Quantitative structure-activity relationship analyses on the free energy change during complex formation between substituted benzenesulfonamides (BSAs) and bovine carbonic anhydrase II (bCA II) were performed using generilized Born/surface area (GB/SA) and ab initio fragment molecular orbital (FMO) calculations for the whole complex structures. The result shows that the overall free energy change is governed by the contribution from solvation and dissociation free energy changes accompanying by complex formation. The FMO-IFIE (interfragment interaction energy) analysis quantitatively revealed that the intrinsic interaction energy of bCA II with BSAs is mostly from interactions with amino acid residues in the active site of bCA II. The "Zn block" (Zn(2+) and three histidine residues coordinated to Zn(2+)) in the active site shows the lowest interaction energy and the greatest variance of interaction energy with BSAs through their coordination interaction. The proposed procedure was demonstrated to provide a quantitative basis for understanding a ligand-protein interaction at electronic and atomic levels.

We carried out full ab initio molecular orbital calculations on complexes between neuraminidase-1 (N1-NA) in the influenza A virus and a series of eight sialic acid analogues including oseltamivir (Tamiflu) in order to quantitatively examine the binding mechanism and variation in the inhibitory potency at the atomic and electronic levels. FMO-MP2-IFIE (interfragment interaction energy at the MP2 level of ab initio fragment molecular orbital calculations) analyses quantitatively revealed (1) that the complex formation is driven by strong electrostatic interactions of charged functional groups in the analogues with ionized amino acid residues and water molecules in the active site of N1-NA, and (2) that the variation in the inhibitory potency among the eight analogues is determined by the dispersion and/or hydrophobic interaction energies of the 3-pentyl ether and charged amino moieties in oseltamivir with certain residues and water molecules in the active site of N1-NA. The current results will be useful for the development of new antiinfluenza drugs with high potency against various subtypes of wild-type and drug-resistant NAs.

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We carried out full ab initio fragment molecular orbital (FMO) calculations for complexes comprising human neuraminidase-2 (hNEU2) and sialic acid analogues including anti-influenza drugs zanamivir (Relenza) and oseltamivir (Tamiflu) in order to examine the variation in the observed inhibitory activity toward hNEU2 at the atomic and electronic levels. We recently proposed the LERE (linear expression by representative energy terms)-QSAR (quantitative structure-activity relationship) procedure. LERE-QSAR analysis quantitatively revealed that the complex formation is driven by hydrogen-bonding and electrostatic interaction of hNEU2 with sialic acid analogues. The most potent inhibitory activity, that of zanamivir, is attributable to the strong electrostatic interaction of a positively charged guanidino group in zanamivir with negatively charged amino acid residues in hNEU2. After we confirmed that the variation in the observed inhibitory activity among sialic acid analogues is excellently reproducible with the LERE-QSAR equation, we examined the reason for the remarkable difference between the inhibitory potencies of oseltamivir as to hNEU2 and influenza A virus neuraminidase-1 (N1-NA). Several amino acid residues in close contact with a positively charged amino group in oseltamivir are different between hNEU2 and N1-NA. FMO-IFIE (interfragment interaction energy) analysis showed that the difference in amino acid residues causes a remarkably large difference between the overall interaction energies of oseltamivir with hNEU2 and N1-NA. The current results will be useful for the development of new anti-influenza drugs with high selectivity and without the risk of adverse side effects.

A quantitative structure-activity relationship study was carried out on a series of cyclic urea type HIV-1 protease inhibitors. In order to determine the atomic and electronic mechanisms in detail, three-dimensional and electronic descriptors were calculated with the molecular dynamics and ab initio fragment molecular orbital calculation of the whole complex structure of HIV-1 protease with each inhibitor. Two descriptors showing correlation with the inhibitory potency were the total interaction energy and the change in the accessible surface area on complex formation with HIV-1 protease. The major contributions to the total electronic interaction energy were found to be from Asp25/25', Asp30/30' and Ile50/50'. The interaction energy with Asp30/30' was nicely correlated with the total electronic interaction energy and also with the charge transfer from Asp30/30', which is in close contact with the substituted moiety in each inhibitor. As well as the hydrophobic interaction, the charge redistribution among the inhibitor and surrounding residues was suggested to govern the variation in the inhibitory potency. The results obtained in this work can help us to reinterpret the classical QSAR descriptors proposed by Garg et al.