Probing the Binding Pathway of BRACO19 to a Parallel-Stranded Human Telomeric G-Quadruplex Using Molecular Dynamics Binding Simulation with AMBER DNA OL15 and Ligand GAFF2 Force Fields

Machireddy, Babitha; Kalra, Gurmannat; Jonnalagadda, Subash C.; Ramanujachary, Kandalam V.; Wu, Chun

doi:10.1021/acs.jcim.7b00287

Cited by 45 publications

(38 citation statements)

References 76 publications

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“… 112 Systematic benchmarking studies up to 1864 crystal complexes have shown that relative MM-GBSA binding energy is a powerful tool to rank ligand binding affinity. 113 − 117 This is also supported by our previous studies, in which the binding energy of between anticancer drug doxorubicin and a B-DNA fragment (d(CGATCG)2), 98 between anticancer drug daunomycin and a TGGGT G-quadruplex DNA, 118 between RHPS4 and human telomeric G-quadruplexes/duplex, 110 between telomestatin and a hybrid telomeric G-quadruplex, 45 and between BRACO19 and a parallel-stranded telomeric G-quadruplex 119 were successfully assessed by this MM-GBSA protocol.…”

Section: Methodssupporting

confidence: 81%

Binding of Telomestatin, TMPyP4, BSU6037, and BRACO19 to a Telomeric G-Quadruplex–Duplex Hybrid Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent

et al. 2018

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A promising anticancer therapeutic strategy is the stabilization of telomeric G-quadruplexes using G-quadruplex-binding small molecules. Although many G-quadruplex-specific ligands have been developed, their low potency and selectivity to G-quadruplexes over duplex remains unsolved. Recently, a crystal structure of a telomeric 3′ quadruplex–duplex hybrid was reported and the quadruplex–duplex interface was suggested to a good target to address the issues. However, there are no high-resolution complex structures reported for G-quadruplex ligands except for a docked BSU6037. In this study, molecular dynamic (MD) binding simulations with a free ligand were used to study binding poses and dynamics of four representative ligands: telomestatin, TMPyP4, BSU6037, and BRACO19. The MD data showed that BSU6037 was able to fully intercalate into the interface whereas TMPyP4 and BRACO19 could only maintain partial intercalation into the interface and telomestatin only binds at the quadruplex and duplex ends. Both linear ligands, BSU6037 and BRACO19, were able to interact with the interface, yet they were not selective over duplex DNA. The DNA geometry, binding modes, and binding pathways were systematically characterized, and the binding energy was calculated and compared for each system. The interaction of the ligands to the interface was by the means of an induced-fit binding mechanism rather than a lock–key mechanism, consisting of the DNA unfolding at the interface to allow entrance of the drug and then the refolding and repacking of the DNA and the ligand to further stabilize the G-quadruplex. On the basis of the findings in this study, modifications were suggested to optimize the interface binding for TMPyp4 and telomestatin.

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Section: Methodssupporting

confidence: 81%

Binding of Telomestatin, TMPyP4, BSU6037, and BRACO19 to a Telomeric G-Quadruplex–Duplex Hybrid Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent

et al. 2018

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“…BRACO-19 was optimized from disubstituted acridine derivative, and was first reported as a telomerase inhibitor with an IC 50 value of 115 nM [151]. BRACO-19 can bind to the telomeric G-quadruplex via three binding modes, top stacking, bottom intercalation, and groove binding [171]. The mechanism and anti-tumor activity of BRACO-19 are well studied.…”

Section: G-quadruplex Interacting Compoundsmentioning

confidence: 99%

Developing Novel G-Quadruplex Ligands: From Interaction with Nucleic Acids to Interfering with Nucleic Acid–Protein Interaction

et al. 2019

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G-quadruplex is a special secondary structure of nucleic acids in guanine-rich sequences of genome. G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, and transcription and translation of oncogenes or other cancer-related genes. Therefore, targeting G-quadruplexes has become a novel promising anti-tumor strategy. Different kinds of small molecules targeting the G-quadruplexes have been designed, synthesized, and identified as potential anti-tumor agents, including molecules directly bind to the G-quadruplex and molecules interfering with the binding between the G-quadruplex structures and related binding proteins. This review will explore the feasibility of G-quadruplex ligands acting as anti-tumor drugs, from basis to application. Meanwhile, since helicase is the most well-defined G-quadruplex-related protein, the most extensive research on the relationship between helicase and G-quadruplexes, and its meaning in drug design, is emphasized.

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“…The previously validated FF99SB force field with parmbsc1 and χ OL3+OL15 modifications was applied for G4s. 27,32 The standard Amber parameter (radius 2.658 Å and well depth 0.00328 kJ/mol) and the calibrated parameter (radius 1.705 Å and well depth 0.1936829 kJ/mol) were used for the environmental K + and the ones located between G-tetrad layers, respectively. 24,33 The simulations were conducted by following the same procedure in our previous report.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Retracted: Molecular insight into the selective binding between human telomere G‐quadruplex and a negatively charged stabilizer

Wang

et al. 2020

Clin Exp Pharma Physio

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The single‐strand human telomere overhang forms intramolecular high‐order structures named G‐quadruplex (G4) under physiological conditions. Telomere G4 stabilization prevents telomere lengthening by telomerase in cancer cells representing a promising strategy in cancer therapy. Using molecular docking and molecular dynamics (MD) simulations, specific binding of the anionic phthalocyanine 3,4ʹ,4ʹʹ,4ʹʹʹ‐tetrasulfonic acid (APC) to the human hybrid (3 + 1) G4s was investigated at the atomic level. We found that APC preferred the end‐stacking binding with the telomere hybrid type II (hybrid‐II) G4 as compared to the groove binding with the hybrid type I (hybrid‐I) G4 remarkable stabilizing effect and more favourable binding free energies. Analysis of non‐covalent interaction and decomposition of the binding free energy revealed that van der Waals interaction played a leading role in the binding of APC and telomere hybrid G4s. These findings provide evidence for the first time to shed light on the designs of selective telomere G4 stabilizers.

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Probing the Binding Pathway of BRACO19 to a Parallel-Stranded Human Telomeric G-Quadruplex Using Molecular Dynamics Binding Simulation with AMBER DNA OL15 and Ligand GAFF2 Force Fields

Cited by 45 publications

References 76 publications

Binding of Telomestatin, TMPyP4, BSU6037, and BRACO19 to a Telomeric G-Quadruplex–Duplex Hybrid Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent

Binding of Telomestatin, TMPyP4, BSU6037, and BRACO19 to a Telomeric G-Quadruplex–Duplex Hybrid Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent

Developing Novel G-Quadruplex Ligands: From Interaction with Nucleic Acids to Interfering with Nucleic Acid–Protein Interaction

Retracted: Molecular insight into the selective binding between human telomere G‐quadruplex and a negatively charged stabilizer

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