3D-QSAR of Pyridoimidazolones as BRAF inhibitors

국문 초록 (Abstract)

항암제의 발견은 점점 BRAF와 같은 가능성 있는 치료 부위에 초점이 맞추어지고 있다. 3D-QASR 연구는 CoMFA와 CoMSIA 및 docking을 이용하여 BRAF에 억제력이 있는 구조들을 사용하여 수행되었다. CoMFA와 CoMSIA 3D-QSAR 모델들은 Surflex-dock 프로그램을 사용하여 BRAF 활성 부위 내에서 docking에 의해 얻어진 것을 사용하였고, 그것들의 전통적인 r2과 cross-validated coeffiecient (q2) 값은 각각 0.974와 0.612가 나왔다. 이 모델들은 test set으로 검증하였다. CoMSIA 3D-QSAR 모델들이 CoMFA 모델들의 수행 결과보다 더 좋았다. CoMSIA contour maps은 BRAF 활성부위 억제의 결합 방법과 BRAF 억제제의 더 좋은 화합물을 제안할 수 있었다.

다국어 초록 (Multilingual Abstract)

Anti-cancer drug discovery has been increasingly focusing on BRAF as a potential therapeutic target. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) and docking simulations were conducted on a series of potent BRAF inhibitors. CoMFA and CoMSIA 3D-QSAR models were performed using a Surflex-Dock program to dock the compounds into the active site of BRAF and they showed conventional (r2) and cross-validated coefficient (q2) values up to 0.974 and 0.612 for CoMSIA, respectively. These models were validated by a test set. The CoMSIA 3D-QSAR models performed better than the CoMFA models. The CoMSIA contour maps proposed a binding mode of the inhibitors at the active site of BRAF and suggested more active compounds for BRAF inhibitor.

목차 (Table of Contents)

• I. INTRODUCTION 01
• II. MATERIALS AND METHODS 05
• A. Materials 05
• Data sets 05
• B. Methods 15
• 1. Molecular docking 15
• 2. Alignment rule 16
• 2-1. Alignment method-1 16
• 2-2. Alignment method-2 17
• 3. CoMFA and CoMSIA 3D QSAR models 18
• III. RESULTS AND DISCUSSION 20
• A. Results 20
• B. Discussion 27
• IV. CONCLUSION 32
• V. REFERENCES 33
• VI. 국문초록 39
• VII. ABSTRACT 40