Computational Modeling on Aquaporin-3 as Skin Cancer Target: A Virtual Screening Study

Abstract

Aquaporin-3 (AQP3) is one of the aquaglyceroporins, which is expressed in the basolateral layer of the skin membrane. Studies have reported that human skin squamous cell carcinoma overexpresses AQP3 and inhibition of its function may alleviate skin tumorigenesis. In the present study, we have applied a virtual screening method that encompasses filters for physicochemical properties and molecular docking to select potential hit compounds that bind to the Aquaporin-3 protein. Based on molecular docking results, the top 20 hit compounds were analyzed for stability in the binding pocket using unconstrained molecular dynamics simulations and further evaluated for binding free energy. Furthermore, examined the ligand-unbinding pathway of the inhibitor from its bound form to explore possible routes for inhibitor approach to the ligand-binding site. With a good docking score, stability in the binding pocket, and free energy of binding, these hit compounds can be developed as Aquaporin-3 inhibitors in the near future.

Mechanistic Insight into Binding of Huperzine A with Human Serum Albumin: Computational and Spectroscopic Approaches

“…Then, 1000 ps simulations were performed in NVT and NPT ensembles at temperature 300 K. To control the temperature and pressure during the simulation, the Berendsen thermostats and barostats were applied. Both the relaxed systems were subjected to a final MD run for 100 ns with a time step of 2 fs [ 47 ]. For analysis purposes, RMSD, RMSF, R g , SASA, and hydrogen bonding were recorded.…”

Aquaglyceroporin Modulators as Emergent Pharmacological Molecules for Human Diseases

“…Protein-ligand docking studies have been used as a virtual screening method of potential AQP modulators, being able to predict their binding modes to the protein ( Martins et al, 2012 ; Madeira et al, 2014b ; Yadav et al, 2020 ). Additionally, molecular docking can be combined with molecular dynamics to confirm the proposed inhibitor binding sites, that can also be characterized through density functional theory calculations ( Muller et al, 2008 ; Martins et al, 2012 ; Verkman et al, 2014 ; de Almeida et al, 2017 ).…”

Aquaporins: A Multidisciplinary Perspective on The Water Channel Proteins

“…In this context, several approaches have been probed including gold(III) compound complexes [43], mercury compounds [44], as well as selective and potent isoform-specific aquaglyceroporin inhibitors [45]. A very recent study has applied a virtual screening method -molecular docking-to select potential compounds that bind to the AQP3, that is overexpressed in human skin squamous cell carcinoma, to be evaluated for the development of inhibitors to alleviate skin tumorigenesis [46]. It has been shown that dexamethasone and ambroxol can stimulate the mRNA and protein expression of AQP3 and AQP5 in a human airway epithelial cell line (A549 cells) which may imply the potential roles of these AQPs in the regulation of airway hypersecretion, as a target for treating related diseases [47].…”