Smoothed Potential MD Simulations for Dissociation Kinetics of Etoposide To Unravel Isoform Specificity in Targeting Human Topoisomerase II

Kuriappan, Jissy Akkarapattiakal; Osheroff, Neil; Vivo, Marco De

doi:10.1021/acs.jcim.9b00605

Cited by 8 publications

(8 citation statements)

References 91 publications

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“…The method was used to predict relative residence times for 4 78-kDa glucose-regulated protein binders (correlation coefficient, R, of 0.85) [262], 4 adenosine A2A receptor binders (R of 0.95) [262], 7 glucokinase activators (R of 0.92 after removal of one outlier) [263], and 7 HSP90 inhibitors (coefficient of determination, R 2 , of 0.89 after removal of one outlier) [264]. Scaled MD was also used to understand why the residence time of the drug etoposide is longer for the human type II topoisomerase (TopoII) α, compared to TopoIIβ [265].…”

Section: Drug-protein Binding Kinetics Estimationmentioning

confidence: 99%

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

et al. 2020

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Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of how MD studies can give important insights into the dynamics and function of identified drug targets such as sirtuins, RAS proteins, or intrinsically disordered proteins. The role of MD in antibody design is also reviewed. In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate molecules for further development. The importance of considering the biological lipid bilayer environment in the MD simulations of membrane proteins is also discussed, using G-protein coupled receptors and ion channels as well as the drug-metabolizing cytochrome P450 enzymes as relevant examples. Lastly, we discuss the emerging role of MD simulations in facilitating the pharmaceutical formulation development of drugs and candidate drugs. Specifically, we look at how MD can be used in studying the crystalline and amorphous solids, the stability of amorphous drug or drug-polymer formulations, and drug solubility. Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple recent studies as examples. In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies.

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Section: Drug-protein Binding Kinetics Estimationmentioning

confidence: 99%

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

et al. 2020

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“…We used docking and atomistic force-field-based molecular dynamics (MD) simulations to model 3f bound to the topoII/DNA cleavage site. − First, the crystal structure of the topoIIα isoform (PDB code 5GWK) was used for the docking studies. , As seen in Figure S2, when the compound was first docked into the cleavage site, the mimic E-ring slightly shifted relative to the position of the E-ring of etoposide in the crystal . Our calculations revealed several key contacts between the ligand and vicinal residues that confer the system a stable, inhibited conformation, thus endorsing the compound’s action as a topoII poison.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, Dynamic Docking, Biochemical Characterization, and in Vivo Pharmacokinetics Studies of Novel Topoisomerase II Poisons with Promising Antiproliferative Activity

et al. 2020

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We previously reported a first set of hybrid topoisomerase II (topoII) poisons whose chemical core merges key pharmacophoric elements of etoposide and merbarone, which are two well-known topoII blockers. Here, we report on the expansion of this hybrid molecular scaffold and present 16 more hybrid derivatives that have been designed, synthesized, and characterized for their ability to block topoII and for their overall drug-like profile. Some of these compounds act as topoII poison and exhibit good solubility, metabolic (microsomal) stability, and promising cytotoxicity in three cancer cell lines (DU145, HeLa, A549). Compound 3f (ARN24139) is the most promising drug-like candidate, with a good pharmacokinetics profile in vivo . Our results indicate that this hybrid new chemical class of topoII poisons deserves further exploration and that 3f is a favorable lead candidate as a topoII poison, meriting future studies to test its efficacy in in vivo tumor models.

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“…Etoposide is another chemotherapy approved for use in treating NSCLC but commonly presents with serious side-effects. This compound forms a bond with both the DNA and topoisomerase II enzyme complex, preventing re-ligation of the DNA and causing apoptosis-inducing breakage in a similar fashion to the mechanism of camptothecin-derived chemotherapies 45 , 53 . Resistance generally comes in two forms: either by acquired activation of cell survival factors or by efflux pumps.…”

Section: Topoisomerase Inhibitorsmentioning

confidence: 99%

Personalized medicine of non-gene-specific chemotherapies for non-small cell lung cancer

Jiang

Cai

et al. 2021

Acta Pharmaceutica Sinica B

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Non-small cell lung cancer is recognized as the deadliest cancer across the globe. In some areas, it is more common in women than even breast and cervical cancer. Its rise, vaulted by smoking habits and increasing air pollution, has garnered much attention and resource in the medical field. The first lung cancer treatments were developed more than half a century ago. Unfortunately, many of the earlier chemotherapies often did more harm than good, especially when they were used to treat genetically unsuitable patients. With the introduction of personalized medicine, physicians are increasingly aware of when, how, and in whom, to use certain anti-cancer agents. Drugs such as tyrosine kinase inhibitors, anaplastic lymphoma kinase inhibitors, and monoclonal antibodies possess limited utility because they target specific oncogenic mutations, but other drugs that target mechanisms universal to all cancers do not. In this review, we discuss many of these non-oncogene-targeting anti-cancer agents including DNA replication inhibitors ( i . e ., alkylating agents and topoisomerase inhibitors) and cytoskeletal function inhibitors to highlight their application in the setting of personalized medicine as well as their limitations and resistance factors.

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Smoothed Potential MD Simulations for Dissociation Kinetics of Etoposide To Unravel Isoform Specificity in Targeting Human Topoisomerase II

Cited by 8 publications

References 91 publications

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

Design, Synthesis, Dynamic Docking, Biochemical Characterization, and in Vivo Pharmacokinetics Studies of Novel Topoisomerase II Poisons with Promising Antiproliferative Activity

Personalized medicine of non-gene-specific chemotherapies for non-small cell lung cancer

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