Current Drug Metabolism - Volume 23, Issue 4, 2022

Binding free energy estimation of drug candidates to their biomolecular target is one of the best quantitative estimators in computer-aided drug discovery. Accurate binding free energy estimation is still a challengeable task even after decades of research, along with the complexity of the algorithm, time-consuming procedures, and reproducibility issues. In this review, we have discussed the advantages and disadvantages of diverse free energy methods like Thermodynamic Integration (TI), Bennett's Acceptance Ratio (BAR), Free Energy Perturbation (FEP), and alchemical methods. Moreover, we discussed the possible application of the machine learning method in proteinligand binding free energy estimation.

Huntington's disease (HD) is a distressing, innate neurodegenerative disease that descends from CAG repeat expansion in the huntingtin gene causing behavioral changes, motor dysfunction, and dementia in children and adults. Mutation in huntingtin (HTT) protein has been suggested to cause neuron loss in the cortex and striatum through various mechanisms, including abnormal regulation of transcription, proteasomal dysfunction, posttranslational modification, and other events regulating toxicity. Pathogenesis of HD involves cleavage of the huntingtin protein followed by the neuronal accumulation of its aggregated form. Several research groups made possible efforts to reduce huntingtin gene expression, protein accumulation, and protein aggregation using inhibitors and molecular chaperones as developing drugs against HD. Herein, we review the mechanism proposed towards the formation of HTT protein aggregation and the impact of therapeutic strategies for the treatment of HD.

Coronavirus disease-2019 (COVID-19) is a highly infectious disease caused by newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the inception of SARS-CoV-2 in Wuhan, China, the virus has traveled more than 200 countries globally. The role of SARS-CoV-2 in COVID-19 has been thoroughly investigated and reviewed in the last 22 months or so; however, a comprehensive outline of miRNAs in SARS-CoV- 2 infection is still missing. The genetic material of SARS-CoV-2 is a single-stranded RNA molecule nearly 29 kb in size. RNA is composed of numerous sub-constituents RNA is found in the cells in a number of forms. including microRNAs (miRNAs). miRNAs play an essential role in biological processes like apoptosis, cellular metabolism, cell death, cell movement, oncogenesis, intracellular signaling, immunity, and infection. Lately, miRNAs have been involved in SARS-CoV-2 infection, though the clear demonstration of miRNAs in the SARS-CoV-2 infection is not fully elucidated. The present review article summarizes recent findings of miRNAs associated with SARS-CoV-2 infection. We presented various facets of miRNAs. miRNAs as the protagonists in viral infection, the occurrence of miRNA in cellular receptors, expression of miRNAs in multiple diseases, miRNA as a biomarker, and miRNA as a therapeutic tool have been discussed in detail. We also presented the vaccine status available in various countries.

Drosophila melanogaster is a prominent organism in developmental biology research and in studies related to pathophysiological conditions like cancer and Alzheimer’s disease. The fruit fly gut contains several cytochrome P450s (CYP450s), which have central roles in Drosophila development and in the normal physiology of the gut. Since the crystal structures of these proteins have not been deciphered yet, we modeled the structure of 29 different D. melanogaster gut CYP450s using Prime (Schrödinger). The sequences of chosen D. melanogaster gut CYP450s were compared with that of their human counterparts. The common gut (and liver) microsomal CYP450s in humans were chosen for structural comparison to find the homology and identity % of D. melanogaster CYPs with that of their human counterparts. The modeled structures were validated using PROCHECK and the best fit models were used for docking several known human pharmacological agents/drugs to the modeled D. melanogaster gut CYP450s. Based on the binding affinities (ΔG values) of the selected drug molecules with the modeled fly gut CYPs, the plausible differences in metabolism of the prominent drugs in humans and flies were projected. The gut is involved in the absorption of oral drugs/pharmacological agents, and hence, upregulation of intestinal CYP450 and their reactions with endobiotics and xenobiotics is envisaged. The insights gleaned from this work can validate D. melanogaster as a model organism for studying intestinal drug metabolism, particularly in the context of a) toxicology of pharmacological agents to the gut cells and b) how gut P450 metabolites/products can influence gut homeostasis. This work can help establish a platform for further in vitro investigations on how intestinal CYP450 metabolism can influence gut health. The data from this work can be used for further in silico studies and this work can serve as a platform for future in vitro investigations on intestinal CYP450-mediated metabolism of endo- and xeno-biotics in D. melanogaster.

Background: Orthosiphon stamineus Benth (O.S) is a traditional south-east Asian herb. The extract of O.S is used in the formulation of ethanolic nanolipid vesicle system to have considerable potential for tumour therapeutics. Methods: The research objective is to develop and characterise the anticancer and antiangiogenic effect of O.S extract in the form of nano-ethanolic spherosomes (ESP) using phospholipids in melanoma. Spherosomes formulation of O.S was developed using the thin-film re-hydration method and converted to gel using Acrypol 1%. The formulations were subjected to optimisation and physical-chemical characterisations like particle size, surface charge, DSC, FTIR, and TEM. Cytotoxicity of O.S and ESP was studied using an endothelial cell line (EA. hy926). Furthermore, anti-melanoma effect of O.S spherosome gel was studied in albino mice after topical administration. Results: ESP-6 with the ratio of extract (O.S): cholesterol: phospholipid (1: 6: 0.5) showed the highest entrapment efficiency (80.56 ± 0.84%) using ultraviolet spectroscopy. In-vivo permeation/penetration studies revealed deeper absorption of ESP-6 compared to a hydroethanolic gel of O.S. In-vitro and in vivo anti-melanoma studies demonstrated the significant tumour-suppressing effect of ESP-6 on murine melanoma. Percentage inhibition of tumour growth by O.S and ESP-6 at 3000 mg/kg showed to be 63.98 ± 7.86% and 87.76 ± 7.90%, respectively. Conclusion: Spherosome vesicles were developed with a smooth surface. The results demonstrated that O.S extract showed no toxicity when tested on the endothelial cell line. O.S loaded in spherosomes has the potential to lower the growth of melanoma in mice. The spherosomes loaded with O.S do not promote tumour growth or act as antiangiogenetic in melanoma.

Background: Aceclofenac is a non-steroidal anti-inflammatory drug and a potent analgesic. However, its oral ingestion may cause gastrointestinal problems, including dyspepsia, abnormal pain, nausea, diarrhea, and ulcerative colitis. Objective: This study aimed to prepare vesicular-based enteric microspheres containing aceclofenac by ionotropic gelation technique to minimize gastric irritation in rats. Methods: The micron-size vesicles were prepared by the ionic-orifice gelation method. Three types of vesicularbased microcapsules containing aceclofenac were prepared by employing sodium alginate as the coating material in combination with Eudragit L100, Eudragit S100, and polyvinylpyrrolidone PVP K90. The drug to sodium alginate to polymer ratios were 1:0.5:0.5, 1:1:1, and 1:1.5:1.5, respectively. Gelation of sodium alginate was induced by the dropwise addition of calcium chloride solution (10 % w/v). Aceclofenac-loaded microspheres were evaluated in terms of aceclofenac content and in vitro drug release, and FTIR, DSC, and XRD were used for physicochemical evaluation of some selected formulae. The effects of microencapsulation on aceclofenac-induced ulcerative activity in male Wistar rats were also investigated. Results: The results indicated no interaction between aceclofenac and microcapsules forming polymers. In addition, microcapsules formulations M1, M4, and M7 gave maximal protection in acidic pH and optimal release in alkaline pH. The histopathological studies revealed that the reduction of ulceration is evident from the macroscopic and microscopic studies, which showed complete protection of the tissue morphology with no ulcers, indicating the effectiveness of the microcapsules system against aceclofenac-induced gastric ulceration in rats again. Conclusion: Ionotropic gelation seems to be a simple, efficient technique to prepare aceclofenac-loaded microspheres with a reduced risk of gastric ulceration. It is possible to overcome the problem of gastric damage while utilizing aceclofenac by avoiding the exposure of the drug to the ulcer-prone area of the gastrointestinal tract.