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Abstract Introduction includes a literature survey on the computer-assisted approaches to identify new inhibitors via pharmacophore, molecular and dynamic modeling, quantum mechanics, docking, structural interaction fingerprints, and statistical learning methods that have been used to identify new inhibitors. Also, it includes a literature survey on phenothiazines that have boosted the structure-based design of novel compounds and the molecular modeling of phenothiazines and application of other computer-aided drug design techniques CHAPTER II: (Computational Methods) This chapter includes the use of computational chemistry and overview on quantum chemical methods, which include semiempirical, Ab Initio and DFT calculations, and detailed description of the procedures that was used throughout this work. The resulting optimized structures are optimized using density functional theory (DFT) with the B3LYP and 6-31 G+(d) basis set. All calculations are performed with the Gaussian 03 software package. The optimized structures of the molecules are visualized with Chemcraft program. Molecular frontier orbitals HOMO and LUMO and molecular electrostatic potential (MEP) of all optimized structures are visualized using GaussView 5.0. The molecular docking simulation is performed using AutoDock 4.2. Quantitative Structure Activity Relationship (QSAR) is carried out using the molecular modelling software material studio version 4.3 Accelrys software company. CHAPTER III: (Results and Discussion) In this chapter, we analysed and discussed the results of the data obtained from computational studies. This chapter is divided into three main parts: PART 1: The effect of quantum chemical parameters On the biological activity of trypanothione reductase inhibitors In this part, the quantum chemical calculations were performed to investigate the effect of electronic and structural parameters on the efficiency of the studied drugs and try to predict the mode of interaction of the inhibitor with the enzyme. The quantum chemical calculations showed an agreement between quantum chemical parameters related to the electronic structure of the investigated compounds and their biological activity. This study displays a good correlation between the theoretical and experimental data, which confirmed that the quantum chemical methods are successful tools for enriching screening experiments aimed at the discovery of novel bioactive compounds PART 2: Molecular docking analysis This part explains the binding of phenothiazines to the target enzyme. The docking studies showed that all the tested compounds would bind to the active site of the enzyme, which could be probably due to the presence of lipophilic groups. It was found from the calculations that electrostatic and the van der Waals forces are the main features of the interaction. Also, good correlations were found between the data obtained from the docking calculations and the calculated quantum chemical parameters. |