structural modelling

Computer-based drug design


Structure-based ligand design shows increasing utility in research of new drugs due in part to the important growth of structural data. Using a structure-based strategy our efforts focus on the identification of chemical compounds with the required biological activity and the optimization of identified compounds to improve their biological activity.
D-alanyl - D-alanine ligase is an enzyme that has an essential role in bacterial cell wall biosynthesis. It represents a viable antimicrobial target. A short series of novel derivatives based on a 2-phenylbenzoxazole scaffold was designed de novo on the basis of computational data. The best compound was found to fully inhibit the D‑alanyl - D-alanine ligase of E. faecalis with an IC50 of 400 µM .
Myeloperoxidase (MPO) has been reported as a contributing factor in many inflammatory syndromes. Because of these deleterious effects, the development of therapeutic intervention strategies aiming at an efficient MPO inhibition is needed. The development of inhibitors has been conducted using flufenamic acid as a lead compound. Computational docking of the drug and its analogs in the MPO active site was performed. Several molecules were then synthesized and assessed for the measurement of their inhibiting activity. Most of the synthesized molecules had an activity in the same range as flufenamic acid (~ 1µMm).
Exploiting the structure-based docking of 5-fluorotryptamine, a known MPO inhibitor, a series of 3-(aminoalkyl)-5-fluoroindole analogs was designed and synthesized. The most potent molecules (~15 nM) possess a 4 or 5 carbon aminoalkyl side chain and no substituent on its amino group.

 

Lipid – protein modeling in apoliporotein


Human apolipoprotein E (apoE) stabilizes lipoprotein particles and plays an important role in regulating cholesterol homeostasis. A lipid-binding induced conformational change in the N-terminal domain is essential for apoE to serve as a ligand for the low-density lipoprotein receptor (LDLR). We performed and analyzed Molecular dynamics (MD) simulations to explore the conformational transitions of apoE.