Unlocking potential inhibitors for Bruton's tyrosine kinase through in-silico drug repurposing strategies.

Bruton's tyrosine kinase (BTK) is a non-receptor protein kinase that plays a crucial role in various biological processes, including immune system function and cancer development. Therefore, inhibition of BTK has been proposed as a therapeutic strategy for various complex diseases. In this study, we aimed to identify potential inhibitors of BTK by using a drug repurposing approach. To identify potential inhibitors, we performed a molecular docking-based virtual screening using a library of repurposed drugs from DrugBank. We then used various filtrations followed by molecular dynamics (MD) simulations, principal component analysis (PCA), and Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) analysis to further evaluate the binding interactions and stability of the top-ranking compounds. Molecular docking-based virtual screening approach identified several repurposed drugs as potential BTK inhibitors, including Eltrombopag and Alectinib, which have already been approved for human use. All-atom MD simulations provided insights into the binding interactions and stability of the identified compounds, which will be helpful for further experimental validation and optimization. Overall, our study demonstrates that drug repurposing is a promising approach to identify potential inhibitors of BTK and highlights the importance of computational methods in drug discovery.

A virtual screening investigation to identify bioactive natural compounds as potential inhibitors of cyclin-dependent kinase 9.

Cyclin-dependent kinase 9 (CDK9) is a transcription-associated protein involved in controlling the cell cycle and is often deregulated in stress conditions. CDK9 is being studied as a well-known druggable target for developing effective therapeutics against a wide range of cancer, cardiac dysfunction and inflammatory diseases. Owing to the significance of CDK9 in the etiology of hematological and solid malignancies, its structure, biological activity, regulation and its pharmacological inhibition are being explored for therapeutic management of cancer. We employed a structure-based virtual high-throughput screening of bioactive compounds from the IMPPAT database to discover potential bioactive inhibitors of CDK9. The preliminary results were obtained from the Lipinski criteria, ADMET parameters and sorting compounds without any PAINS patterns. Subsequently, binding affinity and selectivity analyses were used to find effective CDK9 hits. This screening resulted in the identification of two natural compounds, Glabrene and Guggulsterone with high affinity and specificity for the CDK9 binding site. Both compounds exhibit drug-like characteristics, as projected by ADMET analysis, physicochemical data and PASS evaluation. Both compounds preferentially bind to the ATP-binding pocket of CDK9 and interact with functionally important residues. Further, the dynamics and consistency of CDK9 interaction with Glabrene and Guggulsteron were evaluated through all-atom molecular dynamic (MD) simulations which suggested the stability of both complexes. The results might be deployed to introduce novel CDK9 inhibitors that may treat life-threatening diseases, including cancer.Communicated by Ramaswamy H. Sarma.

TF and TCF4 gene polymorphisms are linked to autism spectrum disorder: a case-control study.

OBJECTIVE: Although the prevalence of autism spectrum disorder (ASD) is increasing, appropriate diagnosis and prevention strategies are still lacking. This case-control study was designed to explore the association between ASD and the rs1867503 and rs9951150 polymorphisms of the TF and TCF4 genes, respectively. METHODS: Ninety-six children with ASD and 118 healthy children were recruited and polymerase chain reaction-restriction fragment length polymorphism technique was applied for genotyping. RESULTS: The frequencies of the mutant allele G were 48% and 44% for the rs1867503 and rs9951150 polymorphisms, respectively. In our analysis, both TF and TCF4 polymorphisms were associated with an increased risk of developing ASD. AG heterozygotes (OR = 3.18), GG mutant homozygotes (OR = 2.62), AG + GG combined genotypes (OR = 2.98), and G mutant alleles of TF rs1867503 (OR = 1.94) were associated with a significantly elevated risk of ASD. Likewise, AG heterozygotes (OR = 2.92), GG mutant homozygotes (OR = 2.36), AG + GG combined genotypes (OR = 2.72), and G minor alleles of TCF4 rs9951150 (OR = 1.92) were associated with a significantly elevated risk of ASD. CONCLUSIONS: Our results indicate that TF rs1867503 and TCF4 rs9951150 polymorphisms may be strongly associated with the development of ASD in Bangladeshi children.

Unravelling Binding of Human Serum Albumin with Galantamine: Spectroscopic, Calorimetric, and Computational Approaches.

Human serum albumin (HSA), an abundant plasma protein, binds to various ligands, acting as a transporter for numerous endogenous and exogenous substances. Galantamine (GAL), an alkaloid, treats cognitive decline in mild to moderate Alzheimer's disease and other memory impairments. A vital step in pharmacological profiling involves the interaction of plasma protein with the drugs, and this serves as an essential platform for pharmaceutical industry advancements. This study is carried out to understand the binding mechanism of GAL with HSA using computational and experimental approaches. Molecular docking revealed that GAL preferentially occupies Sudlow's site I, i.e., binds to subdomain IIIA. The results unveiled that GAL binding does not induce any conformational change in HSA and hence does not compromise the functionality of HSA. Molecular dynamics simulation (250 ns) deciphered the stability of the HSA-GAL complex. We performed the fluorescence binding and isothermal titration calorimetry (ITC) to analyze the actual binding of GAL with HSA. The results suggested that GAL binds to HSA with a significant binding affinity. ITC measurements also delineated thermodynamic parameters associated with the binding of GAL to HSA. Altogether, the present study deciphers the binding mechanism of GAL with HSA.

Alzheimer's Disease - Future Therapy Based on Dendrimers.

Alzheimer's disease (AD) is characterized by the loss of neurons. It is the most common cause of dementia in the elderly population accompanied by pathological degeneration of neurofibrillary tangles. Senile plaques are formed with beta-amyloid, hyperphosphoryled tau protein, apolipoprotein E and presenilin associated with protease activity [amyloid beta (Aß), gamma-secretase (γS)]. The molecular mechanisms of neurodegeneration include apoptosis, oxidative stress (free radical generation), inflammation, immune activation, and others. The lack of effective treatments for AD stems mainly from the incomplete understanding the causes of AD. Currently, there are several hypotheses explaining the early mechanisms of AD pathogenesis. Recent years witnessed an unprecedented research growth in the area of nanotechnology, which uses atomic, molecular and macromolecular methods to create products in microscale (nanoscale) dimensions. In this article, we have discussed the role of nanotechnology in the development and improvement of techniques for early diagnosis and effective treatment of AD. Since AD pathology is practically irreversible, applications of disease-modifying treatments could be successful only if early diagnosis of AD is available. This review highlights various possibilities for the early diagnosis and therapy of AD and investigates potential adaptation of nanoparticles-dendrimers as a class of well-defined branched polymers that are chemically synthesized with a well-defined shape, size and nanoscopic physicochemical properties reminiscent of the proteins for the treatment of neurodegenerative diseases.