Non-Steroidal Anti-Inflammatory Drugs in Cyclooxygenases 1 and 2 : Binding modes and mechanisms from computational methods and free energy calculations

• Main Author: Shamsudin Khan, Yasmin
• Format: Doctoral Thesis
• Language: English
• Published: Uppsala universitet, Beräkningsbiologi och bioinformatik 2017
• Subjects: molecular dynamics simulations; binding free energy; molecular docking; cyclooxygenase; non-steroidal anti-inflammatory drugs; free energy perturbation; potentials of mean force; Pharmaceutical Biotechnology; Läkemedelsbioteknik
• Online Access: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-328478; http://nbn-resolving.de/urn:isbn:978-91-513-0073-3

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used classes of drugs. They target the cyclooxygenases (COX) 1 and 2 to reduce the physiological responses of pain, fever, and inflammation. Due to their role in inducing angiogenesis, COX proteins have also been identified as targets in cancer therapies. In this thesis, I describe computational protocols of molecular docking, molecular dynamics simulations and free energy calculations. These methods were used in this thesis to determine structure-activity relationships of a diverse set of NSAIDs in binding to their target proteins COX-1 and 2. Binding affinities were calculated and used to predict the binding modes. Based on combinations of molecular dynamics simulations and free energy calculations, binding mechanisms of sub-classes of NSAIDs were also proposed. Two stable conformations of COX were probed to understand how they affect inhibitor affinities. Finally, a brief discussion on selectivity towards either COX isoform is discussed. These results will be useful in future de novo design and testing of third-generation NSAIDs.