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. 2021 Mar;129(3):37009.
doi: 10.1289/EHP7466. Epub 2021 Mar 26.

Discovery of New Protein Targets of BPA Analogs and Derivatives Associated with Noncommunicable Diseases: A Virtual High-Throughput Screening

Diana Montes-Grajales  1 , Xiomara Morelos-Cortes  1 , Jesus Olivero-Verbel  1
Affiliations

Discovery of New Protein Targets of BPA Analogs and Derivatives Associated with Noncommunicable Diseases: A Virtual High-Throughput Screening

Diana Montes-Grajales et al. Environ Health Perspect. 2021 Mar.

Abstract

Background: Bisphenol A analogs and derivatives (BPs) have emerged as new contaminants with little or no information about their toxicity. These have been found in numerous everyday products, from thermal paper receipts to plastic containers, and measured in human samples.

Objectives: The objectives of this research were to identify in silico new protein targets of BPs associated with seven noncommunicable diseases (NCDs), and to study their protein-ligand interactions using computer-aided tools.

Methods: Fifty BPs were identified by a literature search and submitted to a virtual high-throughput screening (vHTS) with 328 proteins associated with NCDs. Protein-protein interactions between predicted targets were examined using STRING, and the protocol was validated in terms of binding site recognition and correlation between in silico affinities and in vitro data.

Results: According to the vHTS, several BPs may target proteins associated with NCDs, some of them with stronger affinities than bisphenol A (BPA). The best affinity score (the highest in silico affinity absolute value) was obtained after docking 4,4'-bis(N-carbamoyl-4-methylbenzensulfonamide)diphenylmethane (BTUM) on estradiol 17-beta-dehydrogenase 1 (-13.7 kcal/mol). However, other molecules, such as bisphenol A bis(diphenyl phosphate) (BDP), bisphenol PH (BPPH), and Pergafast 201 also exhibited great affinities (top 10 affinity scores for each disease) with proteins related to NCDs.

Discussion: Molecules such as BTUM, BDP, BPPH, and Pergafast 201 could be targeting key signaling pathways related to NCDs. These BPs should be prioritized for in vitro and in vivo toxicity testing and to further assess their possible role in the development of these diseases. https://doi.org/10.1289/EHP7466.

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Figures

Figure 1A is a three-dimensional view of the chemical complex structure of 4,4 prime-Bis(N-carbamoyl-4-methylbenzensulfonamide)diphenylmethane (B T U M) and Proprotein convertase subtilisin/kexin type 9 (P C S K 9) complex. Figure 1B is a three-dimensional view depicting the binding site and interactions for the following residues: V A L 3 5 9 B, C Y S 3 5 8 B, I L E 4 1 6 B, T H R 4 5 9 B, V A L 4 6 0 B, V A L A 4 7 5 B, V A L 6 5 5 B, T H R 6 5 3 B, V A L 6 5 0 B, and T H R 6 2 3 B. The arrows with circles depict hydrogen-bond donor features.
Figure 1.
(A) Three-dimensional view of the 4,4′-bis(N-carbamoyl-4-methylbenzensulfonamide)diphenylmethane/proprotein convertase subtilisin/kexin type 9 (BTUM/PCSK9) complex, showing (B) the binding site and interactions predicted by LigandScout 3.1. Contact residues: VAL359B, CYS358B, ILE416B, THR459B, VAL460B, ALA475B, VAL655B, THR653B, VAL650B, and THR623B. The black arrows with circles represent hydrogen-bond donor features.
Figure 2A is a three-dimensional view of the chemical complex structure of 3-(3-Tosylureido)phenyl p-toluenesulfonate (Pergafast 201) and L-lactate dehydrogenase A chain (L D H A) complex. Figure 2B is a three-dimensional view depicting the binding site and interactions for the following residues: T R P 1 8 7 B, A R G 1 7 0 B, A L A 1 6 7 B, L E U 6 9 A, P H E 7 0 A, L E U 1 8 2 B, A R G 2 6 8 D, L E U 1 8 2 D, T R P 1 8 7 D, L E U 6 9 C, A L A 1 6 7 D, and A R G 1 7 0 D. The arrows depict hydrogen-bond acceptor features, and double-sided arrows symbolize aromatic ring interactions.
Figure 2.
(A) Three-dimensional view of the 3-(3-tosylureido)phenyl p-toluenesulfonate/l-lactate dehydrogenase A chain (Pergafast 201/LDHA) complex, showing (B) the binding site and interactions predicted by LigandScout 3.1. Contact residues: TRP187B, ARG170B, ALA167B, LEU69A, PHE70A, LEU182B, ARG268D, LEU182D, TRP187D, LEU69C, ALA167D, and ARG170D. The red arrows represent hydrogen-bond acceptor features, and the blue double-sided arrows symbolize aromatic ring interactions.
Figure 3A is a three-dimensional view of the chemical complex structure of 4,4 prime-Bis(N-carbamoyl-4-methylbenzensulfonamide)diphenylmethane (B T U M) and Estradiol 17-beta-dehydrogenase 1 (D H B 1) complex. Figure 3B is a three-dimensional view depicting the binding site and interactions for the following residues: V A L 2 2 5 X, P H E 2 5 9 X, L E U 1 4 9 X, V A L 1 4 3 X, M E T 1 4 7 X, G L Y 1 4 4 X, S E R 1 4 2 X, P H E 1 9 2 X, V A L 1 8 8 X, I L E 1 4 X, T H R 1 9 0 X, A R G 3 7 X, T H R 1 4 0 X, A L A 9 1 X , V A L 1 1 3 X, and V A L 6 6 X.
Figure 3.
(A) Three-dimensional view of the 4,4′-bis(N-carbamoyl-4-methylbenzensulfonamide)diphenylmethane/estradiol 17-beta-dehydrogenase 1 (BTUM/DHB1) complex, showing (B) the binding site and interactions predicted by LigandScout 3.1. Contact residues: VAL225X, PHE259X, LEU149X, VAL143X, MET147X, GLY144X, SER142X, PHE192X, VAL188X, ILE14X, THR190X, ARG37X, THR140X, ALA91X, VAL113X, and VAL66X.
Figure 4A is a three-dimensional view of the chemical complex structure of Bisphenol A bis(diphenyl phosphate) (B D P) and NAD-dependent protein deacetylase sirtuin-2 (S I R 2) complex. Figure 4B is a three-dimensional view depicting the binding site and interactions for the following residues: P H E 1 4 3 A, L E U 2 0 6 A, P H E 1 9 0 A, P H E9 6 A, I L E 2 3 2 A, P H E 2 3 5 A, P H E 1 3 1 A, P H E 1 1 9 A, T Y R 1 0 4 A, L E U 1 0 3 A, L E U 1 3 4 A, A L A 1 3 5 A, L E U 1 3 8 A, T Y R 1 3 9 A, and I L E 9 3 A. The double-sided arrows depict aromatic ring interactions.
Figure 4.
(A) Three-dimensional view of the bisphenol A bis(diphenyl phosphate)/NAD-dependent protein deacetylase sirtuin-2 (BDP/SIR2) complex, showing (B) the binding site and interactions predicted by LigandScout 3.1. Contact residues: PHE143A, LEU206A, PHE190A, PHE96A, ILE232A, PHE235A, PHE131A, PHE119A, TYR104A, LEU103A, LEU134A, ALA135A, LEU138A, TYR139A, and ILE93A. The blue double-sided arrows represent aromatic ring interactions. Note: NAD, nicotinamide adenine dinucleotide.
Figure 5A is a three-dimensional view of the chemical complex structure of Bisphenol P H (B P P H) and Poly [A D P-ribose] polymerase 1 (P A R P 1) complex. Figure 5B is a three-dimensional view depicting the binding site and interactions for the following residues: T Y R 9 0 7 B, I L E 8 7 2 B, G L Y 8 6 3 B, A L A 8 9 8 B, T Y R 8 9 6 B, A L A 8 8 0 B, and T Y R 8 8 9 B. The arrows with circles depict hydrogen-bond donor features.
Figure 5.
(A) Three-dimensional view of the bisphenol PH/poly [ADP-ribose] polymerase 1 (BPPH/PARP1) complex, showing (B) the binding site and interactions predicted by LigandScout 3.1. Contact residues: TYR907B, ILE872B, GLY863B, ALA898B, TYR896B, ALA880B, and TYR889B. The black arrows with circles represent hydrogen-bond donor features. Note: ADP, adenine diphosphate.
Figure 6A is a three-dimensional view of the chemical complex structure of 4,4 prime-Bis(N-carbamoyl-4-methylbenzensulfonamide)diphenylmethane (B T U M) and Bile salt-activated lipase (C E L) complex. Figure 6B is a three-dimensional view depicting the binding site and interactions for the following residues: L E U 1 2 4 A, T H R 1 4 0 A, T Y R 1 2 3 A, T Y R 1 0 5 A, A S N 8 4 A, P H E 6 0 A, A S N 1 4 2 A, V A L 1 4 5 A, A L A 1 0 8 A, V A L 2 8 8 A, and V A L 2 8 5 A. The arrows depict hydrogen-bond acceptor features, arrows with circles show hydrogen-bond donor features, and double-sided arrows symbolize aromatic ring interactions.
Figure 6.
(A) Three-dimensional view of the 4,4′-bis(N-carbamoyl-4-methylbenzensulfonamide)diphenylmethane/bile salt-activated lipase (BTUM/CEL) complex, showing (B) the binding site and interactions predicted by LigandScout 3.1. Contact residues: LEU124A, THR140A, TYR123A, TYR105A, ASN84A, PHE60A, ASN142A, VAL145A, ALA108A, VAL288A, and VAL285A. The red arrows represent hydrogen-bond acceptor features, black arrows with circles represent hydrogen-bond donor features, and blue double-sided arrows symbolize aromatic ring interactions.
Figure 7A is a three-dimensional view of the chemical complex structure of 4,4 prime-Bis(N-carbamoyl-4-methylbenzensulfonamide)diphenylmethane (B T U M) and N A D-dependent protein deacetylase sirtuin-6 (S I R 6) complex. Figure 7B is a three-dimensional view representing the binding site and interactions for the following residues: A S N 2 4 0 A, V A L 2 5 8 A, L E U 2 4 1 A, T Y R 2 5 7 A, G L N 2 4 2 A, A L A 5 8 A, T H R 5 7 A, P H E 6 4 A, A L A 5 3 A, I L E 2 1 9 A, L E U 1 8 6 A, and T R P 1 8 8 A. The arrows depict hydrogen-bond acceptor features.
Figure 7.
(A) Three-dimensional view of the 4,4′-bis(N-carbamoyl-4-methylbenzensulfonamide)diphenylmethane/NAD-dependent protein deacetylase sirtuin-6 (BTUM/SIR6) complex, showing (B) the binding site and interactions predicted by LigandScout 3.1. Contact residues: ASN240A, VAL258A, LEU241A, TYR257A, GLN242A, ALA58A, THR57A, PHE64A, ALA53A, ILE219A, LEU186A, and TRP188A. The red arrows represent hydrogen-bond acceptor features. Note: NAD, nicotinamide adenine dinucleotide.
Figure 8A is a scatter graph of calculated docking affinity scores of bisphenol A analogs and derivatives with several proteins associated with non-communicable diseases versus their experimental half-maximal activity concentration values. The y-axis shows half-maximal activity concentrations ranging from 0 to 70 in increments of 10 across Affinity in kilocalories per mole ranging from negative 6.0 to negative 10.0 in increments of 0.5 on the x axis for R equals 0.7864, p value less than 0.0001, and n equals 55. Figure 8B and 8C are three-dimensional views of superposition of the crystallographic structures and the binding poses resultant from molecular docking of the complexes between Bisphenol B and Estrogen-related receptor gamma (Figure 8B) and Bisphenol E per Estrogen-related receptor gamma (Figure 8C).
Figure 8.
(A) Calculated docking affinity scores of bisphenol A (BPA) analogs and derivatives (BPs) with several proteins associated with noncommunicable diseases (NCDs) vs. their experimental half-maximal activity concentration (AC50) values obtained from PubChem Bioassay (Wang et al. 2017c). The proteins related to NCDs used for validation purposes were estrogen receptor alpha (ESR1), estrogen receptor beta (ESR2), peroxisome proliferator-activated receptor gamma (PPARG), peroxisome proliferator-activated receptor delta (PPARD), vitamin D3 receptor (VDR), and thyroid-stimulating hormone receptor (TSHR). Superposition of the crystallographic structures and the binding poses resultant from molecular docking of the complexes: (B) bisphenol B/estrogen-related receptor gamma (BPB/ERR3; PDB ID: 1I61) and (C) Bisphenol E/Estrogen-related receptor gamma (BPE/ERR3; PDB ID: 6I64). Crystallographic structures are presented in gray.
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