A QSAR model of benzoxazole derivatives as potential inhibitors for inosine 5`-monophosphate dehydrogenase from Cryptosporidium parvum

Abstract

Cryptosporidium parvum is the common enteric protozoan pathogen causing cryptosporidiosis in human. Available drugs to treat cryptosporidiosis are ineffective and there is yet no vaccine against C. parvum. Therefore, it is of interest to design an improved yet effective drug against C. parvum. Here, we docked benzoxazole derivatives (collected from literature) with inosine 5`- monophosphate dehydrogenase (IMPDH) from Cryptosporidium parvum using the program AutoDock 4.2. The docked protein - inhibitor complex structure was optimized using molecular dynamics simulation for 5 ps with the CHARMM-22 force field using NAMD (NAnoscale Molecular Dynamics program) incorporated in visual molecular dynamics (VMD 1.9.2) and then evaluating the stability of complex structure by calculating RMSD values. NAMD is a parallel, object-oriented molecular dynamics code designed for high-performance simulation of large biomolecular systems. A quantitative structure activity relationship (QSAR) model was built using energy-based descriptors as independent variable and pIC50 value as dependent variable of fifteen known benzoxazole derivatives with C. parvum IMPDH protein, yielding correlation coefficient r2 of 0.7948. The predictive performance of QSAR model was assessed using different cross-validation procedures. Our results suggest that a ligand-receptor binding interaction for inosine 5`-monophosphate dehydrogenase using a QSAR model is promising approach to design more potent inosine 5`-monophosphate dehydrogenase inhibitors prior to their synthesis.

Keywords: AutoDock 4.2; Cryptosporidium parvum; benzoxazole derivatives; docking; inosine 5`-monophosphate dehydrogenase.

Figure 1

Crystal structure of the catalytic domain of the inosine monophosphate dehydrogenase from cryptosporidium parvum.

Figure 2

Relationship between experimental (x-axis) and predicted (y-axis) pIC50 values with an r2 value 0.7948 is shown in a QSAR model developed using multiple linear regression analysis.

Figure 3

Docking orientation of compounds with IMPDH protein.

Figure 4

Graph displaying root mean square deviation (RMSD) of compounds – protein complex versus time (5 ps) at 310 K, resulted in highest peak at 0.98 Å.