Targeting Anti-Apoptotic Bcl-2 Proteins with Triterpene-Heterocyclic Derivatives: A Combined Dual Docking and Molecular Dynamics Study
Abstract
1. Introduction
2. Results and Discussion
2.1. Molecular Docking and Candidate Selection
2.2. Single-Structure MM-GBSA on Docked Poses
2.3. Molecular Dynamics Simulation
3. Materials and Methods
3.1. Ligand Design and Compound Library Construction
3.2. Molecular Docking
3.2.1. Docking with PyRx—Vina
3.2.2. Docking with Schrödinger—Glide
3.3. Candidate Selection Criteria: Scoring and Ranking
3.4. MM-GBSA on Docked Poses
3.5. Molecular Dynamics Simulation
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Rank | GLIDE—Bcl-XL (kcal/mol) | VINA—Bcl-XL (kcal/mol) | GLIDE—Bcl-2 (kcal/mol) | VINA—Bcl-2 (kcal/mol) | GLIDE—MCL1 (kcal/mol) | VINA—Mcl-1 (kcal/mol) | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | ABT-737 | −9.45 | BT2 | −11.4 | Navitoclax | −12.49 | BTzNaf1 | −11.7 | S63845 | −11.40 | BOxNaf1 | −9.8 |
2 | BOxPhCl1 | −8.79 | BT1 | −11.3 | BOxPhCl5 | −8.22 | Navitoclax | −11.4 | BTzPhCl4 | −7.88 | BTzNaf1 | −9.1 |
3 | BTzPhCl7 | −8.72 | BOxNaf1 | −10.9 | BOxPhDMN3 | −7.97 | BOxNaf3 | −10.9 | BTzPhDMN1 | −7.56 | BT4 | −8.8 |
4 | BT5 | −8.70 | ABT-737 | −10.8 | BOxPhCl3 | −7.91 | BT2 | −10.7 | BTzNaf8 | −7.35 | BTzNaf4 | −8.8 |
5 | BOxPhCl8 | −8.56 | BOxNaf2 | −10.7 | BOxPh6 | −7.89 | BOxNaf1 | −10.6 | BTzNaf7 | −7.35 | S63845 | −8.8 |
6 | BOxPhCl4 | −8.48 | BOxNaf3 | −10.7 | BOx9 | −7.79 | BT1 | −10.5 | BTzNaf9 | −7.15 | BOxPhCl1 | −8.8 |
7 | BTz9 | −8.48 | BOxPhCl1 | −10.7 | BTzPhCl5 | −7.76 | BtzPh1 | −10.3 | BOxPhCl7 | −7.13 | BtzPhCl3 | −8.7 |
8 | BOxNaf5 | −8.46 | BtzPhCl1 | −10.4 | BTzPhCl8 | −7.63 | BtzPh2 | −10.3 | BOxPhCl3 | −7.12 | BtzPhOMe1 | −8.6 |
9 | BOxPhOMe1 | −8.17 | BOxPh1 | −10.4 | BTz5 | −7.60 | BOxNaf4 | −10.3 | BTzNaf2 | −7.05 | BOxNaf3 | −8.6 |
10 | BTzNaf7 | −7.98 | BT3 | −10.3 | BOxPh3 | −7.57 | BTzNaf3 | −10.2 | BOxNaf6 | −7.03 | BOxPh2 | −8.6 |
11 | BOxNaf1 | −7.94 | BOxPhCl4 | −10.3 | BTz7 | −7.56 | BOxNaf2 | −10.2 | BTzPhCl5 | −7.02 | BtzPh2 | −8.5 |
12 | BOxPhDMN7 | −7.92 | BtzPh2 | −10.2 | BOxPh2 | −7.51 | BOxPh1 | −10.2 | BTzNaf5 | −7.02 | BT2 | −8.4 |
13 | BT1 | −7.89 | BtzPhDMN1 | −10.2 | BOxNaf3 | −7.32 | BOxPh2 | −10.2 | BOxPhOMe9 | −7.00 | BTzNaf2 | −8.4 |
14 | BTzPhCl3 | −7.87 | BT5 | −10.1 | BOxPhCl7 | −7.31 | BOxPhCl1 | −10.2 | BOxPh4 | −6.96 | BtzPhOMe4 | −8.4 |
15 | BOxNaf4 | −7.81 | BtzPhOMe1 | −10.1 | BT6 | −7.30 | BT3 | −10.1 | BOxPh5 | −6.94 | BT3 | −8.3 |
16 | BOxPh6 | −7.78 | BOxPhCl2 | −10.1 | BT5 | −7.23 | BT4 | −10 | BTzPhCl3 | −6.90 | BTzNaf6 | −8.3 |
17 | BTzPhOMe7 | −7.78 | BOxNaf4 | −10 | BTz4 | −6.96 | BTzNaf2 | −10 | BOxNaf7 | −6.79 | BtzPh1 | −8.3 |
18 | BTz7 | −7.77 | BOxNaf5 | −9.9 | BTz3 | −6.95 | BtzPhCl1 | −10 | BOxPhCl6 | −6.76 | BtzPhCl4 | −8.3 |
19 | BT3 | −7.73 | BT8 | −9.8 | BTzPh9 | −6.93 | BOxPhCl2 | −9.8 | BTzPhOMe4 | −6.76 | BOxNaf2 | −8.3 |
20 | BOxNaf3 | −7.71 | BtzPhCl2 | −9.8 | BOxPhOMe2 | −6.89 | BOxPhOMe1 | −9.8 | BTzNaf3 | −6.74 | BT1 | −8.2 |
Target | Ligand | G_Bind (kcal/mol) | vdW | Coulomb | Lipo | Solv_GB | Ligand Strain | Receptor Strain | Ligand Efficiency |
---|---|---|---|---|---|---|---|---|---|
Bcl-2 (4LVT) | BOxNaf1 | −73.02 | −60.21 | −19.98 | −29.93 | 39.12 | 9.61 | 14.66 | −1.04 |
Bcl-2 (4LVT) | BOxPhCl1 | −64.58 | −49.68 | −39.74 | −28.82 | 49.66 | 8.77 | 25.50 | −1.01 |
Bcl-2 (4LVT) | BOxNaf3 | −62.48 | −50.12 | −45.20 | −20.18 | 52.52 | 14.59 | 17.31 | −0.84 |
Bcl-2 (4LVT) | BT3 | −52.28 | −54.52 | −0.88 | −19.01 | 27.81 | 8.84 | 23.23 | −0.84 |
Bcl-2 (4LVT) | BT1 | −40.52 | −46.05 | −1.89 | −16.80 | 30.93 | 14.03 | 19.06 | −0.69 |
Bcl-xL (2YXJ) | BOxNaf3 | −102.26 | −87.38 | 13.60 | −41.26 | 25.50 | 6.19 | 30.22 | −1.38 |
Bcl-xL (2YXJ) | BOxNaf1 | −100.10 | −83.97 | 1.75 | −40.52 | 17.35 | 15.35 | 24.24 | −1.43 |
Bcl-xL (2YXJ) | BOxPhCl1 | −85.45 | −67.68 | 4.76 | −30.86 | 5.27 | 5.10 | 15.88 | −1.33 |
Bcl-xL (2YXJ) | BT1 | −71.00 | −68.80 | 6.23 | −24.51 | 11.65 | 4.82 | 15.22 | −1.22 |
Bcl-xL (2YXJ) | BT3 | −66.73 | −61.75 | 8.47 | −20.98 | −0.08 | 13.01 | 8.17 | −1.07 |
Mcl-1 (5LOF) | BOxPhCl1 | −85.94 | −69.04 | −2.14 | −40.39 | 10.26 | 9.84 | 2.41 | −1.34 |
Mcl-1 (5LOF) | BOxNaf1 | −74.58 | −73.31 | −20.37 | −31.13 | 27.60 | 11.30 | 10.58 | −1.06 |
Mcl-1 (5LOF) | BOxNaf3 | −72.75 | −47.65 | −53.88 | −23.40 | 48.51 | 26.30 | 13.73 | −0.98 |
Mcl-1 (5LOF) | BT3 | −70.58 | −64.25 | −4.39 | −29.89 | 9.26 | 4.47 | 11.47 | −1.13 |
Mcl-1 (5LOF) | BT1 | −67.39 | −58.37 | −18.76 | −28.41 | 32.45 | 8.61 | 22.15 | −1.16 |
Ligand | Protein RMSD (Å) | Ligand RMSD (Å) | H-Bonds (≥0.1 frac) | Hydrophobic Contacts (≥0.1 frac) | Water Bridges (≥0.1 frac) |
---|---|---|---|---|---|
BoxNaf1 | 0.8–2.0 (stable, minor drift) | 3.0–5.5 (stable) | Asn140 (0.2–0.3), Gly142 (0.2–0.3), Arg143 (0.1–0.2) | ~9 residues | ~5 residues |
BoxNaf3 | 1.2–1.8 (stable, slight drift) | 4.5–10.5 (fluctuates) | Asn140 (0.1–0.15), Gly142 (0.1–0.15) | ~8 residues | ~4 residues |
BoxPhCl1 | 1.0–1.7 (stable) | 3.5–8.0 (fluctuates) | Asn140 (0.1–0.15), Gly142 (~0.1) | ~7 residues | ~3 residues |
BT1 | 1.0–1.8 (stable, post 20 ns drift) | 4.0–6.5 (post 20 ns drift, fluctuates) | Asn140 (0.2–0.3), Gly142 (0.1–0.2), Arg143 (0.1–0.2) | ~10 residues | ~6 residues |
BT3 | 1.0–2.0 (stable after equilibration) | 2.5–5.5 (mild fluctuation) | Asn140 (0.1–0.2), Gly142 (0.1–0.2) | ~8 residues | ~4 residues |
Ligand | Protein RMSD (Å) | Ligand RMSD (Å) | H-Bonds (≥0.1 frac) | Hydrophobic Contacts (≥0.1 frac) | Water Bridges (≥0.1 frac) |
---|---|---|---|---|---|
BOxNaf1 | ~1.0–1.3 (stable) | ~3.0–5 (stable after 20 ns: 4.2–5) | Arg100 (0.1–0.1) | ~11 residues | ~4 residues |
BOxNaf3 | ~0.9–1.3 (stable) | ~3.2–5.5 (fluctuates) | Gln111 (0.1–0.2), Asn136 (0.2–0.3), Trp137 (0.3–0.4), Gly138 (0.3–0.4) | ~8 residues | ~6 residues |
BOxPhCl1 | ~1.0–2.1 (late upward drift) | ~2–6.5 (highly fluctuates) | His113 (0.3–0.4) | ~10 residues | ~3 residues |
BT1 | ~1.0–1.8 (stable) | ~3.4–5.0 (fluctuates; stabilizes after 20 ns) | Arg100 (0.2–0.3), Gln125 (0.1–0.2) | ~8 residues | ~4 residues |
BT3 | ~1.1–1.6 (stable) | ~2.0–4.0 (fluctuates) | Gly138 (0.7–0.8) | ~6 residues | ~3 residues |
Ligand | Protein RMSD (Å) | Ligand RMSD (Å) | H-Bonds (≥0.1 frac) | Hydrophobic Contacts (≥0.1 frac) | Water Bridges (≥0.1 frac) |
---|---|---|---|---|---|
BOxNaf1 | ~1.5–3.5 (stable) | ~7.5–10.5 (fluctuates) | - | ~7 residues | ~1 residue |
BOxNaf3 | ~2.5–4.5 (stable) | ~7.5–10.5 (fluctuates) | Arg263 (0.1–0.2) | ~8 residues | ~3 residues |
BOxPhCl1 | ~2.0–4.0 (minor fluct.) | ~3.0–9.0 (highly fluctuates) | Arg233 (0.1–0.2), Arg263 (0.2–0.3) | ~4 residues | ~6 residues |
BT1 | ~2.5–3.5 (stable) | ~5.5–8.0 (moderately fluctuates) | Thr226 (0.2–0.3), Arg263 (~0.1) | ~6 residues | ~4 residues |
BT3 | ~2.0–7.5 (highly fluctuates) | ~6.0–9.5 (highly fluctuates) | - | ~9 residues | ~4 residues |
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Mioc, M.; Gruin, S.; Gogulescu, A.; Bătrîna, O.; Jorgovan, M.; Mara, B.-I.; Șoica, C. Targeting Anti-Apoptotic Bcl-2 Proteins with Triterpene-Heterocyclic Derivatives: A Combined Dual Docking and Molecular Dynamics Study. Molecules 2025, 30, 3919. https://doi.org/10.3390/molecules30193919
Mioc M, Gruin S, Gogulescu A, Bătrîna O, Jorgovan M, Mara B-I, Șoica C. Targeting Anti-Apoptotic Bcl-2 Proteins with Triterpene-Heterocyclic Derivatives: A Combined Dual Docking and Molecular Dynamics Study. Molecules. 2025; 30(19):3919. https://doi.org/10.3390/molecules30193919
Chicago/Turabian StyleMioc, Marius, Silvia Gruin, Armand Gogulescu, Oana Bătrîna, Mihaela Jorgovan, Bogdan-Ionuț Mara, and Codruța Șoica. 2025. "Targeting Anti-Apoptotic Bcl-2 Proteins with Triterpene-Heterocyclic Derivatives: A Combined Dual Docking and Molecular Dynamics Study" Molecules 30, no. 19: 3919. https://doi.org/10.3390/molecules30193919
APA StyleMioc, M., Gruin, S., Gogulescu, A., Bătrîna, O., Jorgovan, M., Mara, B.-I., & Șoica, C. (2025). Targeting Anti-Apoptotic Bcl-2 Proteins with Triterpene-Heterocyclic Derivatives: A Combined Dual Docking and Molecular Dynamics Study. Molecules, 30(19), 3919. https://doi.org/10.3390/molecules30193919