PMID- 37943667
OWN - NLM
STAT- MEDLINE
DCOM- 20231123
LR  - 20240501
IS  - 1520-5126 (Electronic)
IS  - 0002-7863 (Print)
IS  - 0002-7863 (Linking)
VI  - 145
IP  - 46
DP  - 2023 Nov 22
TI  - How Robust Is the Ligand Binding Transition State?
PG  - 25318-25331
LID - 10.1021/jacs.3c08940 [doi]
AB  - For many drug targets, it has been shown that the kinetics of drug binding (e.g., 
      on rate and off rate) is more predictive of drug efficacy than thermodynamic 
      quantities alone. This motivates the development of predictive computational 
      models that can be used to optimize compounds on the basis of their kinetics. The 
      structural details underpinning these computational models are found not only in 
      the bound state but also in the short-lived ligand binding transition states. 
      Although transition states cannot be directly observed experimentally due to 
      their extremely short lifetimes, recent successes have demonstrated that modeling 
      the ligand binding transition state is possible with the help of enhanced 
      sampling molecular dynamics methods. Previously, we generated unbinding paths for 
      an inhibitor of soluble epoxide hydrolase (sEH) with a residence time of 11 min. 
      Here, we computationally modeled unbinding events with the weighted ensemble 
      method REVO (resampling of ensembles by variation optimization) for five 
      additional inhibitors of sEH with residence times ranging from 14.25 to 31.75 
      min, with average prediction accuracy within an order of magnitude. The unbinding 
      ensembles are analyzed in detail, focusing on features of the ligand binding 
      transition state ensembles (TSEs). We find that ligands with similar bound poses 
      can show significant differences in their ligand binding TSEs, in terms of their 
      spatial distribution and protein-ligand interactions. However, we also find 
      similarities across the TSEs when examining more general features such as ligand 
      degrees of freedom. Together these findings show significant challenges for 
      rational, kinetics-based drug design.
FAU - Bose, Samik
AU  - Bose S
AD  - Department of Biochemistry and Molecular Biology, Michigan State University, East 
      Lansing, Michigan 48824, United States.
FAU - Lotz, Samuel D
AU  - Lotz SD
AUID- ORCID: 0000-0001-6159-615X
AD  - Department of Biochemistry and Molecular Biology, Michigan State University, East 
      Lansing, Michigan 48824, United States.
FAU - Deb, Indrajit
AU  - Deb I
AD  - Department of Biochemistry and Molecular Biology, Michigan State University, East 
      Lansing, Michigan 48824, United States.
FAU - Shuck, Megan
AU  - Shuck M
AUID- ORCID: 0000-0002-1303-853X
AD  - Department of Pharmacology and Toxicology, Michigan State University, East 
      Lansing, Michigan 48824, United States.
FAU - Lee, Kin Sing Stephen
AU  - Lee KSS
AD  - Department of Pharmacology and Toxicology, Michigan State University, East 
      Lansing, Michigan 48824, United States.
AD  - Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, 
      United States.
AD  - Institute of Integrative Toxicology, Michigan State University, East Lansing, 
      Michigan 48824, United States.
FAU - Dickson, Alex
AU  - Dickson A
AUID- ORCID: 0000-0002-9640-1380
AD  - Department of Biochemistry and Molecular Biology, Michigan State University, East 
      Lansing, Michigan 48824, United States.
AD  - Department of Computational Mathematics, Science and Engineering, Michigan State 
      University, East Lansing, Michigan 48824, United States.
LA  - eng
GR  - R01 AG080186/AG/NIA NIH HHS/United States
GR  - R01 GM130794/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20231109
PL  - United States
TA  - J Am Chem Soc
JT  - Journal of the American Chemical Society
JID - 7503056
RN  - 0 (Ligands)
SB  - IM
MH  - Protein Binding
MH  - Ligands
MH  - *Molecular Dynamics Simulation
MH  - *Drug Design
MH  - Thermodynamics
MH  - Kinetics
PMC - PMC11059145
MID - NIHMS1986283
COIS- Notes The authors declare no competing financial interest.
EDAT- 2023/11/09 18:42
MHDA- 2023/11/23 06:42
PMCR- 2024/04/30
CRDT- 2023/11/09 12:43
PHST- 2023/11/23 06:42 [medline]
PHST- 2023/11/09 18:42 [pubmed]
PHST- 2023/11/09 12:43 [entrez]
PHST- 2024/04/30 00:00 [pmc-release]
AID - 10.1021/jacs.3c08940 [doi]
PST - ppublish
SO  - J Am Chem Soc. 2023 Nov 22;145(46):25318-25331. doi: 10.1021/jacs.3c08940. Epub 
      2023 Nov 9.