PMID- 17607744
OWN - NLM
STAT- MEDLINE
DCOM- 20090721
LR  - 20191210
IS  - 1097-0134 (Electronic)
IS  - 0887-3585 (Print)
IS  - 0887-3585 (Linking)
VI  - 69
IP  - 2
DP  - 2007 Nov 1
TI  - QM/MM linear response method distinguishes ligand affinities for closely related 
      metalloproteins.
PG  - 326-39
AB  - Design of selective ligands for closely related targets is becoming one of the 
      most important tasks in the drug development. New tools, more precise than fast 
      scoring functions and less demanding than sophisticated Free Energy Perturbation 
      methods, are necessary to help accomplish this goal. The methods of intermediate 
      complexity, characterizing individual contributions to the binding energy, have 
      been an area of intense research in the past few years. Our recently developed 
      quantum mechanical/molecular mechanical (QM/MM) modification of the Linear 
      Response (LR) method describes the binding free energies as the sum of 
      empirically weighted contributions of the QM/MM interaction energies and 
      solvent-accessible surface areas for the time-averaged structures of hydrated 
      complexes, obtained by molecular dynamics (MD) simulations. The method was 
      applied to published data on 27 inhibitors of matrix metalloproteinase-3 (MMP-3). 
      The two descriptors explained 90% of variance in the inhibition constants with 
      RMSE of 0.245 log units. The QM/MM treatment is indispensable for 
      characterization of the systems lacking suitable force-field expressions. In this 
      case, it provided characteristics of H-bonds of the inhibitors to Glu202, charges 
      of binding site atoms, and accurate coordination geometries of the ligands to 
      catalytic zinc. The geometries were constrained during the MD simulations, which 
      characterized conformational flexibility of the complexes and helped in the 
      elucidation of the binding differences for related compounds. A comparison of the 
      presented QM/MM LR results with those previously published for inhibition of 
      MMP-9 by the same set of ligands showed that the QM/MM LR approach was able to 
      distinguish subtle differences in binding affinities for MMP-3 and MMP-9, which 
      did not exceed one order of magnitude. This precision level makes the approach a 
      useful tool for design of selective ligands to similar targets, because the 
      results can be safely extrapolated to maximize selectivity.
CI  - (c) 2007 Wiley-Liss, Inc.
FAU - Khandelwal, Akash
AU  - Khandelwal A
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State 
      University, Fargo, North Dakota 58105, USA.
FAU - Balaz, Stefan
AU  - Balaz S
LA  - eng
GR  - 1P20RR16741/RR/NCRR NIH HHS/United States
GR  - P20 RR015566-040003/RR/NCRR NIH HHS/United States
GR  - P20 RR015566-020003/RR/NCRR NIH HHS/United States
GR  - 1P20RR15566/RR/NCRR NIH HHS/United States
GR  - P20 RR016471/RR/NCRR NIH HHS/United States
GR  - P20 RR016471-055391/RR/NCRR NIH HHS/United States
GR  - P20 RR015566/RR/NCRR NIH HHS/United States
GR  - P20 RR015566-050003/RR/NCRR NIH HHS/United States
GR  - P20 RR015566-030003/RR/NCRR NIH HHS/United States
GR  - P20 RR016471-087234/RR/NCRR NIH HHS/United States
GR  - P20 RR015566-010003/RR/NCRR NIH HHS/United States
GR  - P20 RR016471-077190/RR/NCRR NIH HHS/United States
GR  - P20 RR016471-066969/RR/NCRR NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Validation Study
PL  - United States
TA  - Proteins
JT  - Proteins
JID - 8700181
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Ligands)
RN  - 0 (Matrix Metalloproteinase Inhibitors)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
SB  - IM
MH  - Computer Simulation
MH  - Hydroxamic Acids/chemistry/metabolism
MH  - Ligands
MH  - Linear Models
MH  - Matrix Metalloproteinase 3/chemistry/*metabolism
MH  - Matrix Metalloproteinase 9/chemistry/*metabolism
MH  - Matrix Metalloproteinase Inhibitors
MH  - *Models, Chemical
MH  - Protein Binding
MH  - *Quantum Theory
MH  - *Thermodynamics
PMC - PMC2896063
MID - NIHMS83443
EDAT- 2007/07/04 09:00
MHDA- 2009/07/22 09:00
PMCR- 2010/07/02
CRDT- 2007/07/04 09:00
PHST- 2007/07/04 09:00 [pubmed]
PHST- 2009/07/22 09:00 [medline]
PHST- 2007/07/04 09:00 [entrez]
PHST- 2010/07/02 00:00 [pmc-release]
AID - 10.1002/prot.21500 [doi]
PST - ppublish
SO  - Proteins. 2007 Nov 1;69(2):326-39. doi: 10.1002/prot.21500.