Highly efficient synthesis of isoxazolones and pyrazolones using g-C3N4·OH nanocomposite with their in silico molecular docking, pharmacokinetics and simulation studies.

An environmentally friendly, versatile multicomponent reaction for synthesizing isoxazol-5-one and pyrazol-3-one derivatives has been developed, utilizing a freshly prepared g-C3N4·OH nanocomposite as a highly efficient catalyst at room temperature in aqueous environment. This innovative approach yielded all the desired products with exceptionally high yields and concise reaction durations. The catalyst was well characterized by FT-IR, XRD, SEM, EDAX, and TGA/DTA studies. Notably, the catalyst demonstrated outstanding recyclability, maintaining its catalytic efficacy over six consecutive cycles without any loss. The sustainability of this methodology was assessed through various eco-friendly parameters, including E-factor and eco-score, confirming its viability as a green synthetic route in organic chemistry. Additionally, the gram-scale synthesis verifies its potential for industrial applications. The ten synthesized compounds were also analyzed via a PASS online tool to check their several pharmacological activities. The study is complemented by in silico molecular docking, pharmacokinetics, and molecular dynamics simulation studies. These studies discover 5D as a potential candidate for drug development, supported by its favorable drug-like properties, ADMET studies, docking interaction, and stable behavior in the protein binding cavity.

Machine learning ensembles, neural network, hybrid and sparse regression approaches for weather based rainfed cotton yield forecast.

Cotton is a major economic crop predominantly cultivated under rainfed situations. The accurate prediction of cotton yield invariably helps farmers, industries, and policy makers. The final cotton yield is mostly determined by the weather patterns that prevail during the crop growing phase. Crop yield prediction with greater accuracy is possible due to the development of innovative technologies which analyses the bigdata with its high-performance computing abilities. Machine learning technologies can make yield prediction reasonable and faster and with greater flexibility than process based complex crop simulation models. The present study demonstrates the usability of ML algorithms for yield forecasting and facilitates the comparison of different models. The cotton yield was simulated by employing the weekly weather indices as inputs and the model performance was assessed by nRMSE, MAPE and EF values. Results show that stacked generalised ensemble model and artificial neural networks predicted the cotton yield with lower nRMSE, MAPE and higher efficiency compared to other models. Variable importance studies in LASSO and ENET model found minimum temperature and relative humidity as the main determinates of cotton yield in all districts. The models were ranked based these performance metrics in the order of Stacked generalised ensemble > ANN > PCA ANN > SMLR ANN > LASSO> ENET > SVM > PCA SMLR > SMLR SVM > SMLR. This study shows that stacked generalised ensembling and ANN method can be used for reliable yield forecasting at district or county level and helps stakeholders in timely decision-making.

Uncovering the role of aquaporin and chromobox family members as potential biomarkers in head and neck squamous cell carcinoma via integrative multiomics and in silico approach.

Head and neck squamous cell carcinoma (HNSC) is a diverse group of tumors arising from oral cavity, oropharynx, larynx, and hypopharynx squamous epithelium, posing significant morbidity. Aquaporins (AQPs) are membrane proteins forming water channels, some associated with carcinomas. Chromobox (CBX) family is known to modulate physiological and oncological processes. In our study, we analyzed AQPs and CBXs having significant expression followed by their prognostic and mutational assessment. Next, we performed enrichment and tumor infiltration analysis followed by HPA validation. Lastly, we established a 3-node miRNA-TF-mRNA regulatory network and performed protein-protein docking of the highest-degree subnetwork motif between TF and mRNA. Significant upregulation of CBX3/2 and downregulation of AQP3/5/7 correlated with poor overall survival (OS) in HNSC patients. The most significant pathway, GO-BP, GO-MF, and GO-CC terms associated with AQP3 and CBX3 were passive transport by aquaporins, response to vitamin, glycerol channel activity, and condensed chromosome, centromeric region. AQP3 negatively correlated with [Formula: see text] T cells, positively with [Formula: see text] T cells and B cells, and negatively with tumor purity, whereas CBX3 positively correlated with [Formula: see text] T cells, negatively with [Formula: see text] T cells and B cells, and positively with tumor purity. Three-node miRNA-TF-mRNA regulatory network revealed a highest-degree subnetwork motif comprising one TF (SMAD3), one miRNA (miR-423-5p), and one mRNA (AQP3). Protein-protein interaction studies suggested a direct interaction between AQP3 and Smad3 proteins. We concluded that AQP3 and CBX3 hold potential as treatment strategies and individual prognostic biomarkers, while further protein-protein interaction studies of AQP3 could offer insights into its interactions with Smad3 proteins.

Digital pathology for nonalcoholic steatohepatitis assessment.

Histological assessment of nonalcoholic fatty liver disease (NAFLD) has anchored knowledge development about the phenotypes of the condition, their natural history and their clinical course. This fact has led to the use of histological assessment as a reference standard for the evaluation of efficacy of drug interventions for nonalcoholic steatohepatitis (NASH) - the more histologically active form of NAFLD. However, certain limitations of conventional histological assessment systems pose challenges in drug development. These limitations have spurred intense scientific and commercial development of machine learning and digital approaches towards the assessment of liver histology in patients with NAFLD. This research field remains an area in rapid evolution. In this Perspective article, we summarize the current conventional assessment of NASH and its limitations, the use of specific digital approaches for histological assessment, and their application to the study of NASH and its response to therapy. Although this is not a comprehensive review, the leading tools currently used to assess therapeutic efficacy in drug development are specifically discussed. The potential translation of these approaches to support routine clinical assessment of NAFLD and an agenda for future research are also discussed.

Characterizing patterns of seasonal drought stress for use in common bean breeding in East Africa under present and future climates.

Common bean (Phaseolus vulgaris L.) is the second most important source of dietary protein and the third most important source of calories in Africa, especially for the poor. In East Africa, drought is an important constraint to bean production. Therefore, breeding programs in East Africa have been trying to develop drought resistant varieties of common bean. To do this, breeders need information about seasonal drought stress patterns including their onset, intensity, and duration in the target area of the breeding program, so that they can mimic this pattern during field trials. Using the Decision Support for Agrotechnology Transfer (DSSAT) v4.7 model together with historical and future (Coupled Model Inter-comparison Project 6, CMIP6) climate data, this study categorized Ethiopia, Tanzania, and Uganda into different target population of environments (TPEs) based on historical and future seasonal drought stress patterns. We find that stress-free conditions generally dominate across the three countries under historical conditions (50-80% frequency). These conditions are projected to increase in frequency in Ethiopia by 2-10% but the converse is true for Tanzania (2-8% reduction) and Uganda (17-20% reduction) by 2050 depending on the Shared Socioeconomic Pathway (SSP). Accordingly, by 2050, terminal drought stresses of various intensities (moderate, severe, extreme) are prevalent in 34% of Uganda, around a quarter of Ethiopia, and 40% of the bean growing environments in Tanzania. The TPEs identified in each country serve as a basis for prioritizing breeding activities in national programs. However, to optimize resource use in international breeding programs to develop genotypes that are resilient to future projected stress patterns, we argue that common bean breeding programs should focus primarily on identifying genotypes with tolerance to severe terminal drought, with co-benefits in relation to adaptation to moderate and extreme terminal drought. Little to no emphasis on heat stress is warranted by 2050s.

Computational studies to explore inhibitors against the cyclin-dependent kinase 12/13 enzyme: an insilco pharmacophore modeling, molecular docking and dynamics approach.

Cancer is enlisted among the deadliest disease all over the world. The cyclin-dependent kinases 12 and 13 have been identified as cell cycle regulators. They conduct transcription and co-transcriptional processes by phosphorylating the C-terminal of RNA polymerase-II. Inhibition of CDK12 and 13 selectively presents a novel strategy to treat triple-negative breast cancer, but dual inhibitors are still lacking. Here, we report the screening of the natural product compound class against the dual CDK12/13 enzyme by employing various in silico methods. Complexes of CDK12 enzymes are used to form common feature pharmacophore models, whereas we perform receptor-based pharmacophore modelling on CDK13 enzyme owing to the availability of a single PDB. On conducting screening over the representative pharmacophores, the common drug-like screened natural products were shortlisted for conducting molecular docking studies. After molecular docking calculations, the candidates that showed crucial interaction with CDK12 and CDK13 enzymes were shortlisted for simulation studies. Five common docked candidates were selected for molecular dynamics simulations and free energy calculations. Based on the cut-off criteria of free energy calculations, one common hit was selected as the dual CDK12/13 inhibitor. The outcome concluded that the hit with ID CNP0386383 possesses drug-like properties, displays crucial interaction in the binding pocket, and shows stable dynamic behaviour and higher binding energy than the experimentally reported inhibitor of both CDK12 and CDK13 enzymes.Communicated by Ramaswamy H. Sarma.

Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach.

Cancer has been viewed as one of the deadliest diseases worldwide. Among various types of cancer, breast cancer is the most common type of cancer in women. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a promising druggable target and is overexpressed in cancerous cells, like, breast cancer. We conducted structure-based modeling on the allosteric site of the enzyme. Targeting the allosteric site avoids the problem of drug resistance. Pharmacophore modeling, molecular docking, HYDE assessment, drug-likeness, ADMET predictions, simulations, and free-energy calculations were performed. The RMSD, RMSF, RoG, SASA, and Hydrogen-bonding studies showed that seven candidates displayed stable behaviour. As per the literature, average superimposed simulated structures revealed a similar protein conformational change in the αE'-ßf' loop, causing its displacement away from the allosteric site. The MM-PBSA showed tight binding of six compounds with the allosteric pocket. The effect of inhibitors interacting in the allosteric site causes a decrease in the binding energy of J49 (active-site inhibitor), suggesting the effect of allosteric binding. The PCA and FEL analysis revealed the significance of the docked compounds in the stable behaviour of the complexes. The outcome can contribute to the development of potential natural products with drug-like properties that can inhibit the MTHFD2 enzyme.

Bactericidal activity of esculetin is associated with impaired cell wall synthesis by targeting glutamate racemase of Neisseria gonorrhoeae.

Neisseria gonorrhoeae (NG), the causative organism of gonorrhea, has been classified by the World Health Organization as 'Priority' two organism owing to its increased resistance to antibiotics and even failure of recommended dual therapy with ceftriaxone and azithromycin. As a result, the general and reproductive health of infected individuals is severely compromised. The imminent public health catastrophe of antimicrobial-resistant gonococci cannot be understated, as t he of severe complications and sequelae of infection are not only increasing but their treatment has also become more expensive. Tenacious attempts are underway to discover novel drug targets as well as new drugs to fight against NG. Therefore, a considerable number of phytochemicals have been tested for their remedial intercession via targeting bacterial proteins. The MurI gene encodes for an enzyme called glutamate racemase (MurI) that is primarily involved in peptidoglycan (PG) biosynthesis and is specific to the bacterial kingdom and hence can be exploited as a potential drug target for the treatment of bacterial diseases. Accordingly, diverse families of phytochemicals were screened in silico for their binding affinity with N. Gonorrhoeae MurI (NG-MurI) protein. Esculetin, one of the shortlisted compounds, was evaluated for its functional, structural, and anti-bacterial activity. Treatment with esculetin resulted in growth inhibition, cell wall damage, and altered permeability as revealed by fluorescence and electron microscopy. Furthermore, esculetin inhibited the racemization activity of recombinant, purified NG-MurI protein, one of the enzymes required for peptidoglycan biosynthesis. Our results suggest that esculetin could be further explored as a lead compound for developing new drug molecules against multidrug-resistant strains.

Drought and salinity stresses induced physio-biochemical changes in sugarcane: an overview of tolerance mechanism and mitigating approaches.

Sugarcane productivity is being hampered globally under changing environmental scenarios like drought and salinity. The highly complex nature of the plant responses against these stresses is determined by a variety of factors such as genotype, developmental phase of the plant, progression rate and stress, intensity, and duration. These factors influence plant responses and can determine whether mitigation approaches associated with acclimation are implemented. In this review, we attempt to summarize the effects of drought and salinity on sugarcane growth, specifically on the plant's responses at various levels, viz., physiological, biochemical, and metabolic responses, to these stresses. Furthermore, mitigation strategies for dealing with these stresses have been discussed. Despite sugarcane's complex genomes, conventional breeding approaches can be utilized in conjunction with molecular breeding and omics technologies to develop drought- and salinity-tolerant cultivars. The significant role of plant growth-promoting bacteria in sustaining sugarcane productivity under drought and salinity cannot be overlooked.

Investigating the link between miR-34a-5p and TLR6 signaling in sepsis-induced ARDS.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are lung complications diagnosed by impaired gaseous exchanges leading to mortality. From the diverse etiologies, sepsis is a prominent contributor to ALI/ARDS. In the present study, we retrieved sepsis-induced ARDS mRNA expression profile and identified 883 differentially expressed genes (DEGs). Next, we established an ARDS-specific weighted gene co-expression network (WGCN) and picked the blue module as our hub module based on highly correlated network properties. Later we subjected all hub module DEGs to form an ARDS-specific 3-node feed-forward loop (FFL) whose highest-order subnetwork motif revealed one TF (STAT6), one miRNA (miR-34a-5p), and one mRNA (TLR6). Thereafter, we screened a natural product library and identified three lead molecules that showed promising binding affinity against TLR6. We then performed molecular dynamics simulations to evaluate the stability and binding free energy of the TLR6-lead molecule complexes. Our results suggest these lead molecules may be potential therapeutic candidates for treating sepsis-induced ALI/ARDS. In-silico studies on clinical datasets for sepsis-induced ARDS indicate a possible positive interaction between miR-34a and TLR6 and an antagonizing effect on STAT6 to promote inflammation. Also, the translational study on septic mice lungs by IHC staining reveals a hike in the expression of TLR6. We report here that miR-34a actively augments the effect of sepsis on lung epithelial cell apoptosis. This study suggests that miR-34a promotes TLR6 to heighten inflammation in sepsis-induced ALI/ARDS. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03700-1.

Balancing water and radiation productivity suggests a clue for improving yields in wheat under combined water deficit and terminal heat stress.

Sustaining crop yield under abiotic stresses with optimized resource use is a prerequisite for sustainable agriculture, especially in arid and semi-arid areas. Water and heat stress are major abiotic stresses impacting crop growth and yield by influencing complex physiological and biochemical processes during the life cycle of crops. In a 2-year (2015-2017) research, spring wheat cv. HD-2967 was grown under deficit irrigation and delayed sowing conditions to impose water and terminal heat stresses, respectively. The data were analyzed for seasonal crop water use, radiation interception, water productivity (WP), and radiation productivity (RP) under combined water deficit and terminal heat stresses. Seasonal crop water use was significantly affected by stresses in the order of water + terminal heat > water > terminal heat. Water stress showed minimal effect on the light extinction coefficient and consequently on seasonal intercepted photosynthetically active radiation (IPAR). However, seasonal IPAR was primarily affected by combined water + terminal heat and terminal heat stress alone. The slope of crop water use and IPAR, i.e., canopy conductance, an indicator of canopy stomatal conductance, was more influenced by water stress than by terminal heat stress. Results showed that linear proportionality between WP and RP is no longer valid under stress conditions, as it follows a curvilinear relation. This is further supported by the fact that independent productivity (either water or radiation) lacked the ability to explain variability in the final economic yield or biomass of wheat. However, the ratio of RP to WP explained the variability in wheat yield/biomass under individual or combined stresses. This suggests a clue for improving higher wheat yield under stress by managing WP and RP. The highest biomass or yield is realized when the ratio of RP to WP approaches unity. Screening of genotypes for traits leading to a higher ratio of RP to WP provides an opportunity for improving wheat productivity under stressed environments.

Identifying natural product inhibitors against CDK9 enzyme via combined multicomplex-based pharmacophore modeling, interaction studies and molecular dynamics simulations.

In the current work, multicomplex-based pharmacophore modeling was performed on the CDK9 enzyme. The generated models possess five, four, and six features, which were subjected to the validation process. Among them, six feature models were selected as representative models to conduct the virtual screening process. The screened drug-like candidates were chosen to perform molecular docking to study their interaction patterns within the binding cavity of the CDK9 protein. Based on the docking score and presence of crucial interactions, out of 780 filtered candidates, only 205 were docked. These docked candidates were further accessed via HYDE assessment. Based on ligand efficiency and Hyde score, only nine candidates passed the criteria. The stability of these nine complexes, along with the reference, was studied by molecular dynamics simulations. Out of nine, only seven displayed stable behaviour during the simulations, and their stability was further assessed by molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA)-based free binding energy calculations and per residue contribution. From the present contribution, we obtained seven unique scaffolds that can be utilized as the starting lead for the development of CDK9 anticancer compounds.

Combined Multiomics and In Silico Approach Uncovers PRKAR1A as a Putative Therapeutic Target in Multi-Organ Dysfunction Syndrome.

Despite all epidemiological, clinical, and experimental research efforts, therapeutic concepts in sepsis and sepsis-induced multi-organ dysfunction syndrome (MODS) remain limited and unsatisfactory. Currently, gene expression data sets are widely utilized to discover new biomarkers and therapeutic targets in diseases. In the present study, we analyzed MODS expression profiles (comprising 13 sepsis and 8 control samples) retrieved from NCBI-GEO and found 359 differentially expressed genes (DEGs), among which 170 were downregulated and 189 were upregulated. Next, we employed the weighted gene co-expression network analysis (WGCNA) to establish a MODS-associated gene co-expression network (weighted) and identified representative module genes having an elevated correlation with age. Based on the results, a turquoise module was picked as our hub module. Further, we constructed the PPI network comprising 35 hub module DEGs. The DEGs involved in the highest-confidence PPI network were utilized for collecting pathway and gene ontology (GO) terms using various libraries. Nucleotide di- and triphosphate biosynthesis and interconversion was the most significant pathway. Also, 3 DEGs within our PPI network were involved in the top 5 significantly enriched ontology terms, with hypercortisolism being the most significant term. PRKAR1A was the overlapping gene between top 5 significant pathways and GO terms, respectively. PRKAR1A was considered as a therapeutic target in MODS, and 2992 ligands were screened for binding with PRKAR1A. Among these ligands, 3 molecules based on CDOCKER score (molecular dynamics simulated-based score, which allows us to rank the binding poses according to their quality and to identify the best pose for each system) and crucial interaction with human PRKAR1A coding protein and protein kinase-cyclic nucleotide binding domains (PKA RI alpha CNB-B domain) via active site binding residues, viz. Val283, Val302, Gln304, Val315, Ile327, Ala336, Ala337, Val339, Tyr373, and Asn374, were considered as lead molecules.

Targeting Apoptotic Pathway of Cancer Cells with Phytochemicals and Plant-Based Nanomaterials.

Apoptosis is the elimination of functionally non-essential, neoplastic, and infected cells via the mitochondrial pathway or death receptor pathway. The process of apoptosis is highly regulated through membrane channels and apoptogenic proteins. Apoptosis maintains cellular balance within the human body through cell cycle progression. Loss of apoptosis control prolongs cancer cell survival and allows the accumulation of mutations that can promote angiogenesis, promote cell proliferation, disrupt differentiation, and increase invasiveness during tumor progression. The apoptotic pathway has been extensively studied as a potential drug target in cancer treatment. However, the off-target activities of drugs and negative implications have been a matter of concern over the years. Phytochemicals (PCs) have been studied for their efficacy in various cancer cell lines individually and synergistically. The development of nanoparticles (NPs) through green synthesis has added a new dimension to the advancement of plant-based nanomaterials for effective cancer treatment. This review provides a detailed insight into the fundamental molecular pathways of programmed cell death and highlights the role of PCs along with the existing drugs and plant-based NPs in treating cancer by targeting its programmed cell death (PCD) network.

Hydrogen Peroxide and GA3 Levels Regulate the High Night Temperature Response in Pistils of Wheat (Triticum aestivum L.).

High night temperature (HNT) impairs crop productivity through the reproductive failure of gametes (pollen and pistil). Though female gametophyte (pistil) is an equal partner in the seed-set, the knowledge of the antioxidant system(s) and hormonal control of HNT tolerance or susceptibility of pistils is limited and lacking. The objectives of this study were to determine the antioxidant mechanism for homeostatic control of free radicals, and the involvement of abscisic acid (ABA) and gibberellic acid (GA3) in HNT stress protection in the wheat pistils of contrasting wheat genotypes. We hypothesized that HNT tolerance is attributed to the homeostatic control of reactive oxygen species (ROS) and hormonal readjustment in pistils of the tolerant genotype. The ears of two contrasting wheat genotypes-HD 2329 (susceptible) and Raj 3765 (tolerant) were subjected to two HNTs (+5 °C and +8 °C) over ambient, in the absence and presence of dimethylthiourea (DMTU), a chemical trap of hydrogen peroxide (H2O2). Results showed that HNTs significantly increased ROS in pistils of susceptible genotype HD 2329 to a relatively greater extent compared to tolerant genotype Raj 3765. The response was similar in the presence or absence of DMTU, but the H2O2 values were lower in the presence of DMTU. The ROS levels were balanced by increased activity of peroxidase under HNT to a greater extent in the tolerant genotype. Cytosolic glyceraldehyde-3-phosphate dehydrogenase (GAPC) activity was inversely related to H2O2 production within a critical range in Raj 3765, indicating its modulation by H2O2 levels as no change was observed at the transcriptional level. The hormonal status showed increased ABA and decreased GA3 contents with increasing temperature. Our study elucidates the role of H2O2 and GA3 in stress tolerance of pistils of tolerant genotype where GAPC acts as a ROS sensor due to H2O2-mediated decrease in its activity.

Glycerol based carbon sulfonic acid catalyzed synthesis, in silico studies and in vitro biological evaluation of isonicotinohydrazide derivatives as potent antimicrobial and anti-tubercular agents.

The present pathway involves synthesis of isonicotinohydrazide derivatives using isoniazid and diversely substituted aldehydes in the presence of EtOH and catalytic amount of glycerol based carbon sulfonic acid catalyst. The developed pathway has so many merits like excellent yields (91-98%), short reaction time (4-10 min), easy reaction set up, no need of column chromatography, large substrate scope, easily recyclable and reusable catalyst. The synthesized compounds were screened for antimicrobial and anti-tubercular activity and it was observed that compounds possessed high biological potency against the Gram positive and Gram negative bacterial and fungal strains. Regarding anti-tubercular activity, compound 3m exhibited high % inhibition against Mycobacterium tuberculosis H37RV strain. Based on the outcome of in vitro studies, all the synthesized compounds were docked against E. coli (1KZN), C. albicans (1IYL), and M. tuberculosis H 37 Rv strain (2NSD). The synthesized derivatives were docked within the binding site of 1KZN, and 1IYL. However, with 2NSD, apart from 3h, all the derivatives displayed interaction within the binding cavity of the protein. All the crucial interactions with Asn46, Asp73, and Arg136 in 1KZN, His227, Leu451 in 1IYL, and Tyr158 in 2NSD were witnessed in the top-scored docked candidates. Molecular docking studies revealed the importance of the substitution at R position on isonicotinohydrazide scaffold. The nitrogen atoms of hydrazide moiety were involved in forming hydrogen bonding with the active site amino acids, and the substitution at the R position occupy the hydrophobic position in the binding pocket. Also, the functional groups present on the substituted R position were involved in forming hydrogen bonding with the crucial active site residues.

US Food and Drug Administration Approval Summary: Fam-Trastuzumab Deruxtecan-nxki for Human Epidermal Growth Factor Receptor 2-Low Unresectable or Metastatic Breast Cancer.

PURPOSE: The US Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd) for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry 1 + or immunohistochemistry 2+/in situ hybridization-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. PATIENTS AND METHODS: Approval was based on DESTINY-Breast04, a phase III, randomized, open-label, multicenter trial in patients with unresectable or metastatic HER2-low breast cancer, determined at a central laboratory. A total of 557 patients were randomly assigned (2:1) to receive either T-DXd 5.4 mg/kg intravenously once every 3 weeks (n = 373) or physicians' choice of chemotherapy (n = 184). RESULTS: The study met its primary efficacy end point of progression-free survival (PFS) by blinded independent central review assessment in the hormone receptor-positive (HR+) cohort (N = 494) with an estimated hazard ratio (HR) of 0.51(95% CI, 0.40 to 0.64; P < .0001). Key secondary end points were also met, including PFS in the intent-to-treat population with an HR of 0.50 (95% CI, 0.40 to 0.63; P < .0001), overall survival (OS) in the HR+ cohort with an HR of 0.64 (95% CI, 0.48 to 0.86; P = .0028) and OS in the intent-to-treat with an HR of 0.64 (95% CI, 0.49 to 0.84; P = .0010). The safety profile of T-DXd was consistent with previously approved indications, and no new safety signals were observed in this study population. CONCLUSION: The approval of T-DXd in HER2-low metastatic breast cancer was based on statistically significant and clinically meaningful PFS and OS improvements observed in the DESTINY-Breast04 trial and represents the first approved therapy specifically for the treatment of HER2-low metastatic breast cancer.

Structure-guided pharmacophore based virtual screening, docking, and molecular dynamics to discover repurposed drugs as novel inhibitors against endoribonuclease Nsp15 of SARS-CoV-2.

COVID-19 (Corona Virus Disease of 2019) caused by the novel 'Severe Acute Respiratory Syndrome Coronavirus-2' (SARS-CoV-2) has wreaked havoc on human health and the global economy. As a result, for new medication development, it's critical to investigate possible therapeutic targets against the novel virus. 'Non-structural protein 15' (Nsp15) endonuclease is one of the crucial targets which helps in the replication of virus and virulence in the host immune system. Here, in the current study, we developed the structure-based pharmacophore model based on Nsp15-UMP interactions and virtually screened several databases against the selected model. To validate the screening process, we docked the top hits obtained after secondary filtering (Lipinski's rule of five, ADMET & Topkat) followed by 100 ns molecular dynamics (MD) simulations. Next, to revalidate the MD simulation studies, we have calculated the binding free energy of each complex using the MM-PBSA procedure. The discovered repurposed drugs can aid the rational design of novel inhibitors for Nsp15 of the SARS-CoV-2 enzyme and may be considered for immediate drug development.

Pharmacophore-based virtual screening of ZINC database, molecular modeling and designing new derivatives as potential HDAC6 inhibitors.

To date, many HDAC6 inhibitors have been identified and developed but none is clinically approved as of now. Through this study, we aim to obtain novel HDAC6 selective inhibitors and provide new insights into the detailed structural design of potential HDAC6 inhibitors. A HypoGen-based 3D QSAR HDAC6 pharmacophore was built and used as a query model to screen approximately 8 million ZINC database compounds. First, the ZINC Database was filtered using ADMET, followed by pharmacophore-based library screening. Using fit value and estimated activity cutoffs, a final set of 54 ZINC hits was obtained that were further investigated using molecular docking with the crystal structure of human histone deacetylase 6 catalytic domain 2 in complex with Trichostatin A (PDB ID: 5EDU). Through detailed in silico screening of the ZINC database, we shortlisted three hits as the lead molecules for designing novel HDAC6 inhibitors with better efficacy. Docking with 5EDU, followed by ADMET and TOPKAT analysis of modified ZINC hits provided 9 novel potential HDAC6 inhibitors that possess better docking scores and 2D interactions as compared to the control ZINC hit molecules. Finally, a 50 ns MD analysis run followed by Protein-Ligand Interaction Energy (PLIE) analysis of the top scored hits provided a novel molecule N1 that showed promisingly similar results to that of Ricolinostat (a known HDAC6 inhibitor). The comparable result of the designed hits to established HDAC6 inhibitors suggests that these compounds might prove to be successful HDAC6 inhibitors in future. Designed novel hits that might act as good HDAC6 inhibitors derived from ZINC database using combined molecular docking and modeling approaches.