THEORETICAL INSIGHT AND MOLECULAR RECOGNITION OF OXATUB[4]ARENE-BASED ORGANIC MACROCYCLE AS A POTENTIAL DRUG DELIVERY FOR ANTIPSYCHOTIC DRUG RISPERIDONE

• Main Author: Firdaus Akmal, Mohammad
• Format: Theses
• Language: Indonesia
• Subjects: Kimia
• Online Access: https://digilib.itb.ac.id/gdl/view/64833
• Institution: Institut Teknologi Bandung

Neurological diseases such as schizophrenia and other psychotic disorders can be treated with one of the second generation antipsychotic drugs, the benzisoxazole derivative, namely risperidone (RSP), which is hydrophobic; making it difficult to dissolve effectively into body fluids. RSP has been produced and marketed by the drug industry for the treatment of various neurological diseases, but because of its properties it requires a solution to the problem of its low solubility in aqueous solvents. One of the applications of nanotechnology in the fields of medicinal chemistry and supramolecular chemistry is the development of molecular drug delivery systems. Adequate drug delivery technology can be used to increase the bioavailability and solubility of hydrophobic drugs in body fluids. Oxatub[4]arene (TA4) is a new type of organic macrocyclic which has ?-electron-rich and hydrophobic nanocavities and has previously been reported to form stable host-guest inclusion complexes with several aromatic compounds. TA4 consists of four naphthalene units linked by 1.5 ether bridge bonds (CH2-O-CH2). As a result, in addition to having a cavity with a relatively large width and depth, the cavity is also non-specific or can be adapted to the structure of the guest molecule. This must be due to the presence of the four conformers of TA4 due to the flexibility of the bridge and the rotation of the naphthalene ring. HTA4 is the hydroxylated form of TA4 which has a higher polarity so it was chosen as a host molecule that has the potential to dissolve RSP in aqueous solvents.In this in silico study, theoretical investigations and molecular recognition of four RSP-docked HTA4 conformers (RSP@HTA4) were carried out. The aim was to analyze the binding mode, stability, thermodynamic parameters, and intermolecular interactions that determine the feasibility of HTA4 as a potential drug delivery agent from RSP. The entire structure was optimized and studied with a DFT based B3LYP/def2-SVP approach. Visualization of the optimized structure showed a consistent mode of RSP binding in the cavity of each HTA4 conformer, namely in the benzisoxazole and piperidine moieties. In addition, based on the quantum descriptors obtained from ab initio calculations, it was found that the conformer complex RSP@HTA4-III has the highest stability, lowest reactivity, and the formation is the most energetically favorable. By reviewing the ?G value of the inclusion process, it was found that only the complex formation with HTA4-II and HTA4-III hosts was spontaneous, so it can be said that the two conformers were selected in the RSP introductory supramolecular system. All noncovalent interactions involved and responsible for complex stabilization were described using NBO and NCI-RDG analysis. Further analysis using QTAIM characterized strong interactions within the complex while weak interactions were modeled using IGMH, followed by ?-stacking interactions which were specifically analyzed using LOLIPOP and IRI-?. It is these noncovalent interactions that are responsible for the stabilization of the,RSP@HTA4 complex. With the results from this pre-experimental study demonstrating and proving the good stability of RSP@HTA4 as well as future toxicological analysis for HTA4 applications, it is hoped that it will provide insight and support to produce an affordable and appropriate drug delivery system for use with RSP or other similar drugs.