Computational Investigation Identified Potential Chemical Scaffolds for Heparanase as Anticancer Therapeutics

Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration and pharmacokinetic (PK) properties. In the present study, a ligand-based pharmacophore model was generated from a dataset of well-known active small molecule Hpse inhibitors which were observed to display favorable PK properties. The compounds from the InterBioScreen database of natural (69,034) and synthetic (195,469) molecules were first filtered for their drug-likeness and the pharmacophore model was used to screen the drug-like database. The compounds acquired from screening were subjected to molecular docking with Heparanase, where two molecules used in pharmacophore generation were used as reference. From the docking analysis, 33 compounds displayed higher docking scores than the reference and favorable interactions with the catalytic residues. Complex interactions were further evaluated by molecular dynamics simulations to assess their stability over a period of 50 ns. Furthermore, the binding free energies of the 33 compounds revealed 2 natural and 2 synthetic compounds, with better binding affinities than reference molecules, and were, therefore, deemed as hits. The hit compounds presented from this in silico investigation could act as potent Heparanase inhibitors and further serve as lead scaffolds to develop compounds targeting Heparanase upregulation in cancer.     

The tale of proteolysis targeting chimeras (PROTACs) for Leucine-Rich Repeat Kinase 2 (LRRK2)

Here we present the rational design and synthetic methodologies towards proteolysis-targeting chimeras (PROTACs) for the recently-emerged target leucine-rich repeat kinase 2 (LRRK2). Two highly potent, selective, brain-penetrating kinase inhibitors were selected, and their structure was appropriately modified to assemble a cereblon-targeting PROTAC. Biological data show strong kinase inhibition and the ability of the synthesized compounds to enter the cells. However, data regarding the degradation of the target protein are inconclusive. The reasons for the inefficient degradation of the target are further discussed.     

Regression analysis of surface roughness and micro-structural study in rotary ultrasonic drilling of BK7

Ceramic materials have tremendous demand in manufacturing sectors. However, poor machinability impedes their widespread applications on an industrial scale. BK-7 falls in the same category and is normally processed by ultrasonic machining. But nowadays rotary ultrasonic machining is overtaking the ultrasonic machining for processing difficult to cut materials because of its superlative material removal mechanism. Current study aims to improve the surface quality of BK7 by studying the effect of input factors on surface roughness during rotary ultrasonic machining. Response surface methodology has been used to observe the effect of input variables ― spindle speed, feed rate and ultrasonic power ― on surface roughness (SR). Thereafter, central composite design was employed to estimate the regression coefficients of quadratic model for surface roughness. Fitness of developed quadratic model was checked by ANOVA test, which also revealed that all the model terms of input factors were significant except feed and speed interaction. Feed has the maximum impact over surface roughness descended by moderate impact of power and spindle speed. The study was further reinforced on observing the surface integrity of processed surfaces using scanning electron microscopic images. Mixed flow of material was observed to occur at lower feed rate and higher levels of rpm and ultrasonic power.     

A comparative study of the tensile properties of compression molded and 3D printed PLA specimens in dry and water saturated conditions

Journal of Mechanical Science and Technology - This research work presents a comparative study of the tensile properties of polylactic acid (PLA) specimens per ASTM D638-14 fabricated by...     

Optimisation of process parameters to develop nutritionally rich spray‐dried honey powder with vitamin C content and antioxidant properties

The aim of present research was to optimise the conditions to develop nutritionally rich honey powder using honey, whey protein concentrate (WPC), aonla (Emblica officinalis. Gaertn) and basil (Ocimum sanctum) extract with the help of co‐current spray drier. Response surface methodology was applied to study the effects of inlet temperature (160–180 °C), whey protein concentrate (25–35%), feed flow rate (0.08–0.13 mL s^?1), aonla extract (6–8%) and basil extract (6–8%) on product responses, viz. bulk density, hygroscopicity, antioxidant activity (AOA), total phenolic content (TPC) and vitamin C. Statistical analysis revealed that independent variables significantly affected all the responses. The results demonstrated that increasing inlet temperature lowered the bulk density, hygroscopicity, AOA, TPC and vitamin C, whereas addition of aonla extract and basil extract increased the AOA (82.73%), TPC (63.27%) and total vitamin C content (94.89%) as these functional compounds were encapsulated by WPC. Similarly, with increase in feed flow rate and WPC, there was increase and decrease in the bulk density and hygroscopicity, respectively. The recommended optimum spray‐drying conditions were inlet air temperature (170 °C), feed rate (0.11 mL s^?1), whey protein concentrate (35%), aonla (8%) and basil extract (6%).