WaterMap and Molecular Dynamic Simulation-Guided Discovery of Potential PAK1 Inhibitors Using Repurposing Approaches was written by Biswal, Jayashree;Jayaprakash, Prajisha;Rayala, Suresh Kumar;Venkatraman, Ganesh;Rangaswamy, Raghu;Jeyaraman, Jeyakanthan. And the article was included in ACS Omega in 2021.Safety of (2S,3R,4S,5S,6R)-2-(3-Hydroxy-5-((E)-4-hydroxystyryl)phenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol The following contents are mentioned in the article:
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 mols. out of ~2162 drug mols., based on their docking energies and mol. interaction patterns. From the mols. that were considered for WaterMap anal., seven mols., 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 mols., only Acalabrutinib, Flubendazole, and Trazodone mols. 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 mol. dynamics simulation results. Moreover, detailed MD simulation trajectory analyses suggested that the drug mols. 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 mol. Trazodone displayed a loss of crucial interaction with Leu347, which was essential to inhibit the kinase activity of PAK1. The MO and electrostatic potential analyses elucidated the reactivity and strong complementarity potentials of the drug mols. 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 anal. This study involved multiple reactions and reactants, such as (2S,3R,4S,5S,6R)-2-(3-Hydroxy-5-((E)-4-hydroxystyryl)phenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (cas: 27208-80-6Safety of (2S,3R,4S,5S,6R)-2-(3-Hydroxy-5-((E)-4-hydroxystyryl)phenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol).
(2S,3R,4S,5S,6R)-2-(3-Hydroxy-5-((E)-4-hydroxystyryl)phenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (cas: 27208-80-6) belongs to alcohols. Alcohols are weak acids. The most acidic simple alcohols (methanol and ethanol) are about as acidic as water, and most other alcohols are somewhat less acidic. Tertiary alcohols cannot be oxidized at all without breaking carbon-carbon bonds, whereas primary alcohols can be oxidized to aldehydes or further oxidized to carboxylic acids.Safety of (2S,3R,4S,5S,6R)-2-(3-Hydroxy-5-((E)-4-hydroxystyryl)phenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
Referemce:
Alcohol – Wikipedia,
Alcohols – Chemistry LibreTexts