PMID- 35855326
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220907
IS  - 1040-0400 (Print)
IS  - 1572-9001 (Electronic)
IS  - 1040-0400 (Linking)
VI  - 33
IP  - 5
DP  - 2022
TI  - A computational evaluation of FDA medicines' ability to inhibit hypoxia-inducible 
      factor prolyl hydroxylase-2 (PHD-2) for acute respiratory distress syndrome.
PG  - 1391-1407
LID - 10.1007/s11224-022-02012-z [doi]
AB  - COVID-19 infection is associated with a significant fatality rate in individuals 
      suffering from severe acute respiratory distress syndrome (ARDS). Among the 
      several possibilities, inhibition of hypoxia-inducible factor prolyl 
      hydroxylase-2 or prolyl hydroxylase domain-containing protein 2 (PHD2) in a 
      hypoxia-independent way is a prospective therapeutic target for the treatment of 
      ARDS. Vadadustat, Roxadustat, Daprodustat, Desidustat, and Enarudustat are the 
      available clinical trial inhibitors. This study is proposed to focus on the 
      repurposing of FDA-approved drugs as effective PHD2 inhibitors. This 
      computational study utilises e-pharmacophore hypothesis generation from the 
      native ligand-protein complex (PDB ID: 5OX6) based on XP visualiser information. 
      The hypothesis containing five essential features (AAANR) was incorporated for 
      FDA database screening, followed by Glide XP molecular docking and Prime MM-GBSA 
      binding free energy calculations. Top scored ligands were investigated and 
      Fenbufen was identified as an effective PHD-2 inhibitor by comparing with the 
      native co-crystal ligand (Vadadustat). The manual lead optimisation of the 
      Fenbufen structure was adopted to improve inhibitory potency, by increasing the 
      binding affinity and protein-ligand stability. The newly designed compounds B and 
      C showed additional binding interactions, excellent docking scores, binding free 
      energy, and an acceptable range of ADME properties. Also, Fenbufen and compound C 
      owned preferable protein-ligand stability during MD simulation when compared with 
      the co-crystallised clinical trial ligand. Based on our findings, we deduce that 
      Fenbufen can be proposed as an effective repurposable candidate as its structural 
      modification showed a remarkable improvement in PHD2 inhibition. SUPPLEMENTARY 
      INFORMATION: The online version contains supplementary material available at 
      10.1007/s11224-022-02012-z.
CI  - (c) The Author(s), under exclusive licence to Springer Science+Business Media, LLC, 
      part of Springer Nature 2022.
FAU - Chandrasekaran, Jaikanth
AU  - Chandrasekaran J
AUID- ORCID: 0000-0002-5088-9683
AD  - Department of Pharmacology, School of Pharmacy & Technology Management, SVKM'S 
      NMIMS University, Polepally SEZ, TSIIC, Plot no. B4, Green Industrial Park, 
      Jadcherla, Hyderabad Telangana 509 301 India.
FAU - Balasubramaniam, Jayasudha
AU  - Balasubramaniam J
AD  - Department of Pharmacology, PSG College of Pharmacy, Coimbatore, India. GRID: 
      grid.418789.b. ISNI: 0000 0004 1767 5602
LA  - eng
PT  - Journal Article
DEP - 20220709
PL  - United States
TA  - Struct Chem
JT  - Structural chemistry
JID - 101582397
PMC - PMC9282623
OTO - NOTNLM
OT  - ADME prediction
OT  - Acute respiratory distress syndrome (ARDS)
OT  - COVID-19
OT  - Fenbufen
OT  - Hypoxia-inducible factor prolyl hydroxylase-2 (PHD-2) inhibitors
OT  - MD simulations
OT  - Prime MM-GBSA
OT  - e-Pharmacophore modelling
COIS- Conflict of interestThe authors declare no competing interests.
EDAT- 2022/07/21 06:00
MHDA- 2022/07/21 06:01
PMCR- 2022/07/14
CRDT- 2022/07/20 02:14
PHST- 2022/05/02 00:00 [received]
PHST- 2022/06/30 00:00 [accepted]
PHST- 2022/07/21 06:00 [pubmed]
PHST- 2022/07/21 06:01 [medline]
PHST- 2022/07/20 02:14 [entrez]
PHST- 2022/07/14 00:00 [pmc-release]
AID - 2012 [pii]
AID - 10.1007/s11224-022-02012-z [doi]
PST - ppublish
SO  - Struct Chem. 2022;33(5):1391-1407. doi: 10.1007/s11224-022-02012-z. Epub 2022 Jul 
      9.