| Purine nucleoside phosphorylase from Plasmodium falciparum (PfPNP) is an anti-malarial target based on the activity of Immucillins (ImmH). 5’-Methylthio Immucillin (MT-ImmH) was an inhibitor, designed to resemble the transition state of PfPNP in the complexed crystal structure (1Q1G). ImmH derivatives had been synthesized and tested in vitro activities in terms of dissociation constant (Ki) values. Moreover, the binding energy and orientation of these derivatives had been studied by using molecular docking. AutoDock (docking software) was used to predict the binding modes of 5’-substituted Immucillin (ImmH) derivatives as part of antimalarial drug development program. It was performed by analyzing the interaction of such compounds against the active sites of PfPNP. The docking results showed the most optimum orientation and conformation of each compound regarding to the enzyme. The obtained results lead to elucidate the main interaction energy between inhibitor and residues surrounding the binding pocket. Furthermore, the resulting structures are going to be used as basic to design, produce and characterize the novel transition state analogue inhibitor with high specificity for the P. falciparum. In addition, 19 derivatives of Immucillin (ImmH) were being studied and analyzed thoroughly. Subsequently, the correlation between biological activity and structural property of these derivatives had been studied by using 3-Dimensional quantitative Structure Activity Relationship (3D-QSAR) approach in the SYBYL program. Moreover, 19 derivatives of ImmH were being used as training sets for the analysis using the Comparative Molecular Field Analysis (CoMFA) method. Finally, the coefficient contour maps could be derived from the results of such analysis. The coefficient contour maps reveal steric and electrostatic regions favored by the inhibitor molecule that of particular importance for modifying a novel potent inhibitor against P. falciparum purine nucleoside phosphorylase (PfPNP). |