In silico identification of angiotensin-1 converting enzyme inhibitors using text mining and virtual screening

Abstract

Cardiovascular diseases are the world’s leading cause of death. Hypertension is an important risk factor for cardiovascular and renal diseases. Angiotensin-converting enzyme (ACE) can be a possible therapeutic target for managing angiotensin I conversion to angiotensin II and ultimately controlling hypertension. Indole is an significant fragment used in many medicines approved by FDA. For this reason, the molecules in their fragments containing” indol” keywords were taken from the Specs-SC (small compound) database. The predicted therapeutc activity values (TAV) of these compounds against hypertension were evaluated using binary models of QSAR by MetaCore/MetaDrug. For the 26 separate QSAR models of toxicity, molecules with measured TAV greater than 0.5 were used. 3792 non-toxic compounds were investigated by molecular docking study and molecular dynamics simulations for their ACE inhibitory activity. Glide standard precision (SP) of Maestro Molecular Modeling pocket was used to perform molecular docking. Short molecular dynamics (MD) simulations (5-ns) were carried out by initiating the top docking poses of selected 40 molecules. To quantitatively evaluate the predicted binding affinity of a screened compound, average MM/GBSA scores of screened ligands were calculated and based on their binding free energy values, hit compounds were identified for the long (100-ns) MD simulations. Root mean square deviation and root mean square fluctuations were also calculated to assess the structural characteristics and observe fluctuations of the 100-ns time scale. Thus, with the application of text mining and integrated molecular modeling we reported novel indole-based hit inhibitors for ACE-1.

Communicated by Ramaswamy H. Sarma

Keywords:

• ACE-1
• hypertension
• indoles
• molecular docking simulations
• molecular dynamics simulations
• virtual screening
• text mining

Acknowledgement

I sincerely thank Prof. Serdar Durdagi, Head of Department of Biophysics School of Medicine, Bahcesehir University, Turkey, for his valuable suggestions which helped me to elaborate on my research ideas.

Additional information

Funding

This project was financially supported by the Scientific Technical Research Council of Turkey (Program Number 2218).