Correlation Analyses on Binding Affinity of Sialic Acid Analogues and Anti-Influenza Drugs with Human Neuraminidase Using ab Initio MO Calculations on Their Complex Structures – LERE-QSAR Analysis (IV)

Abstract

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.

Revisiting the Hansch–Fujita approach and development of a fundamental QSAR

“…We previously proposed a novel QSAR procedure called linear expression by representative energy terms (LERE)-QSAR [17][18][19][20][21] involving molecular calculations such as an ab initio fragment molecular orbital (FMO) one.…”

“…ΔG sol is replaced by the dominant polar (electrostatic) contribution ΔG sol pol because the non-polar contribution is often negligible, and most of ΔG sol pol is considered to come from the enthalpic contribution. 19) Combining the above three equations yields the following expression (LERE-QSAR equation):…”

“…This instructive case study demonstrates that LERE-QSAR has a considerable advantage over the traditional QSAR, although there is no logical conflict between the two. 17,19) Neuraminidases (NAs) are ubiquitous exoglycohydrolases that hydrolyze the terminal sialic acids of glycoproteins and glycolipids and are widely distributed in nature, from viruses, microorganisms, and fungi to higher animals and humans. 42) Among them, influenza virus NAs have been studied extensively as a target for influenza disease, and anti-influenza drugs have been developed.…”

“…Amino acid residues important for recognition of sialic acids are basically conserved in N1-NA and hNEU2. 19) Table 2 lists sialic acid analogues, Sets I and II compounds used in the study. We constructed complexes of N1-NA and hNEU2 with Sets I and II compounds, respectively, and then performed the LERE-QSAR analysis using the three representative energy terms: ΔE bind (=ΔE HF bind +E disp , FMO/MP2/6-31G), ΔG sol pol (hybrid (CPCM/PB) 30) and PB for N1-NA-Set I and hNEU2-Set II compounds, respectively), and ΔG diss (CPCM/ HF/6-31+ G(d,p)).…”

“…Hence, ΔE HF bind governs ΔG obs in complex formation of hNEU2 with Set II compounds. 19) It should be noted that remarkable differences in the coefficient (γ) and intercept (corresponds to const 3 in Eq. (7)) exist between Eqs.…”