Quantitative Structure Activity Relationships are often used in ligand structure-based drug design. The QSAR relates drugs potency or toxicity with a variety of molecular descriptors. While many descriptors, such as the number of H-bond acceptors, are easy to calculate based on the molecular connectivity, other descriptors may require more advanced calculations. Notably, descriptors that may relate to chemical reactivity of drugs, such as HOMO and LUMO energies, must be obtained from quantum chemical calculation.
HOMO and LUMO refer to Highest Occupied Molecular Orbital and Lowest Unoccupied Molecular Orbital. According to the Frontier Orbital Theory, nucleophilic attack occurs by electron flow from a (HOMO of) nucleophile into the LUMO of the electrophile. In stable molecules, occupied electrons always reside on orbitals with negative energies and unoccupied orbitals have positive energies. The energies of HOMO and LUMO are related to the reactivity of the molecule: molecules with electrons at accessible (near-zero) HOMO level tend to be good nucleophiles because it does not cost much to donate these electrons toward making a new bond. Similarly, molecules with low LUMO energies tend to be good electrophiles because it does not cost much to place an electron into such orbital.
The Gaussian calculation you performed in the previous part produced description of molecular orbitals that MOLDEN is capable of visualizing. To visualize individual orbitals, click on Orbital while in the Density mode. Again, the Space mode (with contour value about 0.075) is easiest to grasp but Euclid is the fastest to quickly visualize orbitals. Notice that the first 6 orbitals in oxamic acid are strongly localized on atoms while many other orbitals are significantly delocalized. The orbital energies are also printed in the Gaussian output, under header Population Analysis Using the SCF Density.
For larger molecules, ab initio quantum mechanical calculations may become time consuming, especially because QSAR studies require that calculations are carried out on many molecules. Semiempirical calculations may be just accurate enough to give reasonably good descriptors for QSAR in a fraction of time. Many commercial programs, including Gaussian, and several free programs, such as MOPAC, and GAMESS, allow semiempirical calculations. Students who wish to try quantum chemistry calculations on their Windows or Linux PCs could download a free program PC GAMESS. Molden can create input files that (after some modification) are accepted by PC GAMESS outputs and MOLDEN can read some information from PC GAMESS output files. The last part of this tutorial illustrates how to perform semiempirical calculations with MOPAC through MOLDEN