Naturally occurring plant-based anticancerous candidates as prospective ABCG2 inhibitors: an in silico drug discovery study

Abstract

ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter related to the clinical multidrug resistance (MDR) phenomenon. Identifying ABCG2 inhibitors could help discover extraordinary curative strategies for carcinoma remediation. Hitherto, there is no medication drug inhibiting ABCG2 transporter, notwithstanding that a considerable number of drugs have been submitted to clinical-trial and investigational phases. In the search for unprecedented chemical compounds that could inhibit the ABCG2 transporter, an in silico screening was conducted on the Naturally Occurring Plant-based Anticancer Compound-Activity-Target (NPACT) database containing 1574 compounds. Inhibitor-ABCG2 binding affinities were estimated based on molecular docking and molecular minimization (MM) calculations and compared to a co-crystallized inhibitor (BWQ) acting as a reference inhibitor. Molecular dynamics (MD) simulations pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations were further executed for compounds with MM-GBSA//MM binding energies lower than BWQ (calc. − 60.5 kcal/mol). NPACT00968 and NPACT01545 demonstrated auspicious inhibitory activities according to binding affinities (ΔGbinding) over the 100 ns MD simulations that were nearly one and a half folds compared to BWQ (− 100.4, − 94.7, and − 62.9 kcal/mol, respectively). Throughout the 100 ns MD simulations, structural and energetical analyses unveiled outstanding stability of the ABCG2 transporter when bound with NPACT00968 and NPACT01545. In silico calculations hold a promise for those two inhibitors as drug candidates of ABCG2 transporter and emphasize that further in vitro and in vivo experiments are guaranteed. Graphical abstract

Exploring Natural Product Activity and Species Source Candidates for Hunting ABCB1 Transporter Inhibitors: An In Silico Drug Discovery Study

“…The general AMBER force field (GAFF2) was employed to parameterize NPASS compounds [ 33 ], while the ABCB1 transporter was parameterized using an AMBER force field of 14SB [ 34 ]. The minutiae of employed MD simulations are characterized in [ 35 , 36 , 37 ]. In this work, both implicit- and explicit-solvent MD simulations were executed.…”

Anxiolytic-like Effects by trans-Ferulic Acid Possibly Occur through GABAergic Interaction Pathways

“…Molecular docking to estimate the active binding affinity of the selected ligands against the active sites of GABA A receptors was conducted with the aid of the PyRx software package. To carry out molecular docking, the dimensions of the gird box were set as 80 × 80 × 80 Å along the x-, y- and z-axes, respectively, and the calculation was run at 200 steps [ 105 ]. The outcome of the docking potential is stored in ‘.csv’ format, while the ligand–protein complex is saved in PDB format.…”

In-Silico Mining of the Toxins Database (T3DB) towards Hunting Prospective Candidates as ABCB1 Inhibitors: Integrated Molecular Docking and Lipid Bilayer-Enhanced Molecular Dynamics Study

“…The information regarding the parameters of the MD simulations is detailed in Refs. [ 41 , 42 , 43 , 44 ]. Briefly, the ABCB1 transporter and the T3DB compounds were defined utilizing the AMBER force field of 14SB and the general AMBER force field (GAFF2), respectively [ 45 , 46 ].…”