Elbasvir

A sensitive and accurate LC/MS method for the determination of elbasvir (ELB) and grazoprevir (GZP) in human plasma was established using daclatasvir (DCT) as an internal standard. The analytes were separated on a Waters Spherisorb phenyl column (150mm×4.6mm ID, 5μm particle size) maintained at 40°C±2°C. Gradient elution, at a flow rate of 0.8mLmin^-1, was used. The mobile phase consists of 90% of acetonitrile mixed to 10% of a 5mM ammonium formate buffer (+0.1% v/v of trimethylamine, pH was adjusted to 3.2 by formic acid) as phase A and 10% of acetonitrile mixed to 90% of the same buffer as phase B. Liquid-liquid extraction with ethyl acetate solvent was used to recuperate compounds from plasma. The method was validated over a concentration range of 2 and 100ng/mL for GZP and between 1 and 50ng/mL for ELB. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels exhibited relative standard deviations (RSD)<15%, and the accuracy values ranged from 94.2 to 107.8%. The robustness of the method was established using a two-level full factorial design.

Non-small cell lung cancer (NSCLC) has been marked as the major cause of death in lung cancer patients. Due to tumor heterogeneity, mutation burden, and emerging resistance against the available therapies in NSCLC, it has been posing potential challenges in the therapy development. Hence, identification of cancer-driving mutations and their effective inhibition have been advocated as a potential approach in NSCLC treatment. Thereof, this study aims to employ the genomic and computational-aided integrative drug repositioning strategy to identify the potential mutations in the selected molecular targets and repurpose FDA-approved drugs against them. Accordingly, molecular targets and their mutations, i.e., EGFR (V843L, L858R, L861Q, and P1019L) and ROS1 (G1969E, F2046Y, Y2092C, and V2144I), were identified based on TCGA dataset analysis. Following, virtual screening and redocking analysis, Elbasvir, Ledipasvir, and Lomitapide drugs for EGFR mutants (>-10.8 kcal/mol) while Indinavir, Ledipasvir, Lomitapide, Monteleukast, and Isavuconazonium for ROS1 mutants (>-8.8 kcal/mol) were found as putative inhibitors. Furthermore, classical molecular dynamics simulation and endpoint binding energy calculation support the considerable stability of the selected docked complexes aided by substantial hydrogen bonding and hydrophobic interactions in comparison to the respective control complexes. Conclusively, the repositioned FDA-approved drugs might be beneficial alone or in synergy to overcome acquired resistance to EGFR and ROS1-positive lung cancers.