Modelling and drug designing of glutamate receptor involved in alzheimer’s disease.

Glutamate receptors dysfunction plays an important role in the pathogenesis and disturbance which is probably a secondary phenomenon to other neurochemical, genetic or metabolic changes, and essential to the development of Alzheimer Disease. Glutamate receptors are synaptic receptors, which are located on the membranes of neuronal cells. Glutamate is used to assemble proteins and also it is abundant in many areas of the body, but it also functions as a neurotransmitter and is particularly abundant in the nervous system. In this work we have modeled a three dimensional structure for Glutamate [NMDA] receptor subunit using MODELLER7V7 software with 2RC7 (Crystal Structure of the NR3A Ligand Binding Core Complex with Glycine) as template. With the aid of Molecular dynamics and Molecular simulations studies it was identified that the generated structure was reliable. This structure was used to identify better inhibitor using docking studies. The drug derivatives were docked to the Glutamate receptor structure into the active site containing residues such as ASP21, LEU30, TYR31, HIS59, and MET60. Among the 21 derivatives 14 were docked and 3rd drug derivative showed better docking energy than the others. Our experimental studies can be further used to develop a better drug for Alzheimer disease.

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.