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.

In Silico Mining of Natural Products Atlas (NPAtlas) Database for Identifying Effective Bcl-2 Inhibitors: Molecular Docking, Molecular Dynamics, and Pharmacokinetics Characteristics

“…All molecular dynamic (MD) simulations were conducted using AMBER16 software [ 41 ]. The specifics of the MD simulations are characterized elsewhere [ 42 , 43 , 44 , 45 ]. Briefly, the AMBER force field of 14SB was used to characterize the Bcl-2 protein [ 46 ].…”

Design and synthesis of new thiazolidinone/uracil derivatives as antiproliferative agents targeting EGFR and/or BRAFV600E

“…The crystal structures of EGFR and BRAF V600E with PDB accession codes: 1M17 ( Stamos et al, 2002 ) and 3OG7 ( Bollag et al, 2010 ), respectively, were obtained and utilized as templates for all docking computations. The pdbqt file of both EGFR and BRAF V600E was prepared as described by Ibrahim et al (2022a) and Ibrahim et al (2022b) . The Lamarckian genetic algorithm (LGA) opted for inhibitor conformational searching and docking parameters involving 25,000,000 energy evaluations and 250 genetic algorithm runs.…”

Click-designed vanilloid-triazole conjugates as dual inhibitors of AChE and Aβ aggregation

“…50 The details of the employed MD simulations are described elsewhere. [51][52][53] Briey, the parameters of the investigated ligands were generated utilizing the general AMBER force eld (GAFF2). 54 AMBER force eld 14SB was employed for AChE and Ab40/42 parametrization.…”