Quantitative structure-activity relationship (QSAR) of indoloacetamides as inhibitors of human isoprenylcysteine carboxyl methyltransferase

Abstract

A QSAR is developed for the isoprenylcysteine carboxyl methyltransferase (ICMT) inhibitory activities of a series of indoloacetamides (n=72) that are structurally related to cysmethynil, a selective ICMT inhibitor. Multivariate analytical tools (principal component analysis (PCA) and projection to latent structures (PLS)), multi-linear regression (MLR) and comparative molecular field analysis (CoMFA) are used to develop a suitably predictive model for the purpose of optimizing and identifying members with more potent inhibitory activity. The resulting model shows that good activity is determined largely by the characteristics of the substituent attached to the indole nitrogen, which should be a lipophilic residue with fairly wide dimensions. In contrast, the substituted phenyl ring attached to the indole ring must be of limited dimensions and lipophilicity.

Figure 1

Figure 1a Loading plot of 1^st and 2^nd principal components (p[1], p[2]) of 72 compounds and 20 descriptors. Figure 1b Score plot of principal components t₁ vs t₂ for compounds (n = 72, 20 descriptors). Compounds are identified in Supplementary Information (Table 1). The ellipse corresponds to the confidence region based on Hotelling T² (0.05). Compounds identified by “ 7” have m.m-bistrifluromethyl groups on the phenyl ring and compounds identified by “J” have no substituent on the indole N. Both sets of compounds are isolated from the rest. Figure 1c Coefficent Plot for PLS model A derived from 70 compounds and 14 descriptors, based on the 1^st component. Descriptors with positive coefficients are directly related to activity while those with negative coefficients are inversely related. Magnitude of parameter indicates its relative contribution to the model. PSA = polar surface area; PV = polar volume; piPh2 = Hansch constant π of substituted phenyl ring; pi N = Hansch constant π of N substituent; CMR = molar refractivity; PL1,PB1, PB5 = Sterimol parameters of phenyl ring; NL1, NB1, NB5 = Sterimol parameters of N substituent; HOMO = highest occupied molecular orbital; LUMO = lowest unoccupied molecular orbital.

Figure 1

Figure 1a Loading plot of 1^st and 2^nd principal components (p[1], p[2]) of 72 compounds and 20 descriptors. Figure 1b Score plot of principal components t₁ vs t₂ for compounds (n = 72, 20 descriptors). Compounds are identified in Supplementary Information (Table 1). The ellipse corresponds to the confidence region based on Hotelling T² (0.05). Compounds identified by “ 7” have m.m-bistrifluromethyl groups on the phenyl ring and compounds identified by “J” have no substituent on the indole N. Both sets of compounds are isolated from the rest. Figure 1c Coefficent Plot for PLS model A derived from 70 compounds and 14 descriptors, based on the 1^st component. Descriptors with positive coefficients are directly related to activity while those with negative coefficients are inversely related. Magnitude of parameter indicates its relative contribution to the model. PSA = polar surface area; PV = polar volume; piPh2 = Hansch constant π of substituted phenyl ring; pi N = Hansch constant π of N substituent; CMR = molar refractivity; PL1,PB1, PB5 = Sterimol parameters of phenyl ring; NL1, NB1, NB5 = Sterimol parameters of N substituent; HOMO = highest occupied molecular orbital; LUMO = lowest unoccupied molecular orbital.

Figure 1

Figure 1a Loading plot of 1^st and 2^nd principal components (p[1], p[2]) of 72 compounds and 20 descriptors. Figure 1b Score plot of principal components t₁ vs t₂ for compounds (n = 72, 20 descriptors). Compounds are identified in Supplementary Information (Table 1). The ellipse corresponds to the confidence region based on Hotelling T² (0.05). Compounds identified by “ 7” have m.m-bistrifluromethyl groups on the phenyl ring and compounds identified by “J” have no substituent on the indole N. Both sets of compounds are isolated from the rest. Figure 1c Coefficent Plot for PLS model A derived from 70 compounds and 14 descriptors, based on the 1^st component. Descriptors with positive coefficients are directly related to activity while those with negative coefficients are inversely related. Magnitude of parameter indicates its relative contribution to the model. PSA = polar surface area; PV = polar volume; piPh2 = Hansch constant π of substituted phenyl ring; pi N = Hansch constant π of N substituent; CMR = molar refractivity; PL1,PB1, PB5 = Sterimol parameters of phenyl ring; NL1, NB1, NB5 = Sterimol parameters of N substituent; HOMO = highest occupied molecular orbital; LUMO = lowest unoccupied molecular orbital.

Figure 2

Plot of the predicted pIC₅₀versus observed pIC₅₀ values of n= 69 compounds (compounds omitted are 3E, 8A1 and 8D) based on best CoMFA model. r² _pred for Training set = 0.868, r² _pred for Test set = 0.601.

Figure 3

Figure 3a Steric map from the CoMFA model showing the alignment based on the indole ring. Green contours (contribution level of 80%) represent areas where steric bulk will enhance activity, and yellow contours (contribution level of 20%) highlight areas which should be kept unoccupied for increased activity. Figure 3b Electrostatic map from the CoMFA model showing the same alignment as in Figure 3a. Blue contours (contribution level of 85%) represent regions where an increase in positive charge will enhance activity, and red contours (contribution level of 15%) highlight areas where more negative charge is favoured.

Figure 3

Figure 3a Steric map from the CoMFA model showing the alignment based on the indole ring. Green contours (contribution level of 80%) represent areas where steric bulk will enhance activity, and yellow contours (contribution level of 20%) highlight areas which should be kept unoccupied for increased activity. Figure 3b Electrostatic map from the CoMFA model showing the same alignment as in Figure 3a. Blue contours (contribution level of 85%) represent regions where an increase in positive charge will enhance activity, and red contours (contribution level of 15%) highlight areas where more negative charge is favoured.