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.
Highlights
The enzyme dihydrofolate reductase (DHFR) (5, 6, 7, 8 tetrahydrofolate, NADP+ oxido-reductase EC 1.5.1.3), utilizing NADPH as a cofactor, catalyzes the reduction of dihydrofolate to tetrahydrofolate
The IC50 values were converted to the corresponding pIC50 (-logIC50) and used as dependent variables in Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) analysis
Predictive power of the resulting models was Partial least square (PLS) analysis evaluated using a test set of 10 molecules (molecule denoted as PLS method (8) was used to linearly correlate the CoMFA fields bold in Table 1 under supplementary material)
Summary
The enzyme dihydrofolate reductase (DHFR) (5, 6, 7, 8 tetrahydrofolate, NADP+ oxido-reductase EC 1.5.1.3), utilizing NADPH as a cofactor, catalyzes the reduction of dihydrofolate to tetrahydrofolate. Similarity indices, AF,K between the compounds of interest were computed by placing a probe atom at analysis for 100 runs was carried out for further validation of the model by statistical sampling of the original dataset to create the intersections of the lattice points using Equation 1 The CoMSIA analyses were performed using four descriptor error value of 0.297 supporting the statistical validity of the fields: steric, electrostatic, hydrophobic and hydrogen bond donor. Figure 1: 1(a) and 1(b) are the predictive versus experimental pIC50 values derived from CoMFA and CoMSIA model for training set (black hole) and test set (white rectangle). 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. 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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