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

Abstract

The P-glycoprotein (P-gp/ABCB1) is responsible for a xenobiotic efflux pump that shackles intracellular drug accumulation. Additionally, it is included in the dud of considerable antiviral and anticancer chemotherapies because of the multidrug resistance (MDR) phenomenon. In the search for prospective anticancer drugs that inhibit the ABCB1 transporter, the Natural Product Activity and Species Source (NPASS) database, containing >35,000 molecules, was explored for identifying ABCB1 inhibitors. The performance of AutoDock4.2.6 software to anticipate ABCB1 docking score and pose was first assessed according to available experimental data. The docking scores of the NPASS molecules were predicted against the ABCB1 transporter. Molecular dynamics (MD) simulations were conducted for molecules with docking scores lower than taxol, a reference inhibitor, pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. On the basis of MM-GBSA calculations, five compounds revealed promising binding affinities as ABCB1 inhibitors with ΔGbinding < −105.0 kcal/mol. The binding affinity and stability of the identified inhibitors were compared to the chemotherapeutic agent. Structural and energetical analyses unveiled great steadiness of the investigated inhibitors within the ABCB1 active site throughout 100 ns MD simulations. Conclusively, these findings point out that NPC104372, NPC475164, NPC2313, NPC197736, and NPC477344 hold guarantees as potential ABCB1 drug candidates and warrant further in vitro/in vivo tests.

Keywords: ABCB1; NPASS; molecular docking; molecular dynamics (MD) simulations; multidrug resistance (MDR).

Figure 1

3D and 2D molecular interactions of the experimental structures (in cyan) and the portended docking poses (in pink) of (i) tariquidar, (ii) elacridar, (iii) taxol, and (iv) zosuquidar in complex with ABCB1 transporter. The predicted docking scores are displayed in kcal/mol.

Figure 2

Components of the MM-GBSA approach for taxol, tariquidar, elacridar, and zosuquidar complexed with ABCB1 transporter over the 100 ns MD simulations.

Figure 3

3D and 2D molecular interactions of the predicted binding mode of NPC197736 within the ABCB1 transporter.

Figure 4

Computed binding affinities for taxol and the top nine potent NPASS compounds complexed with the active site of ABCB1 transporter over 1 ns implicit-solvent MD in addition to 50 ns and 100 ns explicit-solvent MD simulations.

Figure 5

Per-residue energy decomposition of NPC104372, NPC475164, NPC2313, NPC197736, NPC477344, and taxol complexed with ABCB1 transporter.

Figure 6

(a) The number of hydrogen bonds between the identified NPASS compounds and ABCB1 transporter, (b) evaluated MM-GBSA binding energy per frame, (c) center-of-mass (CoM) distances, and (d) root-mean-square deviation (RMSD) of the backbone atoms from the starting structure of NPC104372 (in navy), NPC475164 (in cyan), NPC2313 (in gray), NPC197736 (in light blue), and taxol (in wine) towards ABCB1 transporter throughout 100 ns MD simulations.