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In silico elucidation of potential drug targets against oxygenase domain of Human eNOS Dysfunction

Authors :
Abbeha Malik
Muhammad Nasir Iqbal
Sidrah Ashraf
Muhammad Saleem Khan
Samar Shahzadi
Muhammad Farhan Shafique
Zureesha Sajid
Muhammad Sajid
Sheikh Arslan Sehgal
Source :
PLoS ONE, Vol 18, Iss 4 (2023)
Publication Year :
2023
Publisher :
Public Library of Science (PLoS), 2023.

Abstract

Nitric Oxide (NO) signaling pathway plays a vital role in various physiological and pathophysiological processes including vasodilation, neurogenesis, inflammation, translation and protein regulation. NO signaling pathway is associated with various diseases such as cardiovascular diseases, vision impairment, hypertension and Alzheimer’s disease. Human Endothelial Nitric Oxide Synthase (eNOS) bound with calcium regulatory protein (calmodulin (CaM)) to produce NO which initiates cGMP pathway. The current study employs to screen the novel compounds against human eNOS independent of calcium regulatory protein (CaM). The current effort emphasized that the deficiency of CaM leads to dysfunction of cGMP signaling pathway. In this work, a hybrid approach of high-throughput virtual screening and comparative molecular docking studies followed by molecular dynamic simulation analyses were applied. The screening of top ranked two novel compounds against eNOS were reported that showed effective binding affinity, retrieved through the DrugBank and ZINC database libraries. Comparative molecular docking analyses revealed that Val-104, Phe-105, Gln-247, Arg-250, Ala-266, Trp-330, Tyr-331, Pro-334, Ala-335, Val-336, Tyr-357, Met-358, Thr-360, Glu-361, Ile-362, Arg-365, Asn-366, Asp-369, Arg-372, Trp-447 and Tyr-475 are potent residues for interactional studies. High-throughput virtual screening approach coupled with molecular dynamic simulation and drug likeness rules depicted that ZINC59677432 and DB00456 are potent compounds to target eNOS. In conclusion, the proposed compounds are potent against eNOS based on extensive in silico analyses. Overall, the findings of this study may be helpful to design therapeutic targets against eNOS.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
19326203
Volume :
18
Issue :
4
Database :
Directory of Open Access Journals
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
edsdoj.44625d5e2954648b2af412381aa777b
Document Type :
article