Jawarkar, Rahul D and Zaki, Magdi E A and Al-Hussain, Sami A and Al-Mutairi, Aamal A and Samad, Abdul and Mukerjee, Nobendu and Ghosh, Arabinda and Masand, Vijay H and Long, Chiau Ming * and Rashid, Summya (2024) QSAR modeling approaches to identify a novel ACE2 inhibitor that selectively bind with the C and N terminals of the ectodomain. Journal of Biomolecular Structure and Dynamics, 42 (5). pp. 2550-2569. ISSN 1538-0254
Full text not available from this repository. (Request a copy)Abstract
Due to the high rates of drug development failure and the massive expenses associated with drug discovery, repurposing existing drugs has become more popular. As a result, we have used QSAR modelling on a large and varied dataset of 657 compounds in an effort to discover both explicit and subtle structural features requisite for ACE2 inhibitory activity, with the goal of identifying novel hit molecules. The QSAR modelling yielded a statistically robust QSAR model with high predictivity (R2tr=0.84, R2ex=0.79), previously undisclosed features, and novel mechanistic interpretations. The developed QSAR model predicted the ACE2 inhibitory activity (PIC50) of 1615 ZINC FDA compounds. This led to the detection of a PIC50 of 8.604 M for the hit molecule (ZINC000027990463). The hit molecule's docking score is -9.67 kcal/mol (RMSD 1.4). The hit molecule revealed 25 interactions with the residue ASP40, which defines the N and C termini of the ectodomain of ACE2. The HIT molecule conducted more than thirty contacts with water molecules and exhibited polar interaction with the ARG522 residue coupled with the second chloride ion, which is 10.4 nm away from the zinc ion. Both molecular docking and QSAR produced comparable findings. Moreover, MD simulation and MMGBSA studies verified docking analysis. The MD simulation showed that the hit molecule-ACE2 receptor complex is stable for 400 ns, suggesting that repurposed hit molecule 3 is a viable ACE2 inhibitor.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Angiotensin converting enzyme-2; MD simulation; MMGBSA; QSAR; molecular docking; ACE2 |
| Subjects: | Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Others > Non Sunway Academics Sunway University > School of Medical and Life Sciences [formerly School of Healthcare and Medical Sciences until 2020] |
| Depositing User: | Ms Yong Yee Chan |
| Related URLs: | |
| Date Deposited: | 02 May 2024 02:25 |
| Last Modified: | 15 May 2024 06:45 |
| URI: | http://eprints.sunway.edu.my/id/eprint/2550 |
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