Linker prediction in fragment-based drug design.

• Main Author: Nyam, Ching Wee.
• Other Authors: Mu Yuguang
• Format: Final Year Project
• Language: English
• Published: 2011
• Subjects: DRNTU::Science::Biological sciences::Biophysics
• Online Access: http://hdl.handle.net/10356/46708
• Institution: Nanyang Technological University

Fragment-based drug design is a drug discovery technique where 2 fragments each having some degree of pharmacological activity is covalently tethered together using a linker to reap the energetic benefit of their combined pharmacological action. However, the effects of the linker on the binding energetics of the system are not simple and recent studies have revealed that not only are linkers not a passive medium for bringing the linked fragments together, they also affect the binding energetics of the protein-ligand system in an unpredictable manner. Currently, a pharmaceutical researcher would need to do a careful structural investigation before he/she would be able to predict which linker can optimize the binding affinity of the linked compound with the protein. Consequently, this meant that many potential leads went undiscovered because a suboptimal linker was used when they were screened. This study aims to perform a simulated replication of the experimental results of one such investigation about linker effects, particularly the effects of linker strain and flexibility. The aim of performing such a study is two-fold: to verify the explanation given for the phenomenon studied as well as to better understand the molecular dynamics involved behind the physically observable phenomenon.