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 (ΔG_binding) 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.

Keywords: ABCG2; Molecular docking; Molecular dynamics simulations; Multidrug resistance; NPACT database.

Fig. 1

A workflow diagram of the employed computational approaches in addition to the filtration process

Fig. 2

3D and 2D representations of the anticipated docking poses (in mauve) and experimental structures (in cyan) of a BWQ and b imatinib complexed with ABCG2 transporter

Fig. 3

3D and 2D representations of AMBER-based minimized structures, in addition to the evaluated MM-GBSA//MM binding affinities, of the top two potent compounds and BWQ bound with the ABCG2 transporter

Fig. 4

Calculated MM-GBSA binding energies for BWQ inhibitor and the top potent NPACT compounds complexed with ABCG2 transporter throughout 25 ns and 100 ns MD simulations

Fig. 5

2D representations of binding modes of a NPACT00968, b NPACT01545, and c BWQ bound with ABCG2 transporter according to the average structure throughout the 100 ns MD simulations, as well as components of the MM-GBSA binding energies for d NPACT00968, e NPACT01545 and f BWQ in complex with ABCG2's active site over the MD course of 100 ns

Fig. 6

Per-residue decomposition of the total binding energy (kcal/mol) of NPACT00968, NPACT01545 and BWQ bound with ABCG2 transporter

Fig. 7

a Evaluated MM-GBSA binding energy per frame, b center-of-mass (CoM) distances and c root-mean-square deviation (RMSD) of the backbone atoms from the starting structure of NPACT00968 (in gray), NPACT01545 (in violet), and BWQ (in black) against the ABCG2 transporter during 100 ns MD simulations