PMID- 37423019
OWN - NLM
STAT- MEDLINE
DCOM- 20230814
LR  - 20230817
IS  - 1873-4243 (Electronic)
IS  - 1093-3263 (Linking)
VI  - 124
DP  - 2023 Nov
TI  - The role of glycerol-water mixtures in the stability of FKBP12-rapalog-FRB 
      complexes.
PG  - 108556
LID - S1093-3263(23)00154-7 [pii]
LID - 10.1016/j.jmgm.2023.108556 [doi]
AB  - The thermodynamic and biophysical implications of the introduction of a 
      co-solvent during protein-ligand binding remain elusive. Using ternary complexes 
      of 12-kDa FK506 binding protein (FKBP12), FKBP-rapamycin binding (FRB) domain of 
      the mammalian/mechanistic target of rapamycin (mTOR) kinase, and rapamycin 
      analogs (rapalogs) in glycerol-water mixtures, the influence of solvent 
      composition on ligand binding dynamics was explored. The pharmaceutical potential 
      of rapalogs and the utility of glycerol as a co-solvent in drug delivery 
      applications were critical in deciding the system to be studied. Consolidation of 
      existing studies on rapamycin modification was first performed to strategically 
      design a new rapalog called T1. The results from 100-ns dual-boost Gaussian 
      accelerated molecular dynamics simulations showed that protein stability was 
      induced in the presence of glycerol. Reweighting of the trajectories revealed 
      that the glycerol-rich solvent system lowers the energy barrier in the 
      conformational space of the protein while also preserving native contacts between 
      the ligand and the residues in the binding site. Calculated binding free energies 
      using MM/GBSA also showed that electrostatic energy and polar contribution of 
      solvation energy are heavily influenced by the changes in solvation. Glycerol 
      molecules are preferentially excluded through electrostatic interactions from the 
      solvation shell which induce complex stability as seen in existing experiments. 
      Hence, using glycerol as a co-solvent in rapamycin delivery has a significant 
      role in maintaining stability. In addition, compound T1 is a potential 
      mTORC1-selective inhibitor with strong affinity for the FKBP12-FRB complex. This 
      study aims to provide insights on the design of new rapalogs, and the 
      applicability of glycerol as co-solvent for FKBP12-rapalog-FRB complexes.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Lopez, Joshua Jener D
AU  - Lopez JJD
AD  - Institute of Chemistry, College of Science, University of the Philippines 
      Diliman, Quezon City, 1101, Philippines.
FAU - Gaza, Jokent T
AU  - Gaza JT
AD  - Institute of Chemistry, College of Science, University of the Philippines 
      Diliman, Quezon City, 1101, Philippines.
FAU - Nellas, Ricky B
AU  - Nellas RB
AD  - Institute of Chemistry, College of Science, University of the Philippines 
      Diliman, Quezon City, 1101, Philippines. Electronic address: rbnellas@up.edu.ph.
LA  - eng
PT  - Journal Article
DEP - 20230621
PL  - United States
TA  - J Mol Graph Model
JT  - Journal of molecular graphics & modelling
JID - 9716237
RN  - EC 5.2.1.- (Tacrolimus Binding Protein 1A)
RN  - 0 (MTOR Inhibitors)
RN  - PDC6A3C0OX (Glycerol)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 059QF0KO0R (Water)
RN  - 0 (Ligands)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 5.2.1.- (Tacrolimus Binding Proteins)
RN  - 0 (Solvents)
SB  - IM
MH  - Animals
MH  - *Tacrolimus Binding Protein 1A/chemistry/metabolism
MH  - *MTOR Inhibitors
MH  - Glycerol
MH  - TOR Serine-Threonine Kinases
MH  - Water/chemistry
MH  - Ligands
MH  - Sirolimus/pharmacology/metabolism
MH  - Tacrolimus Binding Proteins
MH  - Solvents
MH  - Mammals/metabolism
OTO - NOTNLM
OT  - Gaussian accelerated molecular dynamics
OT  - Glycerol-water mixture
OT  - Rapalogs
OT  - Rapamycin
OT  - mTOR inhibitors
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/07/10 00:42
MHDA- 2023/08/14 06:42
CRDT- 2023/07/09 18:04
PHST- 2022/11/12 00:00 [received]
PHST- 2023/04/27 00:00 [revised]
PHST- 2023/06/16 00:00 [accepted]
PHST- 2023/08/14 06:42 [medline]
PHST- 2023/07/10 00:42 [pubmed]
PHST- 2023/07/09 18:04 [entrez]
AID - S1093-3263(23)00154-7 [pii]
AID - 10.1016/j.jmgm.2023.108556 [doi]
PST - ppublish
SO  - J Mol Graph Model. 2023 Nov;124:108556. doi: 10.1016/j.jmgm.2023.108556. Epub 
      2023 Jun 21.