivatives as potent anticancer agents. The best prediction were obtained with a CoMFA standard model (q(2) = 0.530, r(2) = 0.903) and with CoMSIA combined steric, electrostatic, hydrophobic and hydrogen bond donor fields (q(2) = 0.548, r(2) = 0.909). Both models were validated by a test set of ten compounds producing very good predictive r(2) values of 0.935 and 0.842, respectively. CoMFA and CoMSIA contour maps were then used to analyze the structural features of ligands to account for the activity in terms of positively contributing physiochemical properties such as steric, electrostatic, hydrophobic and hydrogen bond donor fields. The resulting contour maps produced by the best CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series of analogs. This study suggests that the highly electropositive substituents with low steric tolerance are required at 5 position of the pteridine ring and bulky electronegatve substituents are required at the meta-position of the phenyl ring. The information obtained from CoMFA and CoMSIA 3-D contour maps can be used for the design of deazapteridine-based analogs as anticancer agents.

No MeSH data available.


Related in: MedlinePlus