Anthrax lethal factor protease inhibitors: synthesis, SAR, and structure-based 3D QSAR studies

Abstract

We have recently identified a series of compounds that efficiently inhibit anthrax lethal factor (LF) metallo-protease. Here we present further structure-activity relationship and CoMFA (comparative molecular field analysis) studies on newly derived inhibitors. The obtained 3D QSAR model was subsequently compared with the X-ray structure of the complex between LF and a representative compound. Our studies form the basis for the rational design of additional compounds with improved activity and selectivity.

Figure 1

Detail of the X-ray structure of compound 1 in complex with LF (PDB_ID 1ZXV). Side chains of Zn²⁺ coordinating amino-acids are displayed.

Figure 2

Superimpositions of docked conformers used for CoMFA studies. In (A), the structures of the compounds for the training set are displayed, with the compound highlighted in green being compound 1 (whose coordinates are from the PDB_ID 1ZXV). In (B), the aligned structures for the compounds in the test sets are displayed. (C) Calculated versus observed pIC₅₀ values against LF for the compounds in the training set (q² = 0.51, r² = 0.98, # components = 4, # compounds = 17). (D) Predicted versus observed pIC₅₀ values against LF for the 10 compounds in the test set.

Figure 3

Comparison of (A) hydrophobic and hydrophilic potential molecular surface (MOLCAD) of the substrate binding site of LF in complex with compound 8 with (B) CoMFA contour plots of steric field contributions. Comparison of the (C) electrostatic potential molecular surfaces (MOLCAD) with (D) CoMFA contour plots of electrostatic field contributions. In (A), the hydrophobic and hydrophilic areas are displayed in brown and blue, respectively, while green surfaces represent an intermediate hydrophobicity. In (B), green contours indicate the regions where the addition of bulky groups may increase activity and yellow contours indicate the regions where the addition of bulky groups may decrease activity. In (C), positive and negative areas are displayed in red and blue, respectively, while cyan surfaces represent neutral areas. The color code follows the definitions of MOLCAD. In (D), blue contours indicate regions where less electronegative groups may increase activity. Red contours indicate regions where more electronegative groups may increase activity.