In Silico and In Vivo Approaches to Evaluate the Cardioprotective Potential of Citronellal by Targeting HMG-CoA Reductase
Nauseen Bachannagari, G. S. N. Koteswara Rao, Alekhya Kella, Deepak A. Yaraguppi, Niranjan Kumar Raghupathi, Praveen Kumar Pasala, Dintakurthi Sree Naga Bala Krishna Prasanth · Journal of Computational Biophysics and Chemistry · 2025
Cardiovascular diseases are major problems worldwide, and lipid profile deregulation and oxidative stress further exacerbate these conditions. The enzyme HMG-CoA reductase is very important in cholesterol synthesis and is thus highly targeted and important in the therapeutic arena. Compared with statins such as atorvastatin (ATV), citronellal (CIT), a natural monoterpenoid, has been studied for its cardioprotective benefits. The cardioprotective effect of CIT on isoprenaline (ISO)-induced myocardial infarction (MI) was investigated by combining in silico analysis with in vivo rat experiments. In silicoanalysis was used to assess the binding affinity of CIT for HMG-CoA reductase via molecular docking, followed by molecular dynamics simulations to evaluate the stability of the CIT-HMG-CoA reductase complex. In vivo evaluation included ECG measurements, biomarkers of cardiac function, lipid profiles, antioxidant levels, lipid peroxidation and histopathology after CIT treatment in ISO-induced MI rats. Data analyses involved the treatment of the combinations with controls across different parameters. CIT binds to HMG-CoA reductase with an affinity of −5.8 kcal/mol, whereas ATV binds with an affinity of −6.9 kcal/mol because of additional hydrogen bonding and favorable electrostatic interactions with critical active site residues. MD simulations confirmed the stability of both the CIT and ATV complexes, with total binding energies of −80.22 kJ/mol for CIT and −109.69 kJ/mol for ATV. In vivo, CIT treatment (50 mg/kg and 100 mg/kg) significantly reduced ISO-induced MI, as evidenced by the modified lipid profile, decreased CkMB and lactate dehydrogenase levels, and reduced oxidative stress marker levels. Histological studies further confirmed the cardioprotective effects of CIT, which could mitigate cardiac damage. CIT can be used as a natural statin-like HMG-CoA reductase inhibitor with cardioprotective activity against hypercholesterolemia and cardiovascular disorders. These findings suggest that CIT may be a potential cardiovascular health therapy and needs to be tested clinically.