TY - JOUR
T1 - Normal-mode-analysis-monitored energy minimization procedure for generating small-molecule bound conformations
AU - Wang, Qi
AU - Pang, Yuan Ping
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2007/10/10
Y1 - 2007/10/10
N2 - The energy minimization of a small molecule alone does not automatically stop at a local minimum of the potential energy surface of the molecule if the minimum is shallow, thus leading to folding of the molecule and con!7equently hampering the generation of the bound conformation of a guest in the absence of its host. This questions the practicality of virtual screening methods that use conformations at local minima of their potential energy surfaces (local minimum conformations) as potential bound conformations. Here we report a normal-mode-analysis-monitored energy minimization (NEM) procedure that generates local minimum conformations as potential bound conformations. Of 22 selected guest-host complex crystal structures with guest structures possessing up to four rotatable bonds, all complexes were reproduced, with guest mass-weighted root mean square deviations of <1.0 Å, through docking with the NEM-generated guest local minimum conformations. An analysis of the potential energies of these local minimum conformations showed tha 22 (100%), 13 (82%), 16 (73%), and 12 (55%) of the 22 guest bound conformations in the crystal structures had conformational strain energies of less than or equal to 3.8, 2.0, 0.6, and 0.0 kcal/mol, respectively. These results suggest that (1) the NEM procedure can generate small-molecule bound conformations, and (2) guests adopt low-strain-energy conformations for complexation, thus supporting the virtual screening methods that use local minimum conformations.
AB - The energy minimization of a small molecule alone does not automatically stop at a local minimum of the potential energy surface of the molecule if the minimum is shallow, thus leading to folding of the molecule and con!7equently hampering the generation of the bound conformation of a guest in the absence of its host. This questions the practicality of virtual screening methods that use conformations at local minima of their potential energy surfaces (local minimum conformations) as potential bound conformations. Here we report a normal-mode-analysis-monitored energy minimization (NEM) procedure that generates local minimum conformations as potential bound conformations. Of 22 selected guest-host complex crystal structures with guest structures possessing up to four rotatable bonds, all complexes were reproduced, with guest mass-weighted root mean square deviations of <1.0 Å, through docking with the NEM-generated guest local minimum conformations. An analysis of the potential energies of these local minimum conformations showed tha 22 (100%), 13 (82%), 16 (73%), and 12 (55%) of the 22 guest bound conformations in the crystal structures had conformational strain energies of less than or equal to 3.8, 2.0, 0.6, and 0.0 kcal/mol, respectively. These results suggest that (1) the NEM procedure can generate small-molecule bound conformations, and (2) guests adopt low-strain-energy conformations for complexation, thus supporting the virtual screening methods that use local minimum conformations.
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U2 - 10.1371/journal.pone.0001025
DO - 10.1371/journal.pone.0001025
M3 - Article
C2 - 17925873
AN - SCOPUS:40749121385
VL - 2
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 10
M1 - e1025
ER -