The Use of Methods of Computer-Aided Drug Discovery in the Development of Topoisomerase II Inhibitors: Applications and Future Directions

Radaeva, Mariia; Dong, Xuesen; Cherkasov, Artem

doi:10.1021/acs.jcim.0c00325

Cited by 16 publications

(6 citation statements)

References 217 publications

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“…TOPO I drugs or inhibitors are primarily employed in colorectal and ovarian cancer treatments [19]. Examples of topoisomerase I inhibitors include camptothecin derivatives, particularly camptothecin 9, topotecan 10, irinotecan 11, and belotecan 12, which are accepted by the U.S. Food and Drug Administration (FDA) for colon, lung, and ovarian cancer treatments, however, these drugs have certain limitations [20,21]. They can undergo spontaneous inactivation in the blood, requiring longer infusion times due to rapid drug reversal, and some cancer cells with increased membrane transporters may develop resistance to these drugs [11,13].…”

Section: Topoisomerase I Mechanism Of Actionmentioning

confidence: 99%

Prospects of Topoisomerase Inhibitors as Promising Anti-Cancer Agents

Yakkala,

Penumallu,

Shafi

et al. 2023

Pharmaceuticals

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Topoisomerases are very important enzymes that regulate DNA topology and are vital for biological actions like DNA replication, transcription, and repair. The emergence and spread of cancer has been intimately associated with topoisomerase dysregulation. Topoisomerase inhibitors have consequently become potential anti-cancer medications because of their ability to obstruct the normal function of these enzymes, which leads to DNA damage and subsequently causes cell death. This review emphasizes the importance of topoisomerase inhibitors as marketed, clinical and preclinical anti-cancer medications. In the present review, various types of topoisomerase inhibitors and their mechanisms of action have been discussed. Topoisomerase I inhibitors, which include irinotecan and topotecan, are agents that interact with the DNA-topoisomerase I complex and avert resealing of the DNA. The accretion of DNA breaks leads to the inhibition of DNA replication and cell death. On the other hand, topoisomerase II inhibitors like etoposide and teniposide, function by cleaving the DNA-topoisomerase II complex thereby effectively impeding the release of double-strand DNA breaks. Moreover, the recent advances in exploring the therapeutic efficacy, toxicity, and MDR (multidrug resistance) issues of new topoisomerase inhibitors have been reviewed in the present review.

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Section: Topoisomerase I Mechanism Of Actionmentioning

confidence: 99%

Prospects of Topoisomerase Inhibitors as Promising Anti-Cancer Agents

Yakkala,

Penumallu,

Shafi

et al. 2023

Pharmaceuticals

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“…Despite its high impact, yet, finding new materials has traditionally been slow, labor-intensive, and frequently based on serendipity . Computer-aided materials design (CAMD) has emerged in recent decades, facilitated by the rapid development of computing power. − It aims to accelerate materials discovery by screening a large number of virtual materials via computation. However, this also poses a challenge in dealing with a vast chemical space in terms of both accuracy and efficiency since only a limited number of candidates can undergo experimental validation.…”

Section: Introductionmentioning

confidence: 99%

Deep Learning-Based Chemical Similarity for Accelerated Organic Light-Emitting Diode Materials Discovery

Kim,

Lee,

Kim

et al. 2024

J. Chem. Inf. Model.

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Thermally activated delayed fluorescence (TADF) material has attracted great attention as a promising metal-free organic light-emitting diode material with a high theoretical efficiency. To accelerate the discovery of novel TADF materials, computer-aided material design strategies have been developed. However, they have clear limitations due to the accessibility of only a few computationally tractable properties. Here, we propose TADF-likeness, a quantitative score to evaluate the TADF potential of molecules based on a data-driven concept of chemical similarity to existing TADF molecules. We used a deep autoencoder to characterize the common features of existing TADF molecules with common chemical descriptors. The score was highly correlated with the four essential electronic properties of TADF molecules and had a high success rate in large-scale virtual screening of millions of molecules to identify promising candidates at almost no cost, validating its feasibility for accelerating TADF discovery. The concept of TADF-likeness can be extended to other fields of materials discovery.

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“…The first class of inhibitors is Topo II poisons that target the enzyme through DNA cleavage, including DNA intercalators such as doxorubicin and etoposide. The other class of Topoisomerase II inhibitors is non-competitive inhibitors of ATP, such as merbarone ( II ) and dexrazoxane ( III ) 8 , 9 ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors

El‐Kalyoubi

El‐Sebaey

Rashad

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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Novel series of aminopyrimidines bearing a biologically active cyclohexenone 3a–f and oxo-selaneylidene moiety 4 , besides selenadiazolopyrimidines ( 5a–e and 7 ), were synthesised using 5,6-diaminouracils as starting materials. Compound 3a exhibited strong anti-proliferative activity against three cell lines: HepG-2 (IC 50 14.31 ± 0.83 µM), A-549 (IC 50 30.74 ± 0.76 µM), and MCF-7 (IC 50 27.14 ± 1.91 µM). Also, it was four times more selectively cytotoxic against WI-38 cell lines than doxorubicin. Furthermore, Topoisomerase II (IC 50 4.48 ± 0.65 µM) and HSP90 (IC 50 1.78 ± 0.11 µM) were both strongly inhibited in vitro by 3a . The cell cycle was halted at the G1-S phase, and total apoptotic cells were 65 times more than control Hep-G2 cells. Besides, it increased caspase-3 gene expression, triggering mitochondrial cell death. Molecular docking study indicated that it could bind to Topoisomerase II and HSP90 binding sites in an inhibitory mode. Its geometric properties were investigated using the density functional theory (DFT). Furthermore, compound 3a demonstrated in silico good oral bioavailability.

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The Use of Methods of Computer-Aided Drug Discovery in the Development of Topoisomerase II Inhibitors: Applications and Future Directions

Cited by 16 publications

References 217 publications

Prospects of Topoisomerase Inhibitors as Promising Anti-Cancer Agents

Prospects of Topoisomerase Inhibitors as Promising Anti-Cancer Agents

Deep Learning-Based Chemical Similarity for Accelerated Organic Light-Emitting Diode Materials Discovery

Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors

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