Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2.

SARS-CoV, an RNA virus, is contagious and displays a remarkable degree of adaptability, resulting in intricate disease presentations marked by frequent genetic mutations that can ultimately give rise to drug resistance. Targeting its viral replication cycle could be a potential therapeutic option to counter its viral growth in the human body leading to the severe infectious stage. The Mpro of SARS-CoV-2 is a promising target for therapeutic development as it is crucial for viral transcription and replication. The derivatives of ß-diketone and coumarin have already been reported for their antiviral potential and, thus, are considered as a potential scaffold in the current study for the computational design of potential analogs for targeting the viral replication of SARS-CoV-2. In our study, we used novel diketone-hinged coumarin derivatives against the SARS-CoV-2 MPro to develop a broad-spectrum antiviral agent targeting SARS-CoV-2. Through an analysis of pharmacokinetics and docking studies, we identified a list of the top 10 compounds that demonstrated effectiveness in inhibiting the SARS-CoV-2 MPro virus. On the basis of the pharmacokinetics and docking analyses, the top 5 novel coumarin analogs were synthesized and characterized. The thermodynamic stability of compounds KS82 and KS94 was confirmed by their molecular dynamics, and the stability of the simulated system indicated their inhibitory nature. Molecules KS82 and KS94 were further evaluated for their anti-viral potential using Vero E6 cells followed by RT-PCR assay against SARS-CoV-2. The test compound KS82 was the most active with the potential to inhibit SARS-CoV-2 replication in Vero E6 cells. These data indicate that KS82 prevents the attack of the virus and emerges as the primary candidate with promising antiviral properties.

In Silico Approaches to Developing Novel Glycogen Synthase Kinase 3ß (GSK-3ß).

Alzheimer's disease (AD) is caused by plaque agglomeration and entanglement in several areas of the neural cells, which leads to apoptosis. The main etiology of AD is senile dementia, which is linked to amyloid-beta (Aß) deregulation and tau perivascular pathogeny. Hyperphosphorylated tau has a propensity for microtubules, which elevate the instability and tau-protein congregates, leading to accumulation of neurofibrillary tangles (NFTs). Tau hyperphosphorylation is susceptible to GSK-3, which has led to an emerging hypothesis regarding the pathogenesis of AD. Accordingly, attempts have been made to conduct investigations and achieve further advancements on new analogues capable of inhibiting the GSK-3 protein, which are currently in the clinical trials. In this analysis, we have evaluated certain GSK-3 inhibitor variants utilising scaffolding and framework devised techniques with pharmacological characteristics, accompanied by computational screenings (pharmacokinetics and docking). The structure-based designed analogues interacted effectively with the active amino acids of GSK-3ß target protein. The in silico pharmacokinetic studies revealed their drug-like properties. The analogues with best interactions and binding scores will be considered in the future to completely demonstrate their potential relevance as viable GSK-3 inhibitors.

Scaffold Morphing and In Silico Design of Potential BACE-1 (ß-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer Therapeutics.

Alzheimer's disease (AD) is the prime cause of 65-80% of dementia cases and is caused by plaque and tangle deposition in the brain neurons leading to brain cell degeneration. ß-secretase (BACE-1) is a key enzyme responsible for depositing extracellular plaques made of ß-amyloid protein. Therefore, efforts are being applied to develop novel BACE-1 enzyme inhibitors to halt plaque build-up. In our study, we analyzed some Elenbecestat analogues (a BACE-1 inhibitor currently in clinical trials) using a structure-based drug design and scaffold morphing approach to achieve a superior therapeutic profile, followed by in silico studies, including molecular docking and pharmacokinetics methodologies. Among all the designed compounds, SB306 and SB12 showed good interactions with the catalytic dyad motifs (Asp228 and Asp32) of the BACE-1 enzyme with drug-likeliness properties and a high degree of thermodynamic stability confirmed by the molecular dynamic and stability of the simulated system indicating the inhibitory nature of the SB306 and SB12 on BACE 1.

Depth of soil compaction predominantly affects rice yield reduction by reproductive-stage drought at varietal screening sites in Bangladesh, India, and Nepal.

AIMS: Drought is the major constraint to rainfed rice productivity in South Asia, but few reports provide detailed characterization of the soil properties related to drought stress severity in the region. The aim of the study was to provide a compilation of drought breeding network sites and their respective levels of drought stress, and to relate soil parameters with yield reduction by drought. METHODS: This study characterized levels of drought stress and soil nutrient and physical properties at 18 geographically distributed research station sites involved in rice varietal screening in Bangladesh, India, and Nepal, as well as at farmers' fields located near the research stations. RESULTS: Based on soil resistance to penetration profiles, a hardpan was surprisingly absent at about half of the sites characterized. Significant relationships of depth of compaction and yield reduction by drought indicated the effects of soil puddling on susceptibility to cracking, rather than water retention by hardpans, on plant water availability in this region. The main difference between research stations and nearby farmers' fields was in terms of soil compaction. CONCLUSIONS: These results present an initiative for understanding the range of severities of reproductive-stage drought stress in drought-prone rainfed lowland rice-growing areas in South Asia.

Marker-assisted breeding to develop the drought-tolerant version of Sabitri, a popular variety from Nepal.

Sabitri is a rice variety grown in a large part of the rainfed areas of Nepal. It was originally developed for irrigated condition; hence, this variety suffers high yield decline under drought. Two QTLs, qDTY3.2 and qDTY12.1 , with large effects on grain yield under drought were identified in the Sabitri background in separate QTL mapping studies. The present study reports the development of Sabitri near isogenic lines (NILs) with combinations of these two QTLs and their characterization under drought. To do so, marker-assisted backcross breeding (MABB) was combined with phenotypic selection to develop high-yielding drought-tolerant NILs with Sabitri grain type. Apart from this, drought-tolerant variants for grain type with high yield under non-stress were identified among the developed NILs. Early days to flowering of up to 13 days and reduction in plant height of up to 13 cm as compared to Sabitri were observed in the developed NILs. Some of these NILs showed higher yield compared to Sabitri and relatively higher tolerance to drought, indicating the capture of positive alleles and interactions during the course of selection. The developed NILs possessed high yield potential which make them suitable materials for the testing of water-saving technologies in irrigated areas. Based on their performance, these NILs can be deployed in rainfed areas in Nepal and other countries of South Asia to increase yield stability.

qDTY12.1: a locus with a consistent effect on grain yield under drought in rice.

BACKGROUND: Selection for grain yield under drought is an efficient criterion for improving the drought tolerance of rice. Recently, some drought-tolerant rice varieties have been developed using this selection criterion and successfully released for cultivation in drought-prone target environments. The process can be made more efficient and rapid through marker-assisted breeding, a well-known fast-track approach in crop improvement. QTLs have been identified for grain yield under drought with large effects against drought-susceptible varieties. Most of the identified QTLs show large QTL × environment or QTL × genetic background interactions. The development of mapping populations in the background of popular high-yielding varieties, screening across environments, including the target environments, and the identification of QTLs with a consistent effect across environments can be a suitable alternative marker-assisted breeding strategy. An IR74371-46-1-1 × Sabitri backcross inbred line population was screened for reproductive-stage drought stress at the International Rice Research Institute, Philippines, and Regional Agricultural Research Station, Nepalgunj, Nepal, in the dry and wet seasons of 2011, respectively. A bulk segregant analysis approach was used to identify markers associated with high grain yield under drought. RESULTS: A QTL, qDTY12.1, significantly associated with grain yield under reproductive-stage drought stress was identified on chromosome 12 with a consistent effect in two environments: IRRI, Philippines, and RARS, Nepalgunj, Nepal. This QTL explained phenotypic variance of 23.8% and contributed an additive effect of 45.3% for grain yield under drought. The positive QTL allele for qDTY12.1 was contributed by tolerant parent IR74371-46-1-1. CONCLUSIONS: In this study, qDTY12.1 showed a consistent effect across environments for high grain yield under lowland reproductive-stage drought stress in the background of popular high-yielding but drought-susceptible recipient variety Sabitri. qDTY12.1 was also reported previously [Crop Sci 47:507-516, 2007] to increase grain yield under upland reproductive-stage drought stress situations. qDTY12.1 is the only QTL reported so far in rice to have shown a large effect against multiple recipient genetic backgrounds as well as under highly diverse upland and lowland rice ecosystems. qDTY12.1 can be successfully introgressed to improve grain yield under drought of popular high-yielding but drought-susceptible lowland as well as upland adapted varieties following marker-assisted breeding.