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.
