In silico studies of Cilnidipine oxidative degradants for structure confirmation, toxicity prediction and molecular docking

Abstract

AbstractOxidative degradation products (KD1 to KD4 and CD1 to CD3) of Cilnidipine has been isolated and characterized using Mass, FTIR and NMR studies in the reported article. The elucidated structures of CD1 and CD2 are shown 5 chiral centers each against one chiral center of API. The CD1 and CD2 structures could exhibit 16 enantiomeric pairs for each. NMR experimental data confirmed one enantiomer pair out of the possible isomers. Due to the complexity for structure confirmation of CD1 and CD2. In the current study, revisited the elucidated structures of CD1 and CD2 and reconfirmed using computational studies. NMR chemical shifts of hydrogen and carbon atoms of CD1 and CD2 are theoretically generated using the density functional theory (DFT) in DMSO. These values were compared with experimentally obtained chemical shift values. The results are in good agreement with the DFT calculations in terms of the chemical shifts and the stereo-configurations as well. Docking studies are carried out to identify the interactions and mode of binding of the Cilnidipine and their degradation products (KD1 to KD4 and CD1 to CD3) with the N-type Calcium channel subunit. Additionally, 20 drugs acting as Calcium channel blockers are also considered for docking analysis to correlate the affinities of binding. The interactions reveal the amino acid residues which are involved in binding. CD3 molecule shows the highest bind affinity with the ligand molecules with binding energy -9.3 (kcal/mol) and then KD3 with binding energy -8.7 (kcal/mol). Conducted in-silico toxicity predictions for Cilnidipine and their degradation products (KD1 to KD4 and CD1 to CD3). Two complementary methodologies; rule-based and statistical-based methodologies are applied to predict the bacterial mutagenicity and classified the impurities in accordance with ICH M7. The Alerting group is observed in CD1 to CD3 and no alerting group is observed in KD1 to KD4 for bacterial mutagenicity prediction. Based on in-silico toxicity predictions and docking studies, KD3 can be considered as a potential compound for binding with receptor molecule.