Structures
3D Pharmaceutical structures were calculated by MacroModel
4.5 (This software was provided from the Department of Chemistry,
Columbia University, New York).
Presently its higher versions have been purchased from Schroedinger,
Inc.
1. 1000-Step systematic pseudo Monte Carlo conformation searches were carried out with either MM2 or AMBER force field as implemented in MacroModel 4.5 to predict the fully optimized lowest energy structure.
Energies were minimized with the PR conjugate gradient minimizer and convergence
was obtained when the gradient root mean square was less than 0.001 kJ.
All molecular mechanics (MM) calculations assumed a dielectric constant
of 1.0.
2. The molecular dynamics (MD) simulations were carried out at 300K in
vacuum, beginning with the lowest energy structures obtained by the Monte
Carlo conformation search.
The following options were used in MD calculations:
* time step = 0.001 picosecond(ps)
* warm-up time period = 5ps
* production run time period (after the warm-up period) = 100ps
* coupling between the bath and molecule was updated every 0.2ps
The conformers were sampled every 1ps and minimized with MM2 force field.
The final MM calculations represent the fully optimized lowest energy
structures.
3. The data structure files were then transformed to the MDLmol file format
using the Babel
1.1program (working on a SGI platform) for use with MDL Chemscape
Chime.
* Pharmaceuticals containing counter ions such as chlorides and citrates
as salts have been treated as natural species to simplify the molecular
modeling.
* When MM2 lacks complete force field parameters, the MM (calculations)
of the pharmaceutical are carried out with AMBER force field. In such
cases the use of AMBER is noted under the structure frame.
1. Within the MacroModel structure files (*_md.out) containing 100 conformers obtained by the MD simulations, the 50 structure files collected in a time period ranging from 50 to 100ps were transformed to the XMol-xyz formatted files (*_md.xyz) by using BABEL.
babel -ik *_md.out "50-100" -ox CON > *_md.xyz
2. Lone pairs (LP), added to oxygen with MM2 force field, in the xyz structure
files were deleted using the non-interactive editor, SED.
sed '/.LP/D' *_md.xyz > *_md_2.xyz
In these cases, because LP are counted in the total number of atoms (TA),
the number of deleted LP (DLP) was subtracted from the total atom number
described on the top of the xyz structure file.
sed 's/TA/(TA - DLP)/' *_md_2.xyz > *_md_3.xyz
3. The xyz-formatted files (*_md_3.xyz) were embedded in HTML files and
posted on the site. Animfps indicates the number of structures represented
within a period of 1 minute.
<embed src="*_md_3.xyz" display3d=ball&stick animfps=3
startanim=true width=200 height=200>
