| مستخلص: |
Aim: This study aims to develop and establish a computational model that can identifypotent molecules for p21-activating kinase 1 (PAK1) Background: PAK1 is a well-established drug target that has been explored for various therapeuticinterventions. Control of this protein requires an indispensable inhibitor to curb the structuralchanges and subsequent activation of signalling effectors responsible for the progression ofdiseases, such as cancer, inflammatory, viral, and neurological disorders. Objective: The study aims to establish a computational model that could identify active moleculeswhich will further provide a platform for developing potential PAK1 inhibitors. Methods: A congeneric series of 27 compounds were considered for this study, with Ki (nm)covering a minimum of 3 log range. The compounds were developed based on a previouslyreported Group-I PAK inhibitor, namely G-5555. The 27 compounds were subjected to the SP andXP mode of docking to understand the binding mode, its conformation and interaction patterns. Tounderstand the relevance of biological activity from computational approaches, the compoundswere scored against generated water maps to obtain WM/MM ΔG binding energy. Moreover,molecular dynamics analysis was performed for the highly active compound to understand theconformational variability and stability of the complex. We then evaluated the predictable bindingpose obtained from the docking studies. Results: From the SP and XP modes of docking, the common interaction pattern with the aminoacid residues Arg299 (cation-π), Glu345 (Aromatic hydrogen bond), hinge region Leu347, saltbridges Asp393 and Asp407 was observed, among the congeneric compounds. The interactionpattern was compared with the co-crystal inhibitor FRAX597 of the PAK1 crystal structure (PDB id:4EQC). The correlation with different docking parameters in the SP and XP modes was insignificantand thereby revealed that the SP and XPs scoring functions could not predict the active compounds.This was due to the limitations in the docking methodology that neglected the receptor flexibility anddesolvation parameters. Hence, to recognise the desolvation and explicit solvent effects, as well as tostudy the Structure-Activity Relationships (SARs) extensively, WaterMap (WM) calculations wereperformed on the congeneric compounds. Based on displaceable unfavourable hydration sites (HS)and their associated thermodynamic properties, the WM calculations facilitated in understanding thesignificance of correlation in the folds of activity of highly active (19 and 17), moderately active (16and 21) and less active (26 and 25) compounds. Furthermore, the scoring function from WaterMap,namely WM/MM, led to a significant R2 value of 0.72 due to a coupled conjunction with MMtreatment and displaced unfavourable waters at the binding site. To check the “optimal bindingconformation”, molecular dynamics simulation was carried out with the highly active compound 19 toexplain the binding mode, stability, interactions, solvent-accessible area, etc., which could supportthe predicted conformation with bioactive conformation. Conclusion: This study determined the best scoring function, established SARs and predictedactive molecules through a computational model. This will contribute to the development of themost potent PAK1 inhibitors. |
