prostate cancer

This project utilised abiraterone as a lead molecule for further iterative design of novel anti-prostate cancer drugs which modulate the CYP17A1 receptor. The protein data bank crystallographic deposition describing the bound co-ordinates of abiraterone and the CYP17A1 enzyme was selected. Abiraterone and the CYP17A1 were examined using structure activity relationship studies; Sybyl®-X was used to generate the apo-receptor and abiraterone extract. For in silico ligand based drug design, ViCi® Hamburg screened for molecules similar to abiraterone. A protomol for CYP17A1 was generated, usingSybyl®-X, in order to probe areas of instability, within the active site region. Both abiraterone extract and the apo-receptor were later imported into X-SCORE® to calculate the ligand binding affinity and the ligand binding energy (kcal mol-1). A total of three seeds was generated using Sybyl®-X, from which de novo molecules were generated, using LigBuilder®. Novel structures divided into various families were generated having different pharmacophores and filtered in accordance to Lipinski’s rule of five. The protomol and the keysite volumes were then compared using UCSF® Chimera.1000 molecules were generated using in silico based drug design, of which 756 were Lipinski rule compliant; 99 molecules exhibited a total score of 6 or higher, when docked into the protomol. 727 de novo molecules were generated; 465 were found to be Lipinski rule compliant and hence further used in the study for pharmacophoric evaluation. Some of the de novo molecules exhibit a pKd higher than the baseline value of 7.04, for abiraterone molecule.