| Full text | |
| Author(s): |
Lima Silva, Wemenes Jose
;
de Freitas, Renato Ferreira
Total Authors: 2
|
| Document type: | Journal article |
| Source: | Journal of Computer-Aided Molecular Design; v. 37, n. 9, p. 12-pg., 2023-06-28. |
| Abstract | |
Kallikrein 6 (KLK6) is an attractive drug target for the treatment of neurological diseases and for various cancers. Herein, we explore the accuracy and efficiency of different computational methods and protocols to predict the free energy of binding (& UDelta;G(bind)) for a series of 49 inhibitors of KLK6. We found that the performance of the methods varied strongly with the tested system. For only one of the three KLK6 datasets, the docking scores obtained with rDock were in good agreement (R-2 & GE; 0.5) with experimental values of & UDelta;G(bind). A similar result was obtained with MM/GBSA (using the ff14SB force field) calculations based on single minimized structures. Improved binding affinity predictions were obtained with the free energy perturbation (FEP) method, with an overall MUE and RMSE of 0.53 and 0.68 kcal/mol, respectively. Furthermore, in a simulation of a real-world drug discovery project, FEP was able to rank the most potent compounds at the top of the list. These results indicate that FEP can be a promising tool for the structure-based optimization of KLK6 inhibitors. (AU) | |
| FAPESP's process: | 18/11011-7 - Design of inhibitors of kallikreins 5, 6, and 7 using computational methods and fragment-based approaches |
| Grantee: | Renato Ferreira de Freitas |
| Support Opportunities: | Research Grants - Young Investigators Grants |
| FAPESP's process: | 19/08603-2 - Design of inhibitors of kallikreins 5, 6, and 7 using computational methods and fragment-based approaches |
| Grantee: | Renato Ferreira de Freitas |
| Support Opportunities: | Scholarships in Brazil - Young Researchers |
| FAPESP's process: | 21/04450-7 - In silico studies of the free energy of binding of kallikrein inhibitors |
| Grantee: | Wemenes José Lima Silva |
| Support Opportunities: | Scholarships in Brazil - Master |