Practical QM in Drug Design

by Hens Borkent

In this practical we will apply the three aspects discussed in the lecture:

and in particular the latter two, to a paper discussing QSAR in β-lactam antibiotics.
First read the paper, and note that both the charges and the HOMO-LUMO gap are introduced as parameters in the QSAR of 23 compounds. Their relative importance can be taken from the model equation on page 2. Are the signs and values in agreement with your expectations, based on the mechanism in fig. 1?
Next have a look at the output file of a MOPAC/PM3 calculation on compound 21 from the set on page 3.
Do the values agree with those in tables 1 and 2? (Tables as Excel or OpenOffice file.)
Try to locate the orbital that is involved in the reaction mechanism. What do you notice?

In view of the discussion above, we can try to improve the data for the QSAR.

Construct a selected model in SYBYL; save as a .mol2 file.
Read the mol2 file in Molden.
Select [ZMAT editor]. At the bottom of the editor window, select [Mopac], and press [Submit Job]. In the next window,
select PM3 as a method,
replace the Job name 'test' by something more meaningful,
and replace in the second line of keywords the PRNT=2 COMPFG by MMOK VECTORS PRECISE , and
press Submit. Confirm submission with OK.

Check the progress of the calculation with ls -rtl. The job is finished as the .temp and .res files have disappeared.
The input file is the jobname.dat file. If the .out file shows an error message, the .dat file can be edited and the calculation started from the command line with the command: mopac jobname.dat.

The numerical output (orbital coefficients, charges) appears in the jobname.out file. Read this file in Molden to check the geometry, the atom numbering and the calculated (Mulliken) charges (under [Label].
Orbitals can be viewed in Molden by reading the jobname.gpt file and selecting the [Dens. Mode]. Select an [orbital] (top button) and press the [Space] button. Select a contour value of 0.15 and wait for the orbital to appear. In this way one can make sure that the right orbital (C=O pi-star) is selected. Note the coefficient of this orbital at the carbonyl carbon.
A more sophisticated orbital display is the OpenGL option under the [Vr] button next to [Space].

ESP charge calculations can be carried out by a different version of MOPAC, MOPAC93.
Take the .arc file of a minimized structure in an editor: remove everything above the keyword lines and z-matrix, remove the GRAPH and VECTORS keywords and add ESP. Save as a new .dat file.
Submit with mopac93 filename.dat, where mopac93 should be aliased to /mnt/local/mopac93/bin/mopac.csh.
For some reason the ESP calculations are rather time consuming, so it is quite possible that the result is not returned within the practical hours.