Supernatural Inhibitors to Reverse Multidrug Resistance Emerged by Abcb1 Transporter: Database Mining, Lipid-mediated Molecular Dynamics, and Pharmacokinetics Study
Mahmoud A. A. Ibrahim, Khlood A. A. Abdeljawaad, Alaa H. M. Abdelrahman, Mahmoud M. H. Abdelhamid, Mohamed Ahmed Naeem,Gamal A. H. Mekhemer, Peter A. Sidhom, Shaban R. M. Sayed, Paul W. Paré, Mohamed-Elamir F. Hegazy
Abstract
An effective approach to reverse multidrug resistance (MDR) is P-glycoprotein (P-gp, ABCB1) transport inhibition. To identify such molecular regulators, the SuperNatural II database, which comprises > 326,000 compounds, was virtually screened for ABCB1 transporter inhibitors. The Lipinski rule was utilized to initially screen the SuperNatural II database, identifying 128,126 compounds. Those natural compounds were docked against the ABCB1 transporter, and those with docking scores less than zosuquidar (ZQU) inhibitor were subjected to molecular dynamics (MD) simulations. Based on MM-GBA binding energy (ΔGbinding) estimations, UMHSN00009999 and UMHSN00097206 demonstrated ΔGbinding values of –68.3 and –64.1 kcal/mol, respectively, compared to ZQU with a ΔGbinding value of –49.8 kcal/mol. For an investigation of stability, structural and energetic analyses for UMHSN00009999- and UMHSN00097206-ABCB1 complexes were performed and proved the high steadiness of these complexes throughout 100 ns MD simulations.
Introduction
Carcinoma is often an incurable disease, with approximately two million cases reported in 2020 alone [1]. Chemotherapy is one of the most widely used treatments [2], even though remission is observed in only 10% of cancer cases because neoplasm cells rapidly evolve resistant to most anticarcinoma drugs. Tumor cell excretion of chemotherapeutic medications is greatly aided by ATP-binding cassettes (ABC) and other membrane proteins that are powered by ATP hydrolysis [3, 4]. P-glycoprotein (P-gp), also known as ABCB1 (ATP-binding cassette), is among the most effective ABC proteins for drug export [5]. ABCB1 transporter has been recognized as a key component in the emergence of MDR tumor lines [6]. The ABCB1 transporter is encoded by an MDR1 gene having a molecular weight of 170 kilodaltons [7]. The ABCB1 transporter is observed to be expressed at high levels in colorectal cancer [8]. Two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs) work jointly for ABCB1 activation.
Methods
ABCB1 preparation
The RCSB PDB database was used to retrieve the structure of the ABCB1 transporter [25]. The 3d structure of the ABCB1 transporter complexed with the zosuquidar ((2R)-1-(4-((1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c][7]annulen-6-yl)piperazin-1-yl)-3-(quinolin-5-yloxy)propan-2-ol) (ZQU) inhibitor (PDB ID: 6QEE, resolution: 3.90 Å [26]) was used for all in-silico approaches. Modeller software was utilized to build the missing residues [27]. Preparing the protein involved assigning bonds in the correct order, orienting disoriented groups, and removing co-crystalized water molecules and inhibitors. The protonation states of residues were determined, and the missing hydrogens were inserted using the H++ web server [28].
Results
Virtual screening of the SuperNatural II database
The outperformance of AutoDock4.2.6 software in predicting the ZQU-ABCB1 binding pose has been previously reported [39]. According to the published results, the calculated RMSD value between the predicted and experimental binding modes was 0.18 Å, with a docking score of −8.3 kcal/mol. Utilizing the validated docking protocol, the 128,126 pre-screened compounds were virtually screened towards the ABCB1 transporter utilizing standard parameters. According to the standard docking scores, 3,751 natural compounds demonstrated docking scores less than ZQU (calc. −8.4 kcal/mol against the ABCB1 transporter). Accordingly, these 3,751 compounds were re-docked against the ABCB1 transporter utilizing moderate docking parameters. The predicted docking scores for these 3,751 compounds (S1 Table). According to results listed in S1 Table, 376 natural compounds demonstrated docking scores ≤ –10.5 kcal/mol. Thus, these 376 natural compounds were subjected to more expensive computations. The corresponding docking scores are summarized in S2 Table.
Conclusions
Inhibiting the ABCB1 transporter is one of the most effective mechanisms for reversing multidrug resistance (MDR). Herein, in-silico techniques were used for screening the SuperNatural II database to point out potential compounds towards the ABCB1 transporter. On the basis of the docking scores, the potent natural compounds with docking scores ≤ –11.0 kcal/mol were subjected to MD simulations, pursued by MM-GBSA binding energy computations. In accordance with the MM-GBSA results, UMHSN00009999 and UMHSN00097206 showed superior binding energies with average ΔGbinding values of –68.3 and –64.1 kcal/mol over 100 ns MD simulations, respectively, compared to the ZQU (calc. –49.8 kcal/mol). The structural and energetical analyses confirmed inhibitor stability over the 100 ns MD simulation. According to pharmacokinetic properties, UMHSN000099999 and UMHSN00097206 demonstrated good oral bioavailability.
Citation: Ibrahim MAA, Abdeljawaad KAA, Abdelrahman AHM, Abdelhamid MMH, Naeem MA, Mekhemer GAH, et al. (2023) SuperNatural inhibitors to reverse multidrug resistance emerged by ABCB1 transporter: Database mining, lipid-mediated molecular dynamics, and pharmacokinetics study. PLoS ONE 18(7): e0288919. https://doi.org/10.1371/journal.pone.0288919
Editor: Syed Hani Abidi, Nazarbayev University School of Medicine, PAKISTAN
Received: May 18, 2023; Accepted: July 6, 2023; Published: July 26, 2023
Copyright: © 2023 Ibrahim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting information files.
Funding: This study was financially supported by the Researchers Supporting Project, King Saud University, Riyadh, Saudi Arabia in the form of an award (RSPD2023R743). No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0288919#abstract0
