Cassava linamarase is a hydrolyzing enzyme that belongs to a glycoside hydrolase family 1 (GH1). It is responsible for breaking down linamarin to toxic cyanide. The enzyme provides a defensive mechanism for plants against herbivores and has various applications in many fields. Understanding the structure of linamarase at the molecular level is a key to avail its reaction mechanism. In this study, the three-dimensional (3D) structure of linamarase was built for the first time using homology modelling and used to study its interaction with linamarin. Molecular docking calculations established the binding and orientation nature of linamarin, while molecular dynamics (MD) simulation established protein-ligand complexes' stability. Binding-free energy based on MM/PBSA was further used to rescore the docking results. An ensemble structure was found to be relatively stable compared to the modelled structure. This study sheds light on the exploration of linamarase towards understanding its reaction mechanisms. Communicated by Ramaswamy H. Sarma

Linamarin has been reported to have anticancer activities; however, its extraction and isolation using different solvents yield a low amount. Therefore, understanding the physical properties, such as solvents’ solubility, membrane permeability and lipophilicity and how they are associated with different solvents, is a paramount topic for discussion, especially for its potential as a drug. Linamarin has a sugar moiety with many polar groups responsible for its physical properties. Following current trends, a molecular dynamics simulation is performed to investigate its physical properties and how different solvents, such as water, methanol (MeOH), dimethyl sulfoxide (DMSO) and dichloromethane (DCM), affect such properties. In this work, we have investigated the influence of intermolecular and intramolecular hydrogen bonding and the influence of polar and non-polar solvents on the physical properties of linamarin. Furthermore, solvation free-energy and electronic structure analysis are performed. The structural analysis results show that the polar groups of linamarin have strong interactions with all solvents except the etheric oxygen groups. A detailed analysis shows intermolecular hydrogen bonding between polar solvents (water, MeOH and DMSO) and the hydroxyl oxygens of linamarin. Water exhibits the strongest interaction with linamarin’s functional groups among the investigated solvents. The findings show that within the first solvation shell, the number of water molecules is greatest, while MeOH has the fewest. Centrally to the structural analysis, solvation free energy confirms DMSO to be the best solvent since it prefers to interact with linamarin over itself, while water prefers to interact with itself. While the solute–solvent interactions are strongest between linamarin and water, the solvent–solvent interactions are strongest in water. As a result, the solvation free-energy calculations reveal that linamarin solvation is most favourable in DMSO.

Cardiovascular diseases remain a leading cause of global mortality. While statins are pivotal in managing risk, most research focuses on their derivatives. This study provides a novel computational evaluation of statin analogs, addressing a significant literature gap. Our comprehensive in silico approach, integrating ADMET profiling, molecular docking, and extensive 200‐ns molecular dynamics (MD) simulations, investigated the pharmacokinetic behavior, binding affinities, and structural stability of five statin analogs against HMG‐CoA reductase. ADMET analysis showed that analogs of simvastatin, lovastatin, and pravastatin have favorable pharmacological profiles and low toxicity. While docking showed that simvastatin and lovastatin analogs had the strongest affinities, MD offered critical mechanistic insights. The unbound enzyme exhibited significant conformational flexibility. In contrast, binding induced a superior stabilizing effect, confining the protein to a single, compact, low‐energy state, as confirmed by free energy landscape analysis. This ligand‐induced rigidity is a powerful indicator of enhanced inhibitory efficacy and stability. Our findings highlight that statin analogs are a promising class whose unique binding dynamics offer a new, rational pathway for designing more effective HMG‐CoA reductase inhibitors.

Aging is a natural process that is also influenced by some factors like the food someone eats, lifestyle decisions, and impacts on general health. Despite the recognized role of nutrition in modulating the molecular and cellular mechanisms underlying aging, there is a lack of comprehensive exploration into potential interventions that can effectively mitigate these effects. In this study, we investigated the potential anti-aging properties of vitamin D by examining its interactions with key molecular targets involved in aging-related pathways. By using molecular docking and dynamics techniques, we evaluate the interactions and stability of vitamins D2 and D3 with key proteins involved in aging pathways, such as SIRT1, mTOR, AMPK, Klotho, AhR, and MAPK. Our results reveal promising binding affinities between vitamin D and SIRT1 forms, with energy values of −48.33 kJ/mol and −45.94 kJ/mol for vitamins D2 and D3, respectively, in aqueous environments. Moreover, molecular dynamics simulations revealed that the vitamin D3–SIRT1 complex exhibited greater stability compared with the vitamin D2–SIRT1 complex. The study calculated the solvation free energy to compare the solubility of vitamins D2 and D3 in water and various organic solvents. Despite their strong interactions with water, both vitamins exhibited low solubility, primarily due to the high energy cost associated with cavity formation in the aqueous environment. Compared with other solvents, water demonstrated particularly low solubility for both vitamins. This suggested that vitamins D2 and D3 preferred binding to aging receptors over dissolving in bulk aqueous environments, supporting their strong therapeutic interactions with these receptors. These findings shed light on the molecular mechanisms underlying vitamin D’s potential anti-aging effects and lay the groundwork for developing nutraceuticals targeting aging and associated diseases. Understanding these mechanisms holds promise for future interventions aimed at promoting healthy aging and enhancing overall well-being.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health burden, particularly due to multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Rifampicin, a frontline anti-TB drug that inhibits RNA polymerase, has been central to therapy, but rpoB mutations compromise its efficacy. This highlights the need for Rifampicin analogues that target alternative enzymes to sustain therapeutic effectiveness. In this study, a structure-based computational approach was employed to screen Rifampicin analogues against enoylacyl carrier protein reductase (InhA), a validated enzyme in the biosynthesis of mycolic acids. A library of 399 analogues was retrieved from SwissSimilarity and evaluated using ADMET analysis, with the best candidates showing favourable pharmacokinetic profiles and compliance with Lipinski’s Rule of Five. Molecular docking identified ZINC000013629834 (−10.90 kcal/mol) and ZINC000253411694 (−10.36 kcal/mol) as superior to Rifampicin (−9.05 kcal/mol), with ILE21, SER20, and THR196 consistently stabilizing interactions. Molecular dynamics simulations confirmed the stability of the complexes, with RMSD values of 0.167 nm, 0.175 nm, and 0.297 nm for ZINC000013629834, ZINC000253411694, and Rifampicin, respectively. MM/PBSA analysis showed comparable binding free energies. These findings suggest that optimized Rifampicin analogues targeting InhA may overcome rpoB-associated resistance and serve as promising leads for next-generation anti-TB drug development.