Title

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

Authors

Vivek Srivastava¹, Ashutosh Kumar², Bhartendu Nath Mishra^{1, *} and Mohammad Imran Siddiqi²

Affiliation

¹Department of biotechnology, Institute of engineering and technology, Sitapur road, Lucknow 21; ²Molecular and structural biology division, CDRI, Lucknow 01

Email

profbnmishra@gmail.com; * Corresponding author

Article Type

Hypothesis

Date

received March 13, 2008; revised May 22, 2008; accepted June 05, 2008; published June 27, 2008

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 (q² = 0.530, r² = 0.903) and with CoMSIA combined steric, electrostatic, hydrophobic and hydrogen bond donor fields (q² = 0.548, r² = 0.909). Both models were validated by a test set of ten compounds producing very good predictive r² 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 anti - cancer agents.

Keywords

CoMFA; CoMSIA; Cancer; DMDP; QSAR

Citation

Srivastava et al., Bioinformation 2(9): 384-391 (2008)

Edited by

P. Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.