Groundwater being an important component of the hydrological cycle as it sustains the streamflow during precipitation free periods and is a major source of water supply. The dependence on the groundwater has increased drastically over the years leading to over exploitation of the aquifers. Therefore, it is imperative to assess the extent of exploitation and analyse the groundwater level scenarios in the area of interest. The existence of a trend in a hydrological time series can be detected by statistical tests. The present study investigates the application of various methods for identification of trends in groundwater levels in few blocks of Sagar district, which faces severe water scarcity owing to the declining groundwater levels. The non-parametric Kendal rank correlation test as well as the parametric linear regression test has been used for trend detection based on the analysis of the seasonal groundwater levels. Kendal's rank correlation test, has been applied to identify the trend persisting in the data and the linear regression test is used to identify the significance of the slope. The analysis indicates that the time series of groundwater levels are cyclical with characteristics of seasonal variation in all the blocks coupled with a declining trend at Sagar, Khurai and Bina.
The cyclin-dependent kinase 7 (CDK7) plays a crucial role in regulating the cell cycle and RNA polymerase-based transcription. Overexpression of this kinase is linked with various cancers in humans due to its dual involvement in cell development. Furthermore, emerging evidence has revealed that inhibiting CDK7 has anti-cancer effects, driving the development of novel and more cost-effective inhibitors with enhanced selectivity for CDK7 over other CDKs. In the present investigation, a pharmacophore-based approach was utilized to identify potential hit compounds against CDK7. The generated pharmacophore models were validated and used as 3D queries to screen 55,578 natural drug-like compounds. The obtained compounds were then subjected to molecular docking and molecular dynamics simulations to predict their binding mode with CDK7. The molecular dynamics simulation trajectories were subsequently used to calculate binding affinity, revealing four hits—ZINC20392430, SN00112175, SN00004718, and SN00262261—having a better binding affinity towards CDK7 than the reference inhibitors (CT7001 and THZ1). The binding mode analysis displayed hydrogen bond interactions with the hinge region residues Met94 and Glu95, DFG motif residue Asp155, ATP-binding site residues Thr96, Asp97, and Gln141, and quintessential residue outside the kinase domain, Cys312 of CDK7. The in silico selectivity of the hits was further checked by docking with CDK2, the close homolog structure of CDK7. Additionally, the detailed pharmacokinetic properties were predicted, revealing that our hits have better properties than established CDK7 inhibitors CT7001 and THZ1. Hence, we argue that proposed hits may be crucial against CDK7-related malignancies.
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, characterized by the specific loss of dopaminergic neurons in the midbrain. The pathophysiology of PD is likely caused by a variety of environmental and hereditary factors. Many single-gene mutations have been linked to this disease, but a significant number of studies indicate that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a potential therapeutic target for both sporadic and familial forms of PD. Consequently, the identification of potential LRRK2 inhibitors has been the focus of drug discovery. Various investigations have been conducted in academic and industrial organizations to investigate the mechanism of LRRK2 in PD and further develop its inhibitors. This review summarizes the role of LRRK2 in PD and its structural details, especially the kinase domain. Furthermore, we reviewed in vitro and in vivo findings of selected inhibitors reported to date against wild-type and mutant versions of the LRRK2 kinase domain as well as the current trends researchers are employing in the development of LRRK2 inhibitors.
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