In silico Studies of Cilnidipine Degradation Products for Structure Confirmation, Toxicity Prediction and Molecular Docking

Abstract

In this study, a comprehensive analysis of cilnidipine and its degradation products (KD1-KD4 and CD1-CD3) with three main objectives viz. (i) toxicity prediction for bacterial mutagenicity, (ii) assessment of pharmacological activity and (iii) density functional theory (DFT) calculations were performed for structure confirmation. For bacterial mutagenicity prediction, in silico assessments were performed following ICH M7 guidelines. Using rule-based and statistical-based methodologies, predictions revealed an alerting group in CD1-CD3, while no alerting group was observed in KD1-KD4 for bacterial mutagenicity. To assess pharmacological activity, docking studies were conducted to identify the mode of binding and interaction types of cilnidipine and its degradation products with N-type and L-type calcium channel subunits 7VFS and 7UHF, respectively. Additionally, 20 drugs acting as calcium channel blockers were considered for docking analysis to correlate the affinities of binding. The interaction energies revealed that molecule CD3 shows the highest binding affinity with the ligand molecules, with a binding energy of -9.2 (kcal/mol) with 7VFS and -8.7 (kcal/mol) with 7UHF proteins, followed by KD3 with a binding energy of -8.7 (kcal/mol) (7VFS) and -7.9 (kcal/mol) (7UHF). Furthermore, DFT calculations were employed to reassess the structures of degradation products CD1 and CD2 proposed in the literature. Simulating 1H and 13C NMR spectra, the obtained data demonstrated good agreement with experimental results, confirming the proposed stereo-configurations in the literature. Based on in silico bacterial mutagenicity predictions and docking studies, KD3 emerged as a promising compound for receptor binding. Additionally, DFT calculations provided structural insights, affirming stereo-configurations proposed in the existing literature. This multifaceted approach contributed valuable insights into the toxicity, pharmacology and structural aspects of cilnidipine degradation products.