Cancer remains a global health challenge, encompassing over 200 distinct types typically classified by the specific tissues where abnormal cell growth originates. As one of the leading causes of mortality in the 21st century, cancer significantly hinders the increase of global life expectancy. The diversity and complexity of cancer types highlight the urgent need for ongoing research, prevention strategies, and improved treatment options to mitigate its global impact. In the search for new potential drug candidates acting as anticancer agents, numerous synthetic and natural compounds have been developed and tested against various cancer cells. Among these natural compounds, Arylnaphthalene lignan lactones have attracted our interest. These compounds are found in various plant species such as Phyllanthus and Cleistanthus, and exhibit a range of biological activities, including antioxidant, anti-inflammatory and anticancer properties. Arylnaphthalene lignan lactones were subjected to an in silico study to investigate their potential to act against colon cancer by inhibiting a tyrosine kinase, the Epidermal Growth Factor Receptor (EGFR). A docking simulation was performed in the active pocket of the human EGFR complexed with 4-Anilinoquinazoline (PDB: 1M17). The studied derivatives showed excellent stability inside the active site, with estimated docking scores of -8.02 and -7.96 kcal/mol. Additionally, significant interactions similar to those formed by 4-Anilinoquinazoline were present in the studied compounds, including hydrogen bonds with Met769 as well as hydrophobic contacts with residues in the EGFR cavity. Furthermore, ADMET analysis was performed to verify their pharmacokinetic properties and toxicity.

With the development of computer tools over the past 20 years, molecular modeling and more precisely molecular docking (molecular docking) has very quickly entered the field of pharmaceutical research. Our work consists of studying the inhibition of the enzyme EGFR (1M17) involved in cancer disease with deferent inhibitors derived from quinazoline and quinoline by molecular docking. The values of ligands L_1 and L_2 are the best ligands for inhibit the activity of 1M17 since it forms a stable complex with this enzyme by better binding to the active site. The results obtained show that the ligands L1 and L2 give weak interactions with the active site residues EGFR (1M17) which stabilize the complexes formed of this ligands, which gives a better binding at the level of the active site, and an RMSD of L_1 [1,9563 Å] and of L_2 [ 1,2483 Å]. [1, 9563, 1.2483] Å . All the newly designed compounds passed the pharmacokinetic analysis ( ADME – TOX) (adsorption, distribution, metabolism, excretion, and other physicochemical test) passed the drug-likeness test, and they also adhered to the Lipinski rule of five All the newly designed compounds passed the pharmacokinetic analysis (adsorption, distribution, metabolism, excretion, and other physicochemical test) passed the drug-likeness test, and they also adhered to the Lipinski rule of five

Introduction: Malaria is a major public health problem in the world, responsible for the death of millions, particularly in sub-Saharan Africa. Plasmepsins are novel targets for antimalarial drugs and are crucial to the mechanism of action by which these proteases hydrolyze peptide bonds in protein substrates. Plasmepsins I and II are the best-researched members of the aspartic protease enzyme family. The inhibition of these enzymes has pharmacological and therapeutic significance since they are involved in numerous processes, including the development, invasion, and breakdown of host hemoglobin to release amino acids for parasite sustenance. Method: In this study, in silico techniques were used to shed light on the mechanisms underlying the inhibitory effects of quercetin, quercetrin, dihydrostilbene, 4′-methoxy-isoliquiritigenin, and stigmasterol isolated from Globimetula oreophila on plasmepsin I and II proteases. Methods include; predicting their ADME properties and molecular docking analysis. Results: Isolated compounds interacted with active site residues and sub-units, regulating protease specificity, as revealed by molecular docking. The docking analysis performed on Plasmepsin-I showed that, despite the native ligand's (lig0) lower binding energy (-9.2 Kcal/mol), compound DG4 has a better binding affinity within the binding pocket of Plm-I (-8.8 Kcal/mol). It also had the lowest binding energy of -8.8 Kcal/mol with Plm-II. The mechanism of action of these compounds revealed the existence of an aspartic protease inhibitor of plasmepsin I and II. Conclusion: Phytochemicals from G. oreophila could lead to further development of potent plasmepsin inhibitors for the prevention and treatment of malaria.

Staphylococcus aureus is a gram-positive bacterium known to cause mild to severe and potentially fatal infections such as endocarditis, sepsis, meningitis, pneumonia, and bacteremia, among others. The methicillin-resistant strain of Staphylococcus aureus (MRSA) arose because the bacterium acquired an additional penicillin-binding protein by lateral gene transfer, known as penicillin-binding protein 2a (PBP2a). It is responsible for cross-linking peptidoglycan chains in forming the bacterial cell wall. According to The Lancet, MRSA was the deadliest pathogen and drug combination globally in 2019, with 121,000 deaths attributable to antimicrobial resistance. For this reason, the need for developing new PBP2a inhibitors and treating the infections caused by this bacterium is vital. In this work, a systematic study of molecular docking and molecular dynamics was carried out for a series of aza-heterocyclic compounds against PBP2a in order to determine their stability and behavior of the complex over time under physiological conditions through root mean square deviation (RMSD) and the residence of interactions by hydrogen bonds. Additionally, the binding free energy was calculated to estimate the affinity between the ligand and protein, using the MM/GBSA method, obtaining promising results concerning the co-crystallized ligand used as a reference. In addition, the pharmacokinetic properties are discussed showing promising results.

Flavonoid alkaloids represent interesting subgroup of alkaloid family. Several plants containing flavonoid alkaloids are used in the folk medicine for the treatment of various diseases. Interesting biological properties of flavonoid alkaloids make them attractive candidates for lead compounds in drug discovery. Capitavine, or 5,7-dihydroxy-6-(1-methylpiperidin-2-yl)flavone and related compounds belong to piperidine-flavonoid alkaloids, possessing a piperidine ring connected to the C6-position of flavonoid skeleton, while buchenavianine is C8 piperidine-bonded analog. Capitavine derivatives were isolated mainly from Buchenavia capitata, buchevianine derivatives are present mainly in B. macrophylla. It was found, the chloroform extract of the leaves of B. capitata showed anti-HIV activity. The biological activity of capitavine and buchevianine derivatives needs to be investigated within the perspective of their pharmacokinetic properties and the toxicity, which are important factors in finding potential drug candidate. The present in silico study using SwissADME, Osiris and Molinspiration softwares showed, studied capitavine-derived flavonoid alkaloids exhibit considerable bioactivity for GPCR ligand (0.12 to 0.20), as enzyme inhibitor (0.17 to 0.22) and as nuclear receptor ligand (0.07 to 0.28). All compounds exhibit good gastrointestinal absorption and low risk of being irritants, tumorigenic or to have reproductive effect. The risk of mutagenicity was calculated for two compounds related to buchevianin and at this point the role of 5-methoxy group appears to be crucial for the low risk of mutagenicity.

Acetylcholinesterase (AChE) is a key enzyme of cholinergic neurotransmission, acting in mammalians and insects. Depending on the type of mechanism, its inhibitors are relevant for the action of drugs in the treatment of human diseases, including Alzheimer’s disorder, and for the development of insecticides.

We report here on the results of molecular docking calculations performed on the Torpedo californica AChE (PDB ID: 6G1V) complexes of eight natural pyrrolizidine alkaloids (PAs) isolated from Solenthatus lanatus and Echium confusum plants. The data were correlated with the results previously reported by in vitro screening of 7-O-angeloylechinatine N-oxide 3’-O-acetylheliosupine N-oxide, heliosupine N-oxide, heliosupine, 7-O-angeloyllycopsamine N-oxide, echimidine N-oxide, and echimidine 7-O-angeloylretronecine as inhibitors of electric eel AChE.

Due to the known hepatoxicity of these alkaloids that prevents any potential application in human therapy, we focused on inhibiting fruit fly Drosophila melanogaster AChE (PDB ID: 6XYU). This choice is related to the role of AChE as a target of environmentally safe and selective insecticides and to the ethnobotanical interest in extracts from local plants to protect against insects and treat parasites. The data obtained by AutoDock Vina and Protein-Ligand-ANTSystem (PLANTS) indicated the presence of the hydroxylated chain as a crucial feature for the inhibitory activity of these PA structures.

ADME/Toxicity parameters were also predicted for human and eco-toxicities of all metabolites using the admetSAR tool.

The results of this in silico screening may serve as a further indication in investigating these natural molecules as scaffolds for the potential development of insecticides.

Malaria, a devastating disease caused by Plasmodium parasites, continues to pose a significant threat to global health, with increasing resistance to current antimalarial drugs. In this study, we employed an in silico approach to design and evaluate novel 2-pyrazoline carboxamide derivatives as potential protease inhibitors against Plasmodium falciparum. Our results show that all designed ligands exhibit good drug-like properties, satisfying Lipinski's rule of five, and demonstrate low toxicity profiles. Molecular docking studies revealed that five newly designed ligands (P5, P6, P7, P11, and P13) exhibit promising binding affinities and interactions with key protease enzymes involved in the hemoglobin degradation pathway, including Falcipain-2, Falcipain-3, and Plasmepsin-2 with PDB (Protein Data Bank) codes, 6JW9, 3BWK and 1LF3 respectively. Notably, ligand P13 showed the strongest binding affinity with Falcipain-2, forming an additional hydrogen bond with CYS42, a residue essential for the enzyme's catalytic activity. The interactions between the ligands and the enzymes suggest a competitive inhibition mechanism, with the potential to disrupt the hemoglobin degradation pathway and halt the parasite's lifecycle. The biological implications of these findings are significant, as they suggest that these novel ligands could be effective against Plasmodium parasites, particularly in the context of increasing resistance to current antimalarial drugs. Overall, this study provides valuable insights into the potential of novel 2-pyrazoline carboxamide derivatives as protease inhibitors against Plasmodium parasites and highlights their potential as a promising strategy for antimalarial drug development and the importance of in silico approaches in the discovery of novel therapeutics.

Background: Angiogenesis plays a major role in the process of tumour genesis through its capacity to acquire sustenance in the form of nutrients and oxygen. Hence, defining as one of the hallmarks of cancer. Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis both under normal conditions and in disease state, numerous studies has been shown that targeting VEGF has become the most prominent approach to stop tumour growth. Recently, amaranth has become an area of increasing scientific. This is due to its valuable biological properties, and wide pharmacological activity. Therefore it is of interest to study the molecular docking analysis of VEGF with amaranthin compounds as drug target discovery.

Material and methods: A molecular docking study were conclude using autodock vina briefly the VEGF 3D structure was retrieve from protein data bank under the code of 2PVF, Amaranthin were retrieve from PUBCHEM (CID 6325284) both the protein and ligand were prepare using MGLTools then dock using autodick vina (V. 4.0).

Results: the molecular docking results were vizualizate using pymol software ,our results shown that the binding affinity was - 6.8 kcal/mol. Analysis of the docking results showed that selected compound interact with VEGF protein via H bond interactions.

Conclusion: Natural products provide a promising opportunity to discover new compounds that can utilize as drugs given their chemical structure diversity. Of note Amaranthin shown an interesting drug target for targeting VEGF need further studies.

The world today, is being ravaged by the emergence and re-emergence of microbial infections caused by antimicrobial-resistant strains, brought about primarily by the frequent and perhaps unnecessarily used antimicrobial agents. A need therefore arises to develop new antimicrobial drugs that can combat these pathogens resistant to currently available antibiotics. This present study has adopted a multi-enzyme in silico approach in its evaluation of new 2-pyrazolines as antimicrobial agents, by targeting and aiming to inhibit three pivotal enzymes in the bacteria’s life cycle. A library of fifty 2-pyrazolines was tailored to achieve the desired activity. The library of compounds and amoxicillin, a standard antimicrobial drug, were docked into the molecular target enzymes. They were also subjected to toxicity and ADME tests, using PROTOX and swissADME respectively. A moderate toxicity profile was indicated, as more than 90% of the ligands were in ProTox class 4. The majority exhibited advantageous ADME characteristics. A significant number of them demonstrated a binding affinity for the target proteins that was stronger than both the native ligand and the binding affinity of amoxicillin. Ligands 30, 20, and 19 are the notable ones across all target enzymes. These results suggest that these novel ligands may be powerful inhibitors, particularly when it comes to interfering with the formation of bacterial cell walls, folic acid, and nucleotide metabolism. Additional in vivo and in vitro research is required to confirm these results and evaluate their therapeutic potential.

This study presents a comprehensive approach to designing and optimizing small molecule inhibitors targeting Salt-Inducible Kinases 2 and 3 (SIK2 and SIK3), crucial regulators of cellular signaling pathways implicated in various diseases, including cancer, inflammation, and metabolic disorders. By integrating advanced computational methods and expert-driven chemical synthesis, we generated a diverse library of potential inhibitors and meticulously evaluated their pharmacological properties and binding affinities to SIK2.

Through a rigorous analysis of generated data and molecular docking simulations, we successfully identified lead compounds with promising therapeutic potential. Subsequently, employing iterative chemical modifications guided by human expertise, we further optimized these leads, enhancing their efficacy and specificity. Additionally, employing molecular dynamics simulations provided valuable mechanistic insights into the dynamic behavior of optimized compounds within the complex biological environment, elucidating their potential as effective inhibitors of SIK2 activity.

Our findings underscore the efficacy and significance of an integrated computational and experimental approach in the development of novel therapeutics targeting SIK2 and SIK3. By bridging computational predictions with experimental validation, this approach not only accelerates the drug discovery process but also increases the likelihood of identifying clinically relevant compounds. Furthermore, the insights gained from this study lay a solid foundation for future preclinical and clinical investigations, paving the way for the development of effective treatments for diseases associated with dysregulated SIK2 and SIK3 signaling pathways.