WaterMap and Molecular Dynamic Simulation-Guided Discovery of Potential PAK1 Inhibitors Using Repurposing Approaches

Abstract

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.

Pathfinder-Driven Chemical Space Exploration and Multiparameter Optimization in Tandem with Glide/IFD and QSAR-Based Active Learning Approach to Prioritize Design Ideas for FEP+ Calculations of SARS-CoV-2 PLpro Inhibitors

“…This will in turn, allow the determination of favorable and unfavorable waters that can be displaced by inserting functional groups that displace unfavorable waters to achieve a gain in potency [ 69 ]. Several researchers in the industry and in academia have used Water map for this purpose prior to FEP+ calculations with the aim of improving the relative binding affinities of the design ideas and repurposed drugs [ 70 ], an approach that we aim to follow for future studies in this research area. As such, the design of novel chemical matter containing 2-[2-(methanesulfonyl)propan-2-yl]-1 H -benzimidazole, 1,3-dimethyl-1,3-dihydro-2 H -benzimidazol-2-one, 3-[( S )-amino(4-fluorophenyl)methyl]-1,2,4-oxadiazol-5(4 H )-one, and ( S )-1-(4-methylphenyl)-1-(1 H -pyrazol-3-yl)methanamine moieties, instead of the naphthalene moiety that is in GRL-0617, was successfully performed.…”

In Silico Analysis of Protein–Protein Interactions of Putative Endoplasmic Reticulum Metallopeptidase 1 in Schizosaccharomyces pombe

“…The Ermp1 interaction complexes were hydrated in the WaterMap tool, New York, NY, USA [54]. A molecular dynamics simulation was carried out in the presence of the solvent and a thermodynamic analysis of the water in the protein binding site was also performed [52,55]. The WaterMap calculations were run with the default simulation parameters: TIP4P solvent model at 300 K, 1 atmospheric pressure, and 2 ns simulation time.…”

Leveraging the Fragment Molecular Orbital Method to Explore the PLK1 Kinase Binding Site and Polo-Box Domain for Potent Small-Molecule Drug Design

“…These results suggest that Onvansertib obtains selectivity by functional groups by replacing high-energy hydration sites found in the WaterMap of BI2536. Using WaterMap calculations, we performed a solvation analysis that effectively identified specific hydration sites localized near the ATP-binding site, providing valuable insight into their thermodynamic energy profiles [52]. Hydration sites with a predicted free energy (ΔG) greater than 0 kcal/mol upon water addition were classified as unfavorable sites, whereas hydration sites with a predicted free energy ΔG of less than 0 kcal/mol were considered favorable sites [53].…”