Homology modeling and drug designing of 18KDA antigen in mycobacterium leprae.

Most of the antigens of Mycobacterium leprae that have been identified are members of stress protein families. 18kDa antigen of M. leprae is an important antigen in the immune response to leprosy. This protein antigen of M. leprae is related to the family of small heat shock protein. To predict the structure of 18kDa antigen and to understand the mechanisms of inhibitors interaction, a threedimensional model was generated based on the Crystal Structure and assembly of eukaryotic small heat shock protein (PDB: 1GME) by using MODELLER7v7. The structure having a least modeller objective function was used as a starting point for picoseconds-duration molecular dynamics simulations. With the aid of the molecular dynamics and minimization methods, the final refined model was obtained and was further assessed by ERRAT, WHATCHECK and PROCHECK, which suggested that the refined model was reliable. Docking studies were performed by using the models with 2-mercaptoethanol and 3-amino- 5-methylhexanoic acid inhibitors. The results indicate that the 3-amino-5,5-diphenylpentanoic acid has more affinity than the other drug derivatives. The docking studies also suggest that MET-03, ARG-04, ASP-31, ALA-32, TRP-33, ARG-34, GLU-35 ARG-89, GLN-90 LEU-91 and VAL-92 are important determinant residues in binding with ligands. From the docking studies, we also suggest that GLU-35, in 18kDa protein domain is an important residue in binding.

Virtual screening of flavonoids as inhibitory agents of P-glycoprotein.

Flavonoids are constituents of fruits, vegetables, and plant derived beverages, as well as components in herbal dietary supplements. The objective of this investigation was to characterize and determine the effect of the Flavonoids on P-glycoprotein (P-gp) which is an important protein involved in multidrug resistance (MDR). Homology modeling of Pglycoprotein (Human) has been performed based on the crystal structure of the 2HYD (Chain A; Structure of a bacterial multidrug ABC transporter) by using Modeller software. With the aid of the molecular mechanics and molecular dynamics methods, the final model is obtained and is further assessed by procheck and verify 3D graph programs, which showed that the final refined model is reliable. With this model, a flexible docking study of P-glycoprotein with a group of Flavonoids which were selected from the previous publications was performed. The results indicated that GLN- 47, TYR -53, SER -83, ILE- 87, GLY -100, ARG -154 in P- glycoprotein are important determinant residues in binding as they have strong hydrogen bonding with Flavonoids. These hydrogen binding interactions play an important role for stability of the complex. Among the 13 Flavonoids docked, Acetylgenistin showed best docking result with Pglycoprotein. Our results may be helpful for further experimental investigations.