CoMFA and CoMSIA 3D-QSAR analysis of DMDP derivatives as anti-cancer agents.
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.
Srivastava
Vivek
V
Department of biotechnology, Institute of engineering and technology, Sitapur road, Lucknow 21.
Kumar
Ashutosh
A
Mishra
Bhartendu Nath
BN
Siddiqi
Mohammad Imran
MI
J Chemother. 1993 Dec;5(6):393-9
8195830
J Med Chem. 1994 Nov 25;37(24):4130-46
7990113
J Med Chem. 1995 Mar 31;38(7):1060-6
7707309
Antimicrob Agents Chemother. 2000 Oct;44(10):2784-93
10991861
J Chemother. 1993 Dec;5(6):422-9
8195833
J Am Chem Soc. 1988 Aug 1;110(18):5959-67
22148765
J Chemother. 1993 Dec;5(6):377-88
8195829
FASEB J. 1990 May;4(8):2441-52
2185970
J Comput Aided Mol Des. 1993 Oct;7(5):587-619
8294948
J Med Chem. 1996 Mar 15;39(6):1271-80
8632434
J Mol Biol. 2000 Jan 14;295(2):337-56
10623530