WaterMap and Molecular Dynamic Simulation-Guided Discovery of Potential PAK1 Inhibitors Using Repurposing Approaches
| العنوان: | WaterMap and Molecular Dynamic Simulation-Guided Discovery of Potential PAK1 Inhibitors Using Repurposing Approaches |
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| المؤلفون: | Prajisha Jayaprakash, Jayashree Biswal, Ganesh Venkatraman, Raghu Rangaswamy, Jeyakanthan Jeyaraman, Suresh K. Rayala |
| المصدر: | ACS Omega, Vol 6, Iss 41, Pp 26829-26845 (2021) ACS Omega |
| بيانات النشر: | American Chemical Society, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | biology, Chemistry, Kinase, General Chemical Engineering, Active site, General Chemistry, Flubendazole, Article, Hydrophobic effect, chemistry.chemical_compound, Molecular dynamics, Docking (molecular), biology.protein, Biophysics, Kinase activity, DrugBank, QD1-999 |
| الوصف: | p21-Activated kinase 1 (PAK1) is positioned at the nexus of several oncogenic signaling pathways. Currently, there are no approved inhibitors for disabling the transfer of phosphate in the active site directly, as they are limited by lower affinity, and poor kinase selectivity. In this work, a repurposing study utilizing FDA-approved drugs from the DrugBank database was pursued with an initial selection of 27 molecules out of ∼2162 drug molecules, based on their docking energies and molecular interaction patterns. From the molecules that were considered for WaterMap analysis, seven molecules, namely, Mitoxantrone, Labetalol, Acalabrutinib, Sacubitril, Flubendazole, Trazodone, and Niraparib, ascertained the ability to overlap with high-energy hydration sites. Considering many other displaced unfavorable water molecules, only Acalabrutinib, Flubendazole, and Trazodone molecules highlighted their prominence in terms of binding affinity gains through ΔΔG that ranges between 6.44 and 2.59 kcal/mol. Even if Mitoxantrone exhibited the highest docking score and greater interaction strength, it did not comply with the WaterMap and molecular dynamics simulation results. Moreover, detailed MD simulation trajectory analyses suggested that the drug molecules Flubendazole, Niraparib, and Acalabrutinib were highly stable, observed from their RMSD values and consistent interaction pattern with Glu315, Glu345, Leu347, and Asp407 including the hydrophobic interactions maintained in the three replicates. However, the drug molecule Trazodone displayed a loss of crucial interaction with Leu347, which was essential to inhibit the kinase activity of PAK1. The molecular orbital and electrostatic potential analyses elucidated the reactivity and strong complementarity potentials of the drug molecules in the binding pocket of PAK1. Therefore, the CADD-based reposition efforts, reported in this work, helped in the successful identification of new PAK1 inhibitors that requires further investigation by in vitro analysis. |
| اللغة: | English |
| تدمد: | 2470-1343 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a7b240350d58c79b6e9d4caa6ec9d2b2Test https://doaj.org/article/aa730c13bcbc4d3f801ba00717c58a6cTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a7b240350d58c79b6e9d4caa6ec9d2b2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 24701343 |
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