Interaction, intermolecular, between inhibitors

A classical force field is typically used in which the energy expression consists of harmonic terms for bond stretching and angle bending, a Fourier series for each torsional angle, and Coulomb and Lennard-Jones interactions between atoms separated by three or more bonds (Equations 1- 4). The latter non-bonded interactions are also evaluated between intermolecular atom pairs, and they are reduced by a factor of 2 for intramolecular 1,4-interactions. Inhibitors or substrates are represented in an all-atom format with OPLS-AA parameters" though sometimes with partial charges obtained from quantum mechanical wavefunctions. 

Figure 6. Intermolecular interaction between F acetyl-F -methylphenylamide (dipeptide, dp) and photosynthesis inhibitors. Key N atom O atom , ...

One of the successful examples of employment of QSAR in the design and development of an HIV drug is the discovery of Indinavir (L-735,524) (2), one of the first HIVPI approved by the US-FDA. Holloway et aL [163] first reported this compound when they conducted SAR studies on a combined series of isostere derivatives of (43,44). A high correlation between the inter-molecular interaction energy ( int) calculated for HIVPR inhibitor complexes and enzyme inhibition activity was observed. QSAR 51-53 were developed for native, acetylpepstatin-inhibited and L-689,502-inhibited HIVPR, respectively [ 163]. X-ray coordinates and the force field technique were employed in the calculation of int (intermolecular interaction energy). In these QSAR, rev is the cross-validated correlation coefficient. 

Table 7.3 Intermolecular interactions between potent (ICj values< 10 nM) and reversible nonpeptide inhibitors in the DPP-IV binding site of available PDB structures... 

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