Frakefamide

Leflunomide (LEF) is a well-known disease-modifying anti-rheumatic agent (DMARDs) that was approved in 1998 for rheumatoid arthritis (RA) management. It is enzymatically converted into active metabolite teriflunomide (TER) inside the body. LEF and TER possess several pharmacological effects in a variety of diseases including multiple sclerosis, cancer, viral infections and neurobehavioral brain disorders. Despite the aforementioned pharmacological effects exploring these effects in nanomedicine applications has been focused mainly on RA and cancer treatment. This review summarises the main pharmacological, and pharmacokinetic effects of LEF along with highlighting the applications of nanoencapsulation of LEF and its metabolite in different diseases.

Biomolecular association of an anticancer drug, leflunomide (LEF) with human serum albumin (HSA), the leading ligands carrier in human circulation was characterized using biophysical (i.e., fluorescence, absorption and voltammetric) methods and computational (i.e., molecular docking and molecular dynamics simulation) techniques. Evaluations of fluorescence, absorption and voltammetric findings endorsed the complex formation between LEF and HSA. An inverse relationship of Stern-Volmer constant-temperature and hyperchromic shift of the protein's absorption signal with addition of LEF confirmed the LEF quenched the HSA fluorescence through static process. Moderate nature of binding strength (binding constant = 2.76-4.77 × 10⁴ M^-1) was detected towards the LEF-HSA complexation, while the association process was naturally driven via hydrophobic interactions, van der Waals interactions and hydrogen bonds, as evident from changes in entropy (ΔS= + 19.91 J mol^-1 K^-1) and enthalpy (ΔH = - 20.09 kJ mol^-1), and molecular docking assessments. Spectral analyses of synchronous and three-dimensional fluorescence validated microenvironmental fluctuations near Trp and Tyr residues upon LEF binding to the protein. LEF association with HSA significantly defended temperature-induced destabilization of the protein. Although LEF was found to attach to HSA at Sudlow's sites I and II, but exhibited greater preference toward its site I, as detected by the investigations of competitive site-marker displacement. Molecular dynamics simulation assessment revealed that the complex attained equilibrium throughout simulations, showing the LEF-HSA complex constancy.Communicated by Ramaswamy H. Sarma.