ANALYSIS OF QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP (QSAR), PHARMACOPHORE FEATURES AND MOLECULAR DOCKING OF NICOTINAMIDE DERIVATIVES AS ANTI-ANDROGEN

• Main Author: Rahmawati
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/45800
• Institution: Institut Teknologi Bandung

Background : Androgen receptor is a transcription factor that mediates androgen action, plays an important role in the growth and differentiation of the prostate gland and is also expressed in nearly all prostate cancers. Cellular concentrations of the androgen receptor associated with primary lesions, and metastatic progression of the disease into a Castration-Resistant Prostate Cancer (CRPC). Treatment of prostate cancer aims to reduce the concentration of androgens circulate or to block the androgen receptor transcription activation function. nicotinamide derivatives was developed as Non Steroid Anti-Androgen. The aim of present research are to determine the best QSAR equation that showed the quantitative structure and activity relationship of nicotinamide derivatives, determine pharmacophore features which play a role in binding to the receptor, to design new derivative of nicotinamide derivatives which are have stronger activity and evaluation of the interaction between new designed derivatives and androgen receptor. Method : Modeling and geometry optimization of molecular structure were calculated by HyperChem ® 8.0. software. Geometry optimization was performed by ab initio method. QSAR descriptor are were calculated using MOE ® 2009.10 software. Statistical analysis was evaluated by multilinear regression analysis using SPSS ® Statistics 17. Leave One Out cross validation techniques was applied to obtain the QSAR equation with significance statistical criteria. vii Pharmacophore features was created using the ‘Pharmacophore Query Editor’and was applied for interaction study between ligand and protein receptor. In the design of new compounds, substituent selection approach using Hänsch clustering for aromatic rings was conducted. Molecular docking for studying the ligand- receptor interactions was also performed by MOE ® software . Result : The best QSAR equation is Log 1/IC50 = 6.595(±3.255) –0.000053 AM1_E + 0.743(±0.337) AM1_HOMO + 1.156 (±0.587) mr –0.036 (±0.018) vol. The pharmacophore features of androgen receptor antagonist suggests that one aromatic, one proton donor and two proton acceptor, are important for inhibitory activity. There are three new compounds of nicotinamide derivatives which have a theoretical activity better than that of its parent compound. The most active compound has a better affinity, and they have ability to interact with the androgen receptor.