Pentafuhalol-B, a Phlorotannin from Brown Algae, Strongly Inhibits the PLK-1 Overexpression in Cancer Cells as Revealed by Computational Analysis

Abstract

Polo-like kinase-1 (PLK-1) is an essential mitotic serine/threonine (Ser/Thr) kinase that belongs to the Polo-like kinase (PLK) family and is overexpressed in non-small cell lung cancer (NSCLC) via promotion of cell division. Therefore, PLK-1 may act as a promising target for the therapeutic cure of various cancers. Although a variety of anti-cancer drugs, both synthetic and naturally occurring, such as volasertib, onvansertib, thymoquinone, and quercetin, are available either alone or in combination with other therapies, they have limited efficacy, especially in the advanced stages of cancer. To the best of our knowledge, no anticancer agent has been reported from marine algae or microorganisms to date. Thus, the aim of the present study is a high-throughput virtual screening of phlorotannins, obtained from edible brown algae, using molecular docking and molecular dynamic simulation analysis. Among these, Pentafuhalol-B (PtB) showed the lowest binding energy (best of triplicate runs) against the target protein PLK-1 as compared to the reference drug volasertib. Further, in MD simulation (best of triplicate runs), the PtB-PLK-1 complex displayed stability in an implicit water system through the formation of strong molecular interactions. Additionally, MMGBSA calculation (best of triplicate runs) was also performed to validate the PtB-PLK-1 complex binding affinities and stability. Moreover, the chemical reactivity of PtB towards the PLK-1 target was also optimised using density functional theory (DFT) calculations, which exhibited a lower HOMO-LUMO energy gap. Overall, these studies suggest that PtB binds strongly within the pocket sites of PLK-1 through the formation of a stable complex, and also shows higher chemical reactivity than the reference drug volasertib. The present study demonstrated the inhibitory nature of PtB against the PLK-1 protein, establishing its potential usefulness as a small molecule inhibitor for the treatment of different types of cancer.

Searching for Natural Aurora a Kinase Inhibitors from Peppers Using Molecular Docking and Molecular Dynamics

“…This may indicate that either this conformation is more stable under dynamic conditions or the MD was necessary to finding this deeper minimum. The polar surface area (PSA) measures the solvent surface area that is produced by polar groups, such as nitrogen and oxygen atoms of the ligand during the simulation [38]. Polar surface area (PSA) was found to oscillate between 70 and 80 A 3 for 1 and 2, while it reached 100 A 3 for 3.…”

“…The SASA refers to the solvent accessibility that provides the quantitative calculation of ligands with protein-implicit water molecules [38]. The studied ligands differ significantly in terms of this parameter.…”

“…The MolSA measures the water solvent area that ligand molecules acquire. In the MolSA study, the surface area is measured by applying a 1.4 Å probe radius, which is approximately equivalent to the van der Waals surface area and radius of one water molecule [38]. The observed MolSA was found to oscillate around 380, 330, 345 and 510 A 3 , respectively, for 1, 2, 3 and AZD1152.…”

Evaluation of Phytochemicals for Anti‐Tubercular Potential Targeting Enoyl‐Acyl Carrier Protein Reductase (InhA): An In Silico Approach

“…To show the overall stability derived from the MDS trajectories, the RMSD is one of the key parameters that can be used for the evaluation of the structural conformation changes of the complex formed between protein and ligand. [22] Protein structural stability and folding are important aspects to consider since the activity of a protein is usually found when in the native conformation or folding towards the substrate. Protein backbone (C α ) superimposition of ligand bound concerning apo-form revealed deviation within 2 Å (Figure 6A).…”

Network-Derived Radioresistant Breast Cancer Target with Candidate Inhibitors from Brown Algae: A Sequential Assessment from Target Selection to Quantum Chemical Calculation

“…The Desmond program [43], Schrödinger suite 2019 version, was used to perform MD simulation to validate the conformational changes of the protein structure of the "RRbc target" upon binding of selected phytochemicals. The system builder panel was employed to generate an orthorhombic box and solvated with a simple point charge (SPC) water model.…”