Medicinal Chemistry - Online First

Casein Kinase 2 (CK2), discovered as one of the earliest protein kinases, is a ubiquitous Ser/Thr protein kinase-specific to acidic environments. CK2 has been implicated in regulating diverse cellular processes and has been linked to the onset of various diseases, including cancer.

Consequently, modulating CK2 function has emerged as a potential therapeutic strategy. However, currently, available CK2 inhibitors or modulators often lack sufficient specificity and potency.

The results were validated through QSAR of curcumin derivatives, Pharmacophore modeling, virtual screening performed for filtered curcumin-like featured derivatives from the database, and Molecular Docking approaches. Since there is a solved crystal structure of high-resolution X-ray crystal structures of Human protein kinase CK2 alpha in complex with ferulic aldehyde.

Also, structure-based virtual screening was performed against a total of 3253 compounds from different libraries, and only the top 4 best-hit compounds with exceptional docking scores exceeding >-7 kcal/mol (more than 7 kcal/mol) were screened and analyzed. However, to validate their therapeutic potential, these compounds require in-vitro evaluation to assess their CK2 targeting ability.

Histamine Type I Receptor Antagonists (H1 blockers) are widely used to mitigate histamine-induced inflammation, particularly in allergic reactions. Histamine, a biogenic amine found in endothelial cells, vascular smooth muscle, bronchial smooth muscle, and the hypothalamus, is a key player in these responses. H1 blockers are essential in cough syrups and flu medications and are divided into two generations: first-generation H1 blockers, which are sedating and have numerous side effects, and second-generation blockers, which are non-sedating and generally less toxic but may still exhibit cross-reactivity with other receptors.

In this study, a comprehensive database of compounds was utilized alongside fexofenadine as a benchmark to discover compounds with potentially superior efficacy and reduced side effect profiles. In particular, multidimensional K-means clustering, a machine-learning technique, was applied to identify compounds with chemical structures similar to fexofenadine.

Utilizing computational prediction of pharmacokinetic profile and molecular docking experiments, the action of these drugs on the H1 receptor was assessed. Furthermore, the cross-reactivity of antihistamines was investigated by conducting a structure-based pharmacophore feature analysis of the docked poses of highly toxic antihistamines with various receptors.

By identifying and proposing the removal of common toxic features, we aim to facilitate the development of antihistamines with fewer adverse effects.

Heterocyclic derivatives, particularly those containing heteroatoms such as oxygen and nitrogen, represent a significant portion of currently marketed drugs. Among these, the aromatic heterocycle 1,3,4-oxadiazole, characterized by an N=C=O-linkage, stands out due to its remarkable biological activities. These activities include anti-inflammatory, anti-cancer, antioxidant, anti-tubercular, antiviral, anti-diabetic, and antibacterial effects. Notably, several commercially available medications, such as tiodazosin, raltegravir, zibotentan, and nesapidil, incorporate this structural motif.

This review compiles and analyzes existing synthetic methods for preparing 1,3,4-oxadiazole and its derivatives. By examining various synthetic routes and methodologies, the review provides a detailed overview of the strategies employed to generate these biologically active compounds.

The review highlights the potential of 1,3,4-oxadiazole derivatives in addressing the toxicity, side effects, and drug resistance commonly associated with existing anticancer therapies. By combining the 1,3,4-oxadiazole moiety with other heteroatoms, novel hybrid derivatives have been synthesized, demonstrating enhanced pharmacological activities across various therapeutic areas.

This comprehensive review offers valuable insights into the synthesis and pharmacological applications of 1,3,4-oxadiazoles. It serves as a crucial resource for researchers exploring the development of new therapeutic compounds, with the ultimate goal of improving public health. The review builds on existing literature from the last two decades to present an exhaustive examination of the potential of 1,3,4-oxadiazole derivatives in drug development.

We continue to struggle with the prevention and treatment of the influenza virus. The 2009 swine flu pandemic, caused by the H1N1 strain of influenza A, resulted in numerous fatalities. The threat of influenza remains a significant concern for global health, and the development of novel drugs targeting these viruses is highly desirable.

The objective of this study is to explore the inhibitory potential of terpenoid compounds against the Nucleoprotein (NP) of influenza A virus, which is a highly effective drug target due to its ability to facilitate the transcription and replication of viral RNA.

In silico research was performed to identify potential inhibitors of NP. Molecular docking studies were conducted to assess the binding of terpenoid compounds to the active site residues of the target protein. The most promising hits were then subjected to molecular dynamics simulations to examine the stability of the protein-ligand complexes. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) studies and Lipinski's rule of five were employed to evaluate the drug safety and druglikeness of the compounds.

Docking studies revealed that the terpenoid compounds bind strongly to the active site residues of the NP protein. Molecular dynamics simulations demonstrated the stability of the protein-ligand complexes for the best-hit compounds. ADMET studies and Lipinski's filter indicated that the compounds exhibit desirable drug safety and drug-likeness profiles.

This work may contribute significantly to drug discovery and the development of therapeutic agents against the influenza A virus. The identification of terpenoid compounds that bind strongly to the NP protein and exhibit favorable drug-like properties through in silico studies provides a promising foundation for further research and the development of potential inhibitors targeting this critical viral protein.

The marine habitat is a plentiful source of diverse, active compounds that are extensively utilised for their medicinal properties. Pharmaceutical trends have currently changed towards utilising a diverse range of goods derived from the marine environment.

This study aimed to examine the inhibitory effects of bioactive chemicals derived from marine algae and bacteria. The identification of these compounds was carried out through the process of Gas Chromatography-Mass Spectrometry (GC-MS) profiling. Subsequently, these compounds were subjected to docking simulations against a specific set of target proteins that are known to be frequently overexpressed in three distinct types of cancer.

From the docking results, the ligand 1,4:3,6:5,7-Tribenzal-beta-mannoheptitol was found to be effective against the proteins mTOR (PDB ID: 4JSV) and FGFR2 (PDB ID:6V6Q). The findings of this study highlight the significant benefits offered by the tool under investigation, which effectively enhances the efficiency of the docking procedures.

These compounds hold significant potential for further development and exploration in the field of cancer therapeutics.

Breast cancer remains a formidable health concern for women, necessitating the development of potent anticancer agents with improved safety profiles. Dihydropyrimidinones (DHPM), pyrazole, and benzofuran scaffolds have emerged as promising targets due to their diverse pharmacological profiles. In this study, we employed a scaffold hopping approach to design a novel DHPM-Pyrazole-Benzofuran core. A series of compounds (3a–3j) were synthesized using the Biginelli protocol, and their characterization was performed using various techniques such as FTIR, ¹H NMR, and Mass spectroscopy.

Molecular docking studies against kinesin spindle protein Eg5 (1Q0B) performed to find superior binding interactions compared to the prototype Eg5 inhibitor Monastrol. Anti breast cancer potential of these compounds was screened against the breast adrenocarcinoma MCF-7 cell line using an SRB assay.

Compound 3j showed good growth inhibitory activity (GI50=24.08μM) compared to Monastrol (GI50=32μM) employed as a positive control. Moreover, Compound 3j exhibited strong interactions with amino acids GLU-116 and ARG-119 with Eg5 protein 1Q0B.

Compound 3j fits well at the allosteric site of Eg5 protein 1QOB. Compound 3j emerged as the most cytotoxic, displaying significant and impressive growth inhibitory activity (GI50=24.08μM).