• ZOZIMUS DIVYA LOBO C Department of Chemistry, St. Mary’s College (Autonomous), Tuticorin, Tamil Nadu, India, Affiliated to Manonmanium Sundaranar University, Tirunelveli, Tamil Nadu, India.
  • SYED MOHAMED A Department of Chemistry, Sadakathullah Appa College (Autonomous), Tirunelveli, Tamil Nadu, India.
  • GNANENDRA SHANMUGAM 3Department of Biotechnology, Mahendra Arts and Science College, Namakkal, Tamil Nadu, India.


Objective: The objective of this study was to investigate the antihypertensive activity of heterocyclic compounds against angiotensin-converting enzyme (ACE) through molecular docking studies.

Methods: The X-ray crystal three-dimensional (3D) structure of human ACE complexed with lisinopril (PDB ID: 1O86) was retrieved from protein databank. The two-dimensional structures of 10 selected heterocyclic compounds were drawn in ACD-Chemsketch and converted into 3D structures. The 3D structures of compounds were virtually screened in the binding pockets of ACE using FlexX docking program. Further, the chemical entities revealing the molecular electronic structures of the best docked compound (Compound-4) were explored through density functional theory studies.

Results: The Compound-4 showed the highest docking score of −26.6290 kJ/mol with ACE. The Hbond and non-bonded interactions are favored by phenylalanine, leucine, and arginine. The energy gap of 1.60 eV between highest occupied molecular orbital and lowest unoccupied molecular orbitals explained the presence of strong electron-acceptor group. Furthermore, the molecular electrostatic potential studies clearly envisaged the requirement of electropositive and electronegative groups are crucial for the ACE inhibitor activities.

Conclusion: The identification of good ACE inhibitors requires the understanding of the current ACE inhibitors. Thus, the docking interactions of Compound-4 and its molecular electronic structure significantly imply its potential as antihypertensive agent. However, further clinical studies are required to ascertain its potential toxic effects.

Keywords: Angiotensin-converting enzyme, Angiotensin-converting enzyme inhibitors, Docking, Density functional theory studies, Highest occupied molecular orbital, Lowest unoccupied molecular orbitals, Molecular electrostatic potentials.


1. Clark RD, Strizhev A, Leonard JM, Blake JF, Matthew JB. Consensus scoring for ligand/protein interactions. J Mol Graph Model 2002;20:281-95.
2. Gehlhaar DK, Verkhivker G, Rejto PA, Fogel DB, Fogel LJ. Docking Conformationally Flexible Small Molecules into a Protein Binding Site through Evolutionary Programming. Proceedings of the Fourth International Conference on Evolutionary Programming; 1995. p. 615-27.
3. Charifson PS, Corkery JJ, Murcko MA, Walters WP. Consensus scoring: A method for obtaining improved hit rates from docking databases of three-dimensional structures into proteins. J Med Chem 1999;42:5100-9.
4. Izzo JL, Black HR, Goodfriend TL. Hypertension Primer: The Essentials of High Blood Pressure. Philadelphia, PA: Lippincott Williams and Wilkins; 2003.
5. Advanced Chemistry Development, Inc. ACD/Chem Sketch Freeware. Version 12. Toronto, ON, Canada: Advanced Chemistry Development, Inc. Available from:
6. Weininger D. SMILES, a chemical language and information system. Introduction to methodology and encoding rules. J Chem Inf Comput Sci 1998;28:31-6.
7. Natesh R, Schwager SL, Sturrock ED, Acharya KR. Crystal structure of the human angiotensin-converting enzyme-lisinopril complex. Nature 2003;421:551-4.
8. Sussman JL, Lin D, Jiang J, Manning NO, Prilusky J, Ritter O, et al. Protein data bank (PDB): Database of three-dimensional structural information of biological macromolecules. Acta Crystallogr D Biol Crystallogr 1998;54:1078-84.
9. Rarey M, Kramer B, Lengauer T, Klebe G. A fast flexible docking method using an incremental construction algorithm. J Mol Biol 1996;261:470-89.
10. Gnanendra S, Anusuya S, Natarajan J. Molecular modeling and active site analysis of sdiA homolog, a putative quorum sensor for salmonella typhimurium pathogenecity reveals specific binding patterns of AHL transcriptional regulators. J Mol Model 2012;18:4709-19.
11. Sari BL, Mun’im A, Yanuar A, Riadhi R. Screening of ?-glucosidase inhibitors from Terminalia catappa L. fruits using molecular docking method and in vitro test. Int J Pharm Pharm Sci 2016;8:184-9.
12. Anjugam C, Sridevi M, Gnanendra TS. Structure-based docking studies toward exploring the potential anticancer activity of morin against non-melanoma skin cancer therapeutic drug targets. Asian J Pharm Clin Res 2018;11:61-6.
13. Stierand K, Maass PC, Rarey M. Molecular complexes at a glance: Automated generation of two-dimensional complex diagrams. Bioinformatics 2006;22:1710-6.
14. Suresh DM, Amalanathan M, Sebastian S, Sajan D, Hubert Joe I, Bena Jothy V, et al. Vibrational spectral investigation and natural bond orbital analysis of pharmaceutical compound 7-amino-2,4- dimethylquinolinium formate-DFT approach. Spectrochim Acta A Mol Biomol Spectrosc 2013;115:595-602.
15. White WB, Prisant LM, Wright JT Jr. Management of patients with hypertension and diabetes mellitus: Advances in the evidence for intensive treatment. Am J Med 2000;108:238-45.
16. Vázquez-Valadez VH, Abrego VH, Martínez PA, Torres G, Zúñiga O, Escutia D, et al. Docking studies of methylthiomorpholin phenols (LQM300 series) with angiotensin-converting enzyme (ACE). Open Med Chem J 2013;7:30-8.
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How to Cite
LOBO C, Z. D., S. MOHAMED A, and G. SHANMUGAM. “VIRTUAL SCREENING OF HETEROCYCLIC COMPOUNDS AGAINST ANGIOTENSIN-CONVERTING ENZYME FOR POTENTIAL ANTIHYPERTENSIVE INHIBITORS”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 12, no. 2, Jan. 2019, pp. 350-5, doi:10.22159/ajpcr.2019.v12i2.29106.
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