Assessment of the dual role of Lyonia ovalifolia (Wall.) Drude in inhibiting AGEs and enhancing GLUT4 translocation through LC-ESI-QTOF-MS/MS determination and in silico studies.

Introduction: Diabetes mellitus (DM) is a metabolic disorder that results in glucose accumulation in the blood, accompanied by the production of advanced glycation end products (AGEs) through glycation of cellular proteins. These AGEs interfere with insulin signaling and prevent GLUT4 membrane translocation, thereby promoting the accumulation of more glucose in the blood and causing post-diabetic complications. Methods: In this study, we examine the anti-diabetic potential of Lyonia ovalifolia (Wall.) Drude, a well-known ethnomedicinal plant of the Indian Himalayas. Considering its various medicinal properties, we analyzed its ethanolic extract and various solvent fractions for in vitro antiglycation activity and antidiabetic potential, i.e., stimulation of GLUT4 translocation. Result and Discussions: The results showed that the extract and fractions exhibited increased antiglycation activity and an increased level of GLUT4 translocation. Analysis of a further 12 bioactive compounds of ethanolic extract, identified through LC-ESI-QTOF-MS/MS, revealed the presence of three new compounds: leucothol B, rhodoterpenoids A, and leucothol A. Moreover, we performed molecular docking of identified compounds against key proteins of diabetes mellitus: the sirtuin family of NAD (+)-dependent protein deacetylases 6 (SIRT6), aldose reductase (AR), and tyrosine kinase (TK). The results showed that flavonoid luteolin showed the best binding affinity ((-12.3 kcal/mol), followed by eriodictyol, astilbin, and syringaresinol. An ADMET study showed that luteolin, eriodictyol, astilbin, and syringaresinol may be promising drug candidates belonging to the flavonoid class of compounds, with no harmful effects and complying with all the drug-likeness guidelines. Furthermore, molecular dynamics (MD) simulations on a 50 ns timescale revealed that AR protein was most stable with luteolin throughout the simulation period. Therefore, this study reveals for the first time that L. ovalifolia plays an important role in insulin homeostasis, as shown in in vitro and in silico studies.

Physicochemical parameters for design and development of lead herbicide molecules: Is 'Lipinski's rule of 5' appropriate for herbicide discovery?

BACKGROUND: Herbicide use has been a great add-on in agriculture, aiding weed management in crop fields, thereby escalating crop production. However, the development of resistance in weeds against the existing herbicides is a setback. The development of herbicide resistance has compelled the agrochemical industries to replace existing herbicides with novel agrochemicals. Developing new herbicide molecules through traditional methods is time-consuming and cost-prohibitive. The use of high-throughput virtual screening (HTVS) through physicochemical properties, de novo design and combinatorial design of molecules with cutting-edge computational methods is an alternative to the traditional techniques in lead molecule discovery. The lack of optimal physicochemical criteria for screening herbicide-like molecules has become a hindrance in the process. RESULTS: In this study, physicochemical parameters [molecular weight, aromatic atoms, rotatable bonds, hydrogen-bonding capacity, topological polar surface area (TPSA), polarity and solubility] of known herbicide molecules have been studied and evaluated, and optimal criteria have been proposed for target-specific herbicides. Properties including molecular weight and hydrogen (H)-bond acceptor atoms tend to have higher values, but the range of H-bond donor atoms is relatively lower. These are distinguishable characteristics in herbicides when compared with oral drugs. Significant variations in optimal physicochemical parameters between herbicides of different groups (targeting weeds with different modes of action) have been observed. CONCLUSION: The proposed parameters for respective target sites could be used as filters for in silico screening, designing and developing of target-specific lead herbicide molecules. © 2023 Society of Chemical Industry.

Sequence and structural similarities of ACCase protein of Phalaris minor and wheat: An insight to explain herbicide selectivity.

Uncontrolled growth of Phalaris minor in the wheat (Triticum aestivum) crop has remained a problem, leading to a massive reduction in wheat grain production. Herbicides have been used to control the weed, which leads to the development of frequent resistance in P. minor and mutant biotypes were also reported (Trp2027Cys and Ile2041Asn). Development of resistance enforced agro researchers to analyses the action of herbicide on P. minor. In this study, the sequence and structure of P. minor and T. aestivum Acetyl CoA Carboxylase (ACCase) have been analysed to locate the differences in their sequence and structure and to formulate a plausible explanation of the selectivity of herbicides which may help in the rationale discovery of noble herbicides. The sequence and 3D structure analysis of weed and wheat ACCase indicate minute differences in the distantly located amino acid residues. However, proteins are conserved at the binding site of herbicides with no mutation at the catalytic site. Analysis indicates that herbicides selectively target P. minor ACCase might be due to unknown other reasons, but not due to differences in their protein sequence and structure.