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. 2021 May 23;26(11):3115.
doi: 10.3390/molecules26113115.

Structure-Based Discovery of ABCG2 Inhibitors: A Homology Protein-Based Pharmacophore Modeling and Molecular Docking Approach

Minh-Tri Le  1   2 , Viet-Nham Hoang  1   3 , Dac-Nhan Nguyen  1 , Thi-Hoang-Linh Bui  1 , Thien-Vy Phan  1   4 , Phuong Nguyen-Hoai Huynh  1 , Thanh-Dao Tran  1 , Khac-Minh Thai  1
Affiliations

Structure-Based Discovery of ABCG2 Inhibitors: A Homology Protein-Based Pharmacophore Modeling and Molecular Docking Approach

Minh-Tri Le et al. Molecules. .

Abstract

ABCG2 is an ABC membrane protein reverse transport pump, which removes toxic substances such as medicines out of cells. As a result, drug bioavailability is an unexpected change and negatively influences the ADMET (absorption, distribution, metabolism, excretion, and toxicity), leading to multi-drug resistance (MDR). Currently, in spite of promising studies, screening for ABCG2 inhibitors showed modest results. The aim of this study was to search for small molecules that could inhibit the ABCG2 pump. We first used the WISS MODEL automatic server to build up ABCG2 homology protein from 655 amino acids. Pharmacophore models, which were con-structed based on strong ABCG2 inhibitors (IC50 < 1 μM), consist of two hydrophobic (Hyd) groups, two hydrogen bonding acceptors (Acc2), and an aromatic or conjugated ring (Aro|PiR). Using molecular docking method, 714 substances from the DrugBank and 837 substances from the TCM with potential to inhibit the ABCG2 were obtained. These chemicals maybe favor synthesized or extracted and bioactivity testing.

Keywords: ABCG2 inhibitors; homology protein; molecular docking; pharmacophore models; protein reverse transport pump.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The spatial position and the distance of two models (P1) and (P2).
Figure 2
Figure 2
A hydrophobic factor was added to four-point pharmacophore model.
Figure 3
Figure 3
Binding sites determined by Site Finder Distribution of substances depended on biological activity in the satisfied (B) or unsatisfied pharmacophore model set (A).
Figure 4
Figure 4
Factors of five-point pharmacophore model. F3, F4 (the blue): hydrogen bonding acceptors (Acc2); F2, F5 (the green): hydrophobic groups (Hyd); F1 (the orange): an aromatic ring or π conjugated ring (Aro|PiR).
Figure 5
Figure 5
Homology model of ABCG2.
Figure 6
Figure 6
Parameters for evaluating homology model from SWISS-MODEL site.
Figure 7
Figure 7
Ramachandran plot of the best ABCG2 homology model, in which the most favored regions, the additional allowed regions, the generously allowed regions and the disallowed regions were labeled [A, B, L]; [a, b, l, p]; [~a, ~b, ~l, ~p] and [XX], respectively.
Figure 8
Figure 8
The binding site of the inhibitor on ABCG2. The green area represents the hydrophobic zone, the blue area represents the slightly polarized zone, the pink area represents the hydrophilic zone.
Figure 9
Figure 9
Binding sites of 325 substances on the ABCG2 protein.
Figure 10
Figure 10
The frequency of amino acids interacting in the binding site.
Figure 11
Figure 11
Binding site and interactions of JMC_2016_59_6121_51; DS = −16.14 KJ·mol−1.
Figure 12
Figure 12
Structure and biological activity of tetrahydroxy-β-carbolin derivatives.
Figure 13
Figure 13
Binding site and interactions of BMC_2013_21_7858_20; DS = −23.51 KJ·mol−1.
Figure 14
Figure 14
Receiver operating characteristic (ROC) curves of homology models.
Figure 15
Figure 15
Screening scheme of ABCG2 inhibitors.
Figure 16
Figure 16
Parameters used for evaluating the pharmacophore model.
Figure 17
Figure 17
Binding sites determined by Site Finder.
Figure 18
Figure 18
Virtual screening process for ABCG2 inhibitors.
See this image and copyright information in PMC

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