Artificial intelligence predicts normal summer monsoon rainfall for India in 2023.

Inaccuracy in the All Indian Summer Monsoon Rainfall (AISMR) forecast has major repercussions for India's economy and people's daily lives. Improving the accuracy of AISMR forecasts remains a challenge. An attempt is made here to address this problem by taking advantage of recent advances in machine learning techniques. The data-driven models trained with historical AISMR data, the Niño3.4 index, and categorical Indian Ocean Dipole values outperform the traditional physical models, and the best-performing model predicts that the 2023 AISMR will be roughly 790 mm, which is typical of a normal monsoon year.

Diversity of fungal pathogens in leaf spot disease of Indian mulberry and its management.

Leaf spot disease in mulberry significantly affects silk production by reducing the nutritive quality of the leaves. This disease caused by various pathogens, regardless of the localities under the same climatic region. In the present investigation, an approximate incidence rate of 84 % was recorded in Karnataka based on surveys conducted in both farmer fields and germplasm locations. The causative agents have shown diversification, including new candidates such as Bipolaris sorokiniana, Curvularia lunata, Cladosporium sphaerospermum, and Epicoccum sorghinum. These findings mark the first report of these pathogens in Indian mulberry production. The investigation involved detailed pathogenicity assessments on the predominant mulberry silk production cultivar under controlled and field environments. Pathogens were identified using morpho-cultural, microscopic and phylogenetic analyses, including the internal transcribed spacer (ITS). Various concentrations of fungicides, both individually and in combinations, were evaluated to identify effective measures for mitigating yield losses. Among the fungicides tested against the new pathogens, Hexaconazole 5 % SC and Hexaconazole 5 % + Captan 70 % WP demonstrated high promise and cost-effectiveness. Consequently, these fungicides could serve as immediate solutions to prevent further yield reduction. However, it is essential to conduct comprehensive field investigations before recommending them as standard practices. Future research endeavors should focus on assessing the extent of crop loss caused by these newly identified pathogens in mulberry cultivation.

Controlled Release Technologies for Chronotherapy: Current Status and Future Perspectives.

The expression "as sure as night follows a day" emulates those certain cycles in the environment that are always stable. Circadian rhythms are a group of processes that occur within the body in synchronisation with the external factors in a 24 h cycle. Changes in lifestyle and work shifts have disrupted these stable rhythms, which is a leading cause of lifestyle diseases. Associations between these biological clocks and diseases are abundant. However, it is also known that certain drugs work more efficiently and have minimum toxicity when given during a particular phase of the circadian cycle. Chronotherapeutics focuses on treating diseases according to the endogenous processes which mediate xenobiotic metabolism and drug response at a cellular level. Therefore, treatment of those diseases that show aggravation of symptoms according to the circadian rhythms at a particular time is highly beneficial by chronotherapy. In this article, we have emphasised how the changes in rhythms caused diseases and how chronotherapeutic approaches such as controlled drug release technologies can be a better option for these circadian manipulations that seem to influence all types of disease conditions.

Multi-Targeting Approach in Selection of Potential Molecule for COVID-19 Treatment.

The coronavirus disease (COVID-19) is a pandemic that started in the City of Wuhan, Hubei Province, China, caused by the spread of coronavirus (SARS-CoV-2). Drug discovery teams around the globe are in a race to develop a medicine for its management. It takes time for a novel molecule to enter the market, and the ideal way is to exploit the already approved drugs and repurpose them therapeutically. We have attempted to screen selected molecules with an affinity towards multiple protein targets in COVID-19 using the Schrödinger suit for in silico predictions. The proteins selected were angiotensin-converting enzyme-2 (ACE2), main protease (MPro), and spike protein. The molecular docking, prime MM-GBSA, induced-fit docking (IFD), and molecular dynamics (MD) simulations were used to identify the most suitable molecule that forms a stable interaction with the selected viral proteins. The ligand-binding stability for the proteins PDB-IDs 1ZV8 (spike protein), 5R82 (Mpro), and 6M1D (ACE2), was in the order of nintedanib > quercetin, nintedanib > darunavir, nintedanib > baricitinib, respectively. The MM-GBSA, IFD, and MD simulation studies imply that the drug nintedanib has the highest binding stability among the shortlisted. Nintedanib, primarily used for idiopathic pulmonary fibrosis, can be considered for repurposing for us against COVID-19.

Molecular modeling piloted analysis for semicarbazone derivative of curcumin as a potent Abl-kinase inhibitor targeting colon cancer.

The human Abl kinases comprise a family of proteins that are known to be key stimulus drivers in the signaling pathways modulating cell growth, cell survival, cell adhesion, and apoptosis. Recent collative studies have indicated the role of activation of Abl and Abl-related genes in solid tumors; further terming the Abl kinases as molecular switches which promote proliferation, tumorigenesis, and metastasis. The up-regulated Abl-kinase expression in colorectal cancer (CRC) and the role of Abl tyrosine kinase activity in the Matrigel invasion of CRC cells have cemented its significance in CRC advancement. Therefore, the requisite of identifying small molecules which serve as Abl selective inhibitors and designing anti-Abl therapies, particularly for CRC tumors, has driven this study. Curcumin has been touted as an effective inhibitor of cancer cells; however, it is limited by its physicochemical inadequacies. Hence, we have studied the behavior of heterocyclic derivatives of curcumin via computational tools such as pharmacophore-based virtual screening, molecular docking, free-energy binding, and ADME profiling. The most actively docked molecule, 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-carboxamide, was comparatively evaluated against Curcumin via molecular dynamics simulation using Desmond, Schrödinger. The study exhibited the improved stability of the derivative as compared to Curcumin in the tested protein pocket and displayed the interaction bonds with the contacted key amino acids. To further establish the claim, the derivatives were synthesized via the mechanism of cyclization of Curcumin and screened in vitro using SRB assay against human CRC cell line, HCT 116. The active derivative indicated an IC50 value of 5.85 µM, which was sevenfold lower as compared to Curcumin's IC50 of 35.40 µM. Hence, the results base the potential role of the curcumin derivative in modulating Abl-kinase activity and in turn may have potential therapeutic value as a lead for CRC therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-03051-9.

Advances and challenges in nintedanib drug delivery.

INTRODUCTION: Nintedanib (N.T.B) is an orally administered tyrosine kinase inhibitor that has been approved recently by U.S.F.D.A for idiopathic pulmonary fibrosis (I.P.F) and systemic sclerosis-associated interstitial lung disease (S.Sc-I.L.D). N.T.B is also prescribed in COVID-19 patients associated with I.P.F. However, it has an extremely low bioavailability of around 4.7%, and hence, researchers are attempting to address this drawback by different approaches. AREAS COVERED: This review article focuses on enlisting all the formulation attempts explored by researchers to increase the bioavailability of N.T.B while also providing meaningful insight into the unexplored areas in formulation development, such as targeting of the lymphatic system and transdermal delivery. All the patents on the formulation development of N.T.B have also been summarized. EXPERT OPINION: N.T.B has the potential to act on multiple diseases that are still being discovered, but its extremely low bioavailability is a challenge that is to be dealt with for obtaining the full benefit. Few studies have been performed aiming at improving the bioavailability, but there are unexplored areas that can be used, a few of which are explained in this article. However, the ability to reproduce laboratory results when scaling up to the industry level is the only factor to be taken into consideration.

Chitosan-glucuronic acid conjugate coated mesoporous silica nanoparticles: A smart pH-responsive and receptor-targeted system for colorectal cancer therapy.

Glycosylated pH-sensitive mesoporous silica nanoparticles (MSNs) of capecitabine (CAP) were developed for targeting colorectal cancer. The MSNs possessed an average pore diameter of 8.12 ± 0.43 nm, pore volume of 0.73 ± 0.21 cm3/g, and particle size of 245.24 ± 5.75 nm. A high loading of 180.51 ± 5.23 mg/g attributed to the larger pore volume was observed. The surface of the drug-loaded MSNs were capped with chitosan-glucuronic acid (CHS-GCA) conjugate to combine two strategies viz. pH-sensitive, and lectin receptor mediated uptake. In vitro studies demonstrated a pH-sensitive and controlled release of CAP which was further enhanced in the presence of rat caecal content. Higher uptake of the (CAP-MSN)CHS-GCA was observed in HCT 116 cell lines. The glycosylated nanoparticles revealed reduction in the tumors, aberrant crypt foci, dysplasia and inflammation, and alleviation in the toxic features. This illustrated that the nanoparticles showed promising antitumor efficacy with reduced toxicity and may be used as a effective carrier against cancer.

Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19.

The importance of the main protease (Mpro) enzyme of SARS-CoV-2 in the digestion of viral polyproteins introduces Mpro as an attractive drug target for antiviral drug design. This study aims to carry out the molecular docking, molecular dynamics studies, and prediction of ADMET properties of selected potential antiviral molecules. The study provides an insight into biomolecular interactions to understand the inhibitory mechanism and the spatial orientation of the tested ligands and further, identification of key amino acid residues within the substrate-binding pocket that can be applied for structure-based drug design. In this regard, we carried out molecular docking studies of chloroquine (CQ), hydroxychloroquine (HCQ), remdesivir (RDV), GS441524, arbidol (ARB), and natural product glycyrrhizin (GA) using AutoDock 4.2 tool. To study the drug-receptor complex's stability, selected docking possesses were further subjected to molecular dynamics studies with Schrodinger software. The prediction of ADMET/toxicity properties was carried out on ADMET Prediction™. The docking studies suggested a potential role played by CYS145, HIS163, and GLU166 in the interaction of molecules within the active site of COVID-19 Mpro. In the docking studies, RDV and GA exhibited superiority in binding with the crystal structure of Mpro over the other selected molecules in this study. Spatial orientations of the molecules at the active site of Mpro exposed the significance of S1-S4 subsites and surrounding amino acid residues. Among GA and RDV, RDV showed better and stable interactions with the protein, which is the reason for the lesser RMSD values for RDV. Overall, the present in silico study indicated the direction to combat COVID-19 using FDA-approved drugs as promising agents, which do not need much toxicity studies and could also serve as starting points for lead optimization in drug discovery.

SARS-CoV-2 entry inhibitors by dual targeting TMPRSS2 and ACE2: An in silico drug repurposing study.

The coronavirus disease (COVID-19) is spreading between human populations mainly through nasal droplets. Currently, the vaccines have great hope, but it takes years for testing its efficacy in human. As there is no specific drug treatment available for COVID-19 pandemic, we explored in silico repurposing of drugs with dual inhibition properties by targeting transmembrane serine protease 2 (TMPRSS2) and human angiotensin-converting enzyme 2 (ACE2) from FDA-approved drugs. The TMPRSS2 and ACE2 dual inhibitors in COVID-19 would be a novel antiviral class of drugs called "entry inhibitors." For this purpose, approximately 2800 US-FDA approved drugs were docked using a virtual docking tool with the targets TMPRSS2 and ACE2. The best-fit drugs were selected as per docking scores and visual outcomes. Later on, drugs were selected on the basis of molecular dynamics simulations. The drugs alvimopan, arbekacin, dequalinum, fleroxacin, lopinavir, and valrubicin were shortlisted by visual analysis and molecular dynamics simulations. Among these, lopinavir and valrubicin were found to be superior in terms of dual inhibition. Thus, lopinavir and valrubicin have the potential of dual-target inhibition whereby preventing SARS-CoV-2 entry to the host. For repurposing of these drugs, further screening in vitro and in vivo would help in exploring clinically.

Targeting SARS-CoV-2 Main Protease: A Computational Drug Repurposing Study.

BACKGROUND AND AIMS: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) induced Novel Coronavirus Disease (COVID-19) has currently become pandemic worldwide. Though drugs like remdesivir, favipiravir, and dexamethasone found beneficial for COVID-19 management, they have limitations clinically, and vaccine development takes a long time. The researchers have reported key proteins which could act as druggable targets. Among them, the major protease Mpro is first published, plays a prominent role in viral replication and an attractive drug-target for drug discovery. Hence, to target Mpro and inhibit it, we accomplished the virtual screening of US-FDA approved drugs using well-known drug repurposing approach by computer-aided tools. METHODS: The protein Mpro, PDB-ID 6LU7 was imported to Maestro graphical user interphase of Schrödinger software. The US-FDA approved drug structures are imported from DrugBank and docked after preliminary protein and ligand preparation. The drugs are shortlisted based on the docking scores in the Standard Precision method (SP-docking) and then based on the type of molecular interactions they are studied for molecular dynamics simulations. RESULTS: The docking and molecular interactions studies, five drugs emerged as potential hits by forming hydrophilic, hydrophobic, electrostatic interactions. The drugs such as arbutin, terbutaline, barnidipine, tipiracil and aprepitant identified as potential hits. Among the drugs, tipiracil and aprepitant interacted with the Mpro consistently, and they turned out to be most promising. CONCLUSIONS: This study shows the possible exploration for drug repurposing using computer-aided docking tools and the potential roles of tipiracil and aprepitant, which can be explored further in the treatment of COVID-19.

Targeting SARS-CoV-2 RNA-dependent RNA polymerase: An in silico drug repurposing for COVID-19.

Background: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), took more lives than combined epidemics of SARS, MERS, H1N1, and Ebola. Currently, the prevention and control of spread are the goals in COVID-19 management as there are no specific drugs to cure or vaccines available for prevention. Hence, the drug repurposing was explored by many research groups, and many target proteins have been examined. The major protease (M pro), and RNA-dependent RNA polymerase (RdRp) are two target proteins in SARS-CoV-2 that have been validated and extensively studied for drug development in COVID-19. The RdRp shares a high degree of homology between those of two previously known coronaviruses, SARS-CoV and MERS-CoV. Methods: In this study, the FDA approved library of drugs were docked against the active site of RdRp using Schrodinger's computer-aided drug discovery tools for in silico drug-repurposing. Results: We have shortlisted 14 drugs from the Standard Precision docking and interaction-wise study of drug-binding with the active site on the enzyme. These drugs are antibiotics, NSAIDs, hypolipidemic, coagulant, thrombolytic, and anti-allergics. In molecular dynamics simulations, pitavastatin, ridogrel and rosoxacin displayed superior binding with the active site through ARG555 and divalent magnesium. Conclusion: Pitavastatin, ridogrel and rosoxacin can be further optimized in preclinical and clinical studies to determine their possible role in COVID-19 treatment.

Recent advances in the development of asenapine formulations.

INTRODUCTION: Asenapine maleate (AM) is an atypical antipsychotic agent, that has been widely prescribed for the management of schizoaffective disorders. However, the bioavailability of AM is extremely poor due to the extensive first-pass metabolism. With the advancement in pharmaceutical technologies, significant strides have been made to create novel formulations to address the bioavailability problem of AM. AREAS COVERED: This review article provides an insight into all the formulation approaches undertaken by researchers to increase the bioavailability of AM encompassing the works utilizing ultrasound mediated transdermal delivery, nose to brain delivery, intestinal lymphatic system targeting, in situ implants, etc. All the patents associated with AM formulation have also been discussed and summarized. EXPERT OPINION: Numerous studies have been carried out on AM formulations over the recent years, many of these studies have shown significant improvement in bioavailability. We have also mentioned the unexplored domains which can be exploited for further enhancing the bioavailability of AM. Nonetheless, most of these studies are still limited to the research laboratory level and face multiple hurdles before making into the market. Attaining controllability and reproducibility for the production of novel formulations is needed to enable its transition from bench to bedside.

Assessing the behavior management problems during the first dental visit of preschool children using a doll placement test.

CONTEXT: Assessing dental anxiety as a predictor of the likely behavior of the child in the dental operatory is of paramount importance for a clinician to render quality care. AIM: This study aims to correlate the dental anxiety of preschool children as shown during the doll placement test with that of their behavioral patterns during the first dental visit. SETTINGS AND DESIGN: This cross-sectional study was conducted between the ages of 3-7 years. MATERIALS AND METHODS: During their first dental visit, the background variables were elicited from parent/guardian at the reception desk. Later at the play area, the child was given a set of dolls representing dentist, child, and mother to place them in a model dental office having a dental chair. The child was then taken for the initial oral examination, during which the behavior of the child was rated using Frankl's Behavior Rating Scale. The data collected were analyzed using Chi-square test and binary regression analysis. RESULTS: The observed association between the doll placement pattern and the behavior of the patient during dental treatment was statistically significant (P < 0.001). The binary regression analysis showed that the child's unpleasant previous medical and parent's unpleasant dental experiences had higher odds favoring uncooperative behavior (46.63 and 41.93, respectively). CONCLUSIONS: The child's behavior on the dental chair is associated with the doll placement pattern, which is also influenced by experiences of the child during his/her encounter with the medical doctor and previous dental experiences of their parents.

Sustained release timolol maleate loaded ocusert based on biopolymer composite.

In the present investigation, the effect of timolol maleate loaded ocuserts was studied as an alternative for conventional anti-glaucoma formulation. Ocuserts were prepared using natural polymer sodium alginate and ethyl cellulose. Physico-chemical properties along with drug entrapment efficiency (94-98%), content uniformity (93.1% ±â€¯0.264-98.00% ±â€¯0.321), in vitro drug release (83.42% ±â€¯0.35 at end of 12 h), ex vivo permeation all showed satisfactory results, which was found to follow zero order kinetics. Ex vivo permeation studies showed better results, revealed that the permeability coefficient was dependent on polymer type. The sterility test accelerated stability studies and in vivo studies such as eye irritancy test, in vivo drug release of the optimized ocusert was determined. The anti-glaucoma activity was measured using Schiotz tonometer at different time interval. Significant reduction in Intra ocular pressure (IOP) within 3 days was observed in case of rabbits treated with ocusert in comparison to the rabbit treated with marketed eye drop formulation. Hence timolol maleate loaded ocuserts proved to be a promising and viable alternative over conventional eye formulation for the sustained and controlled ophthalmic drug delivery, targeting the drug within the ocular globe thus improving patient compliance for the treatment of glaucoma.