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Several reviews of inhibitors of topoisomerase II have been published, covering research before 2018. Therefore, this review is focused primarily on more recent publications with relevant points from the earlier literature. Topoisomerase II is an established target for anticancer drugs, which are further subdivided into poisons and catalytic inhibitors. While most of the topoisomerase II-based drugs in clinical use are mostly topoisomerase II poisons, their mechanism of action has posed severe concern due to DNA damaging potential, including the development of multi-drug resistance. As a result, we are beginning to see a gradual paradigm shift towards non-DNA damaging agents, such as the lesser studied topoisomerase II catalytic inhibitors. In addition, this review describes some novel selective catalytic topoisomerase II inhibitors. The ultimate goal is to bring researchers up to speed by curating and delineating new scaffolds as the leads for the optimization and development of new potent, safe, and selective agents for the treatment of cancer.

In this study, the interaction of selected pharmaceutical excipients on the function of P-glycoprotein (P-gp) and activity of 6 cytochrome P450 (CYP) isoforms were computationally investigated. At binding free energy cut-off value of −5.0 kcal/mol, the result showed possible modulatory or inhibitory effect by cethyl alcohol on CPY3A4 and P-gp; cetyltrimethyl-ammonium bromide (CTAB) on CYP1A2 and P-gp; dibutyl sebacate on CYP2C9, CYP2E1, and P-gp; sodium caprylate on CYP1A2 and CYP3A4; while most of the tested excipients have good interaction with the cytochromes and P-gp. The predicted pharmacokinetics provided possible inhibitors of the CYPs and P-gp and suggested that aspartame and acetyl tributyl citrate may not permeate blood–brain barrier and not act as P-gp substrates. Target prediction for CTAB showed 100% and 35% probability of target to dynamin-1 (UniProt ID: Q05193) and histamine H3 receptor (UniProt ID: Q9Y5N1), respectively, whereas tricaprylin showed 40% probability of target to 5 Protein kinase C (UniProt IDs: P17252, Q02156, Q04759, P24723, and P05129). This study shows that synergistic effect of some excipients present in a drug formulation and multiple drugs administration is possible through modulation of CYPs activities and P-gp function, and this is crucial for consideration to mitigate toxicity in pediatric and adult populations.

Amyotrophic lateral sclerosis (ALS) is regarded as a fatal neurodegenerative disease that is featured by progressive damage of the upper and lower motor neurons. To date, over 45 genes have been found to be connected with ALS pathology. The aim of this work was to computationally identify unique sets of protein hydrolysate peptides that could serve as therapeutic agents against ALS. Computational methods which include target prediction, protein-protein interaction, and peptide-protein molecular docking were used. The results showed that the network of critical ALS-associated genes consists of ATG16L2, SCFD1, VAC15, VEGFA, KEAP1, KIF5A, FIG4, TUBA4A, SIGMAR1, SETX, ANXA11, HNRNPL, NEK1, C9orf72, VCP, RPSA, ATP5B, and SOD1 together with predicted kinases such as AKT1, CDK4, DNAPK, MAPK14, and ERK2 in addition to transcription factors such as MYC, RELA, ZMIZ1, EGR1, TRIM28, and FOXA2. The identified molecular targets of the peptides that support multi-metabolic components in ALS pathogenesis include cyclooxygenase-2, angiotensin I-converting enzyme, dipeptidyl peptidase IV, X-linked inhibitor of apoptosis protein 3, and endothelin receptor ET-A. Overall, the results showed that AGL, APL, AVK, IIW, PVI, and VAY peptides are promising candidates for further study. Future work would be needed to validate the therapeutic properties of these hydrolysate peptides by in vitro and in vivo approaches.

The global demand for herbal cosmetics is vastly increasing due to their health benefits and relative safety. Glycyrrhiza spp. extracts are used in cosmetic preparations due to their skin-whitening, antisensitizing, and anti-inflammatory properties. The aim of this work is to computationally evaluate the bioactive constituents of licorice (Glycyrrhiza glabra L.) that possess antioxidant, anti-inflammatory, and dermatocosmetic activities, and elucidate the dynamics of their molecular targets. The used methods are skin permeability prediction, target prediction, molecular docking, and molecular dynamic simulation (MDS). The results show that, at a skin permeation cut-off value of −6.0 cm/s, nine phytoconstituents of licorice (furfuraldehyde, glucoliquiritin apioside, glycyrrhizin, isoliquiritin, licopyranocoumarin, licuraside, liquiritigenin, liquiritin, and liquiritin apioside) were workable. Molecular target prediction results indicate probability for tyrosinase, 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1), monoamine oxidase B, steroid 5-alpha-reductase 1, and cyclo-oxygenase-1. On the basis of molecular docking, glucoliquiritin apioside and glycyrrhizin had the best antioxidant, anti-inflammation, and dermatocosmetic activities. MDS results show that the complexes had good stability, and MMGBSA results indicate that the complexes had satisfactory binding energy. Overall, this study demonstrates that licorice extracts are potential antioxidants that could enhance histological dermal and epidermal properties, and reduce the level of inflammatory and wrinkling markers.

Prostate cancer (PCa) is a complex and biologically diverse disease with no curative treatment options at present. This study aims to utilize computational methods to explore potential anti-PCa compounds based on differentially expressed genes (DEGs), with the goal of identifying novel therapeutic indications or repurposing existing drugs. The methods employed in this study include DEGs-to-drug prediction, pharmacokinetics prediction, target prediction, network analysis, and molecular docking. The findings revealed a total of 79 upregulated DEGs and 110 downregulated DEGs in PCa, which were used to identify drug compounds capable of reversing the dysregulated conditions (dexverapamil, emetine, parthenolide, dobutamine, terfenadine, pimozide, mefloquine, ellipticine, and trifluoperazine) at a threshold probability of 20% on several molecular targets, such as serotonin receptors 2a/2b/2c, HERG protein, adrenergic receptors alpha-1a/2a, dopamine D3 receptor, inducible nitric oxide synthase (iNOS), epidermal growth factor receptor erbB1 (EGFR), tyrosine-protein kinases, and C-C chemokine receptor type 5 (CCR5). Molecular docking analysis revealed that terfenadine binding to inducible nitric oxide synthase (-7.833 kcal.mol −1 ) and pimozide binding to HERG (-7.636 kcal.mol −1 ). Overall, binding energy ΔG bind (Total) at 0 ns was lower than that of 100 ns for both the Terfenadine-iNOS complex (-101.707 to -103.302 kcal.mol −1 ) and Ellipticine-TOPIIα complex (-42.229 to -58.780 kcal.mol −1 ). In conclusion, this study provides insight on molecular targets that could possibly contribute to the molecular mechanisms underlying PCa. Further preclinical and clinical studies are required to validate the therapeutic effectiveness of these identified drugs in PCa disease.

Introduction Oritavancin is a semi-synthetic lipoglycopeptide antibiotic primarily used to treat serious infections caused by Gram-positive bacteria. The aim of this study was to elucidate possible molecular targets of oritavancin in human and microbes in relevance to its mechanism of action and model its pharmacokinetics for optimal dose selection in clinical practice. Methods Computational methods were used in this study which include target prediction, molecular docking, molecular dynamics simulation, pharmacokinetics prediction, and physiological-based pharmacokinetics (PBPK) modeling. Results Oritavancin was moderately soluble in water and did not permeate the blood-brain barrier. Seven molecular targets were identified in humans. Molecular docking results showed highest binding affinity of oritavancin with PI3-kinase p110-gamma subunit (−10.34 kcal/mol), followed by Acyl-CoA desaturase (−10.07 kcal/mol) and Cytochrome P450 2C19 (−8.384 kcal/mol). Oritavancin PBPK modelling in adult human showed that infusion has lower peak concentrations (Cmax) compared to bolus administration, with 1200 mg dose yielded Cmax of 16.559 mg/L, 800 mg dose yielded Cmax of 11.258 mg/L, and 200 mg over 3 days dose yielded Cmax of 7.526 mg/L. Notably, infusion gave extended half-life (t 1/2 ) for all doses and slightly higher clearance rates compared to bolus, particularly for the 1200 mg and 800 mg doses. The results corroborated existing clinical pharmacokinetic data, and confirmed the model’s accuracy and predictive capability. Conclusion This comprehensive computational study has provided invaluable insights into the pharmacological profile of Oritavancin, aiding its further development and optimization for clinical use.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a microorganism that causes coronavirus disease 2019 (COVID-19). Mutations affect evolutionary conservation of microorganisms. The fast pace evolutionary changes are currently affecting pathogenicity of SARS-CoV-2. In this study, the structural fluctuations of the amino acid residues in the spike glycoprotein and RNA-dependent RNA polymerase (nsp12) of SARS-CoV-2 were investigated by in silico approach using structural flexibility dynamics to decipher susceptibility to mutation. The result of this study implicated key amino acid residues (with rmsf) which could be very susceptible to mutation, which include residues 50 (3.79 Å), 119 (4.56 Å), 120 (3.53 Å), 220 (3.84 Å), 265 (4.31 Å) of RNA-dependent RNA polymerase (nsp12), as well as residues 477 (4.21 Å), 478 (4.82 Å), 479 (5.40 Å), 481 (5.94 Å), 560 (4.63 Å), 704 (4.02 Å), 848 (4.58 Å), 1144 (4.56 Å) and 1147 (4.61 Å) of spike glycoprotein. The SARS-CoV-2 mutations destabilized the overall protein structure in multiples of amino acid residues which could interfere with active site leading to insensitivity or resistance to the inhibitors. Mutation T478K of Spike glycoprotein showed the highest deviation in the structure. Overall, spike glycoprotein has the highest number of mutations, and these variants could increase the risk to human health if not mitigated in the population.

Morinda citrifolia (Noni) fruit has a long history of dietary use in tropical regions of the world. Pharmacological properties that have been attributed to the fruit include anti-inflammatory, anti-cancer, and antioxidant properties. Xeronine, a small alkaloid which has been patented (US4543212) is one of the bioactive compounds of Noni fruit, which is believed to be capable of modifying the molecular structure of specific inactive proteins thereby regulating proper folding to active enzymes. Despite reports of the potential of Xeronine as therapeutic agent, its presence is controversial and its structure has not been explored. In this study, standard chemoinformatics tools and servers such as ChemSketch, ChemMine, Swisstargetprediction, SwissADME and Swisssimilarity have been employed to predict its possible structure. In addition, synthetic xeronine structures based on the known bioactive components of Noni fruit were designed. Results showed that the hypothetical structure of xeronine provided by the patent inventor is a mystery based on its <5% probable protein targets and no similarity match to the US Food and Drug Administration (FDA) approved drugs and experimental compounds by in silico evaluation. By constrast, final designed xeronine structure possess all the features that were described in the patent document, and has >40% probable protein targets related to neurodegenerative diseases such as Alzheimer’s disease (AD), which possibly justifies the key function stated in the patent.

This study aimed to discover chemiluminescent analogues of luminol, understand their molecular binding to hemoglobin of bloodstains in the household crime, and the mechanism of chemiluminescence. Similarity and clustering analyses of luminol analogues were conducted, and molecular docking was carried out on hemoglobin from Homo sapiens and other four domestic organism namely Gallus gallus, Drosophila melanogaster, Rattus norvegicus, and Canis familiaris. The results show that the order of overall binding score is D. melanogaster > H. sapiens > C. familiaris > R. norvegicus > G. gallus. Seven compounds namely ZINC16958228, ZINC17023010, ZINC19915427, ZINC34928954, ZINC19915369, ZINC19915444, and ZINC82294978, were found to be consistently stable in binding to diverse hemoglobin and possibly have chemiluminescence than luminol. The amino acid residues involved in the interaction of human hemoglobin with the 30 test compounds, show that His45, Lys61, Asn68, Val73, Met76, Pro77, Ala79, Ala82, Leu83, Pro95, Phe98, Lys99, Ser102, Ser133, Ala134, and Thr134 are significant in the mechanism of action of presumptive test compounds. The improved mechanism of chemiluminescent identification of blood hypothesized that nitrite interact with the Fe(II) heme, with the cleavage of a hydroxide ion and the formation of the nitrosonium cation in peroxidase reaction. It was proposed that degradation of rhombic heme complex to fluorescent products is possibly inhibited by nitric oxide from the test compound luminol. This study provides novel insight on the luminol and its actual mechanism for broader possible applications of luminol with careful development of new methodologies.