Current combination therapy of PEG-INF and ribavirin against the Hepatitis C Virus (HCV) genotype-1 infections is ineffective in maintaining sustained viral response in 50% of the infection cases. New compounds in the form of protease inhibitors can complement the combination therapy. Asunaprevir is new to the drug regiment as the NS3-4A protease inhibitor, but it is susceptible to two mutations, namely, R155K and D168A in the protein. Thus, in our study, we sought to evaluate Andrographolide, a labdane-diterpenoid from the Andrographis paniculata plant as an effective compound for inhibiting the NS3-4A protease as well as its concomitant drug-resistant mutants by using molecular docking and dynamic simulations. Our study shows that Andrographolide has best docking scores of −15.0862, −15.2322, and −13.9072 compared to those of Asunaprevir −3.7159, −2.6431, and −5.4149 with wild-type R155K and D168A mutants, respectively. Also, as shown in the MD simulations, the compound was good in binding the target proteins and maintains strong bonds causing very less to negligible perturbation in the protein backbone structures. Our results validate the susceptibility of Asunaprevir to protein variants as seen from our docking studies and trajectory period analysis. Therefore, from our study, we hope to add one more option in the drug regiment to tackle drug resistance in HCV infections.
A sol-gel method was employed to synthesise pure titanium dioxide (TiO 2 ) and surfactant assisted TiO 2 nanoparticles (NPs).The effect of novel surfactant viz., Lauryl lactyl lactate on photocatalytic properties of TiO 2 was studied. TiO 2 NPs were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), UV-Vis Diffuse Reflectance spectra (DRS), Field emission scanning electron microscopy (FE-SEM), Transmission electron microscopy (TEM), Thermo gravimetric analysis (TGA), and Brunauer -Emmet -Teller (BET) surface area. Anatase phase of TiO 2 was confirmed by X-Ray diffraction pattern and the crystallite size was between 9-19 nm. Addition of surfactant improved the BET surface area, surface defects, while the agglomeration of particles was reduced. DRS results revealed that the addition of surfactant to TiO 2 sol induced a red shift of the absorption edge which resulted in the reduction of band gap from 3.23 to 3.21 eV. These physicochemical properties of TiO 2 NPs were correlated with photocatalytic degradation of phenol. About 92% of phenol degradation was observed for surfactant assisted TiO 2 NPs (SA-TiO 2 ). Salicylic acid and caffeine were also degraded using SA-TiO 2 NPs.
Alzheimer disease (AD) is a leading cause of dementia in elderly patients who continue to live between 3 and 11 years of diagnosis. A steep rise in AD incidents is observed in the elderly population in East-Asian countries. The disease progresses through several changes, including memory loss, behavioural issues, and cognitive impairment. The etiology of AD is hard to determine because of its complex nature. The whole exome sequences of late-onset AD (LOAD) patients of Korean origin are investigated to identify rare genetic variants that may influence the complex disorder. Computational annotation was performed to assess the function of candidate variants in LOAD. The in silico pathogenicity prediction tools such as SIFT, Polyphen-2, Mutation Taster, CADD, LRT, PROVEAN, DANN, VEST3, fathmm-MKL, GERP + + , SiPhy, phastCons, and phyloP identified around 17 genes harbouring deleterious variants. The variants in the ALDH3A2 and RAD54B genes were pathogenic, while in 15 other genes were predicted to be variants of unknown significance. These variants can be potential risk candidates contributing to AD. In silico computational techniques such as molecular docking, molecular dynamic simulation and steered molecular dynamics were carried out to understand the structural insights of RAD54B with ATP. The simulation of mutant (T459N) RAD54B with ATP revealed reduced binding strength of ATP at its binding site. In addition, lower binding free energy was observed when compared to the wild-type RAD54B. Our study shows that the identified uncommon variants are linked to AD and could be probable predisposing genetic factors of LOAD.
Objective The CCND1 gene expresses a protein, G1/S-specific cyclin, that regulates the G1/S transition in the cell cycle and also inhibits retinoblastoma (RB) proteins. Overexpression or rearrangements of this gene can result in various tumours. This study aimed to identify possible deleterious non-synonymous single nucleotide polymorphisms (SNP's) of CCND1 using computational methods. Methods SNPs in the human CCND1 gene were retrieved from dbSNP. These SNPs were screened by the Sorting Intolerant From Tolerant (SIFT) algorithm and the PredictSNP classification. Mutants with deleterious SNPs were built using Discovery Studio 3.5, and dynamics studies were performed on native and mutant varieties. Results In Homo sapiens , 1194 SNPs were found, of which 94 were missense and 2 were nonsense SNPs. Three SNPs were found to be deleterious. Molecular dynamics and trajectory analysis showed that there was a significant deviation of the root mean square deviation (RMSD) values in the N216K mutant from the values of the native protein. Conclusion Based on this study, we propose that the SNP with SNP ID rs112525097 (NM_053056.2:c.648C>G) might cause aberrations in CCND1 , which might lead to a change in the function of the G1/S-specific cyclin protein. This, in turn, may lead to the development of acute myeloid leukaemia (AML).
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