Current Issue : October - December Volume : 2019 Issue Number : 4 Articles : 5 Articles
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Cisplatin (cisPt) is one of the strongest anticancer agents with proven clinical activity against\na wide range of solid tumors. Its mode of action has been linked to its ability to crosslink with the\ncanonical purine bases, primarily with guanine. Theoretical studies performed at the molecular level\nsuggest that such nonspecific interactions can also take place with many competitive compounds,\nsuch as vitamins of the B group, containing aromatic rings with lone-pair orbitals. This might be\nan indicator of reduction of the anticancer therapeutic effects of the Cisplatin drug in the presence\nof vitamins of the B group inside the cell nucleus. That is why it seems to be important to connect\nCisPt with nanostructures and in this way prevent the drug from combining with the B vitamins.\nAs a proposal for a new nanodrug, an attempt was made to implement Cispaltin (CisPt) ligand on\nfunctionalized C60 fullerenes and on a cube rhombellane homeomorphic surface. The symmetry of the\nanalyzed nanostructures is an important factor determining the mutual affinity of the tested ligand and\nnanocarriers. The behavior of Cisplatin with respect to rhombellane homeomorphs and functionalized\nfullerenes C60, in terms of their (interacting) energy, geometry and topology was studied and a detailed\nanalysis of structural properties after docking showed many interesting features....
Increasing rifampicin (RIF) dosages could significantly reduce tuberculosis (TB) treatment\ndurations. Understanding the pharmacokinetic-pharmacodynamics (PK-PD) of increasing RIF\ndosages could inform clinical regimen selection. We used intracellular PD modelling (PDi)\nto predict clinical outcomes, primarily time to culture conversion, of increasing RIF dosages.\nPDi modelling utilizes in vitro-derived measurements of intracellular (macrophage) and extracellular\nMycobacterium tuberculosis sterilization rates to predict the clinical outcomes of RIF at increasing doses.\nWe evaluated PDi simulations against recent clinical data from a high dose (35 mg/kg per day) RIF\nphase II clinical trial. PDi-based simulations closely predicted the observed time-to-patient culture\nconversion status at eight weeks (hazard ratio: 2.04 (predicted) vs. 2.06 (observed)) for high dose\nRIF-based treatments. However, PDi modelling was less predictive of culture conversion status at\n26 weeks for high-dosage RIF (99% predicted vs. 81% observed). PDi-based simulations indicate that\nincreasing RIF beyond 35 mg/kg/day is unlikely to significantly improve culture conversion rates,\nhowever, improvements to other clinical outcomes (e.g., relapse rates) cannot be ruled out. This study\nsupports the value of translational PDi-based modelling in predicting culture conversion rates for\nantitubercular therapies and highlights the potential value of this platform for the improved design\nof future clinical trials....
The lipidic prodrug approach is an emerging field for improving a number of biopharmaceutical\nand drug delivery aspects. Owing to their structure and nature, phospholipid (PL)-based prodrugsmay\njoin endogenous lipid processing pathways, and hence significantly improve the pharmacokinetics\nand/or bioavailability of the drug. Additional advantages of this approach include drug targeting by\nenzyme-triggered drug release, blood-brain barrier permeability, lymphatic targeting, overcoming\ndrug resistance, or enabling appropriate formulation. The PL-prodrug design includes various\nstructural modalities-different conjugation strategies and/or the use of linkers between the PL and the\ndrug moiety, which considerably influence the prodrug characteristics and the consequent eects.\nIn this article, we describe how molecular modeling can guide the structural design of PL-based\nprodrugs. Computational simulations can predict the extent of phospholipase A2 (PLA2)-mediated\nactivation, and facilitate prodrug development. Several computational methods have been used to\nfacilitate the design of the pro-drugs, which will be reviewed here, including molecular docking,\nthe free energy perturbation method, molecular dynamics simulations, and free density functional\ntheory. Altogether, the studies described in this article indicate that computational simulation-guided\nPL-based prodrug molecular design correlates well with the experimental results, allowing for more\nmechanistic and less empirical development. In the future, the use of molecular modeling techniques\nto predict the activity of PL-prodrugs should be used earlier in the development process....
While precise mechanisms underlying cardiovascular diseases (CVDs) are still not fully\nunderstood, previous studies suggest that the innate immune system, through Toll-like receptor 4\n(TLR4), plays a crucial part in the pathways leading to these diseases, mainly because of its interplay\nwith endogenous molecules. The Heat-shock protein 70 family (HSP70-70kDa) is of particular interest\nin cardiovascular tissues as it may have dual effects when interacting with TLR4 pathways. Although\nthe hypothesis of the HSP70 family members acting as TLR4 ligands is becoming widely accepted,\nto date no co-crystal structure of this complex is available and it is still unknown whether this process\nrequires the co-adaptor MD2. In this study, we aimed at investigating the interplay between the\nTLR4/MD2 complex and HSP70 family members in the human cardiovascular system through\ntranscriptomic data analysis and at proposing a putative interaction model between these proteins.\nWe report compelling evidence of correlated expression levels between TLR4 and MD2 with HSP70\ncognate family members, especially in heart tissue. In our molecular docking simulations, we found\nthat HSP70 in the ATP-bound state presents a better docking score towards the TLR4/MD2 complex\ncompared to the ADP-bound state (-22.60 vs. -10.29 kcal/mol, respectively). Additionally, we show\nvia a proximity ligation assay for HSP70 and TLR4, that cells stimulated with ATP have higher\nformation of fluorescent spots and that MD2 might be required for the complexation of these proteins.\nThe insights provided by our computational approach are potential scaffolds for future in vivo studies\ninvestigating the interplay between the TLR4/MD2 complex and HSP70 family members in the\ncardiovascular system....
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