As OA contains O(16) and N(12) as two front negative sites(Fig. 3b) which are proposed to be important for binding interactions, an alignment fitting of OA and OA agonists was studied using rigid superimposition with these two atoms and the corresponding Cl(m) and N(15) of 29 and CIT as steric constraints. Similarity comparison of molecules was made using atom based rigid fit method offered by PowerFit 1.0 from MicroSimulations. This methodology uses the well-validated SEAL fitting potential as the objective fitting criteria, and it utilizes the "global search of best fit" from simulated annealing [18, 19]. Distance constraints were defined as above, because the QSAR and molecular modelling results claim the importance of electrostatic property at m-substituents at benzene in SBO and SBT compounds. To a certain degree, the fitting graphic results were similar to what were superimposed by CAChe Visualizer using the same distant constraints and were then rendered by RASMOL (Fig. 2a and Fig. 2b ), and were displayed in Fig. 4a and Fig. 4b. Molecular fitting was totally scored by the volume-based steric overlay, Columbus type electrostatic match, atom-type matching, and distance constraints as indicated below in Table 5. The conformation energy was optimized from MM2 force field with bond stretch, bond angle, dihedral angel, improper torsion, van der Waals, electrostatic(charge partial), and hydrogen bond. The final energy of 29, CIT, and OA was -10.6403, -11.6483, and -10.5948 Kcal/mol, respectively with no remarkable difference. So the total fitting potential of 29 to superimpose with OA was -579.66 Kcal/mol totally, while that of CIT was -345.75Kcal/mol. This result informs that 29 is better superimposed to OA in similarity means by steric overlay and atom-type matching. And it's clearly consistant with QSAR results that although the electrostatic matching of CIT to OA was with no difference of 29, CIT contains higher steric hindrances.

Fig. 4a.gif

Fig. 4a Molecular rigid fitting of 29 with OA according to SEAL annealing alignments*

Fig. 4b.gif

Fig. 4b Molecular rigid fitting of CIT with OA according to SEAL annealing alignments*

*The right graph shows the fitting simulation process of optimization in about 55 steps, hydrogens connected to carbons are omitted for clarity in the structures.


The semiempirical molecular and electrostatic properties of OA, 29 and CIT were further investigated quantitatively using MM2 and PM3 force fields. Table 6-8 listed some electronic descriptors including charge partial, electrophilic susceptibility, nucleophilic susceptibility, density of HOMO and LUMO, superdelocalizability of electrophilic, nucleophilic, and radical attack at atoms position of OA, 29 and CIT. The negative charge partial of OA is mainly distributed to C1(-0.201), C3(-0.183), C5(-0.148), O16(-0.225), and O17(-0.317). While N12 has a slightly negative electron(-0.038au.), those of N15 at 29 and CIT are -0.271 and -0.196au.; S22 of CIT has a positive charge of 0.054au. compared to the negative oxygen(-0.225) at 29. It's interesting that density of HOMO in OA relies on C3 and N12, whereas those of 29 and CIT exits majorly on N15 or S22. It means that these atoms with high values of HOMO have loosely bound electrons which are reactive to electrophilic attack. On the other hand, major density of LUMO disperses on the benzene ring of OA and OA agonists, so the nucleophilic attack may happen mainly on the aromatic rings. The electrophilic, nucleophilic susceptibility, and superdelocalizability investigations make it clear that benzyl ring of OA and N12, O16, and O17 of the chain are suitable for either electrophiles, nucleophiles or radicals. N12 of OA and N15 of 29 and CIT are approximately 2-times more active than the atoms at benzene in accepting an electrophilic attack. On the contratry, these atoms contain about half the activity of nucleophilic superdelocalizability of the benzene ring. Besides, the hetero five-membered ring of 29 and CIT could be considered aromatic and the data outputed in Table 6-8 support the idea. Apparently, Cl8(29), Cl12(CIT), and O16(OA) have the similar behavior in the above mentioned electrostatic properties, except that Cl8 and Cl16 are more easily attacked by an electrophile and compose higher electrophilic susceptibility than O16(OA).


Table6. footnotes

a Ref. structure(Fig.3b)
b Electrophilic and nucleophilic susceptibility are measures of the susceptibility of the substrate to attack by an elctrophile or a nucleophile.
c With high values of Density HOMO means loosely bound electrons which are reactive to electrophilic attack, with high values of Density LUMO means loosely bound electrons which are reactive to nucleophilic attack.
d Superdelocalizability E, superdelocalizability N, superdelocalizability R stand for reactivity by electrophilic attack, nucleophinic attack, and radical attack, respectively. They are based on the distribution of electrons in orbitals and they depend on the reagent energy.


*Ref. structure(Fig.3c) and legend to Table 6.


*Ref. structure(Fig.3a) and legend to Table 6.

The heat of formations Hf0 (by semiempirical method MOPAC) of OA, 29, and CIT differ substantially. It's well accepted that the global minimum conformation of a compound(non-receptor bound) can adopt the active(bound) conformation at a sufficiently low expense of energy. In this sense, OA and 29 may be speculated to absorb the necessary energy more easily than CIT as they are in a relatively low-energy field. The electron affinity of OA is -0.0137eV, while those of 29 and CIT are about 0.2eV. Besides, OA seems not likely to penetrate either the cuticle or the central nervous system(CNS) of insects effectively, since it may be almost fully ionized at physiological pH. OA and OA agonists of oxazolines and thiazolines have an ionization potential of 9.0-9.2eV (Table 9). Derivatization of the polar groups would be one possible solution to this problem in trying to develop potential pest-control agents. In order to optimize the activities of these compounds as octopaminergics agonists and pest-control agents, further detailed and extensive investigations are in progress.

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