PMID- 35654625
OWN - NLM
STAT- MEDLINE
DCOM- 20230410
LR  - 20230410
IS  - 1879-0534 (Electronic)
IS  - 0010-4825 (Linking)
VI  - 146
DP  - 2022 Jul
TI  - Discovery of novel Glutaminase allosteric inhibitors through drug repurposing and 
      comparative MMGB/PBSA and molecular dynamics simulation.
PG  - 105669
LID - S0010-4825(22)00458-9 [pii]
LID - 10.1016/j.compbiomed.2022.105669 [doi]
AB  - GLS1 enzymes (Glutaminase C (GAC) and kidney-type Glutaminase (KGA)) are gaining 
      prominence as a target for tumor treatment including lung, breast, kidney, 
      prostate, and colorectal. To date, several medicinal chemistry studies are being 
      conducted to develop new and effective inhibitors against GLS1 enzymes. 
      Telaglenastat, a drug that targets the allosteric site of GLS1, has undergone 
      clinical trials for the first time for the therapy of solid tumors and 
      hematological malignancies. A comprehensive computational investigation is 
      performed to get insights into the inhibition mechanism of the Telaglenastat. 
      Some novel inhibitors are also proposed against GLS1 enzymes using the drug 
      repurposing approach using 2D-fingerprinting virtual screening method against 2.4 
      million compounds, application of pharmacokinetics, Molecular Docking, and 
      Molecular Dynamic (MD) Simulations. A TIP3P water box of 10 A was defined to 
      solvate both enzymes to improve MD simulation reliability. The dynamics results 
      were validated further by the MMGB/PBSA binding free energy method, RDF, and AFD 
      analysis. Results of these computational analysis revealed a stable binding 
      affinity of Telaglenastat, as well as an FDA approved drug Astemizole (IC(50)  approximately  
      0.9 nM) and a novel para position oriented methoxy group containing Chembridge 
      compound (Chem-64284604) that provides an effective inhibitory action against GAC 
      and KGA.
CI  - Copyright (c) 2022 Elsevier Ltd. All rights reserved.
FAU - Yousaf, Rimsha
AU  - Yousaf R
AD  - Computational Biology Lab, National Center for Bioinformatics (NCB), Quaid-i-Azam 
      University, Islamabad, Pakistan. Electronic address: rimshayousaf@gmail.com.
FAU - Navid, Afifa
AU  - Navid A
AD  - Computational Biology Lab, National Center for Bioinformatics (NCB), Quaid-i-Azam 
      University, Islamabad, Pakistan. Electronic address: afifanavid.bi@gmail.com.
FAU - Azam, Syed Sikander
AU  - Azam SS
AD  - Computational Biology Lab, National Center for Bioinformatics (NCB), Quaid-i-Azam 
      University, Islamabad, Pakistan. Electronic address: syedazam2008@gmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220527
PL  - United States
TA  - Comput Biol Med
JT  - Computers in biology and medicine
JID - 1250250
RN  - 0 (Enzyme Inhibitors)
RN  - EC 3.5.1.2 (Glutaminase)
SB  - IM
MH  - Humans
MH  - Male
MH  - Cell Line, Tumor
MH  - Drug Repositioning
MH  - Enzyme Inhibitors/pharmacology
MH  - *Glutaminase/chemistry/metabolism
MH  - Molecular Docking Simulation
MH  - *Molecular Dynamics Simulation
MH  - Reproducibility of Results
OTO - NOTNLM
OT  - 2D fingerprinting
OT  - Drug repurposing
OT  - GLS1
OT  - MMGB/PBSA
OT  - Molecular dynamics simulation
OT  - Telaglenastat
EDAT- 2022/06/03 06:00
MHDA- 2022/06/25 06:00
CRDT- 2022/06/02 22:03
PHST- 2022/02/02 00:00 [received]
PHST- 2022/05/21 00:00 [revised]
PHST- 2022/05/23 00:00 [accepted]
PHST- 2022/06/03 06:00 [pubmed]
PHST- 2022/06/25 06:00 [medline]
PHST- 2022/06/02 22:03 [entrez]
AID - S0010-4825(22)00458-9 [pii]
AID - 10.1016/j.compbiomed.2022.105669 [doi]
PST - ppublish
SO  - Comput Biol Med. 2022 Jul;146:105669. doi: 10.1016/j.compbiomed.2022.105669. Epub 
      2022 May 27.