Dr Hiroshi Chuman gave this presentation at the International Symposium on Compound Design Technologies held in Tokyo and Osaka, Japan on 19 and 20 March 2014.

Abstract
More than half a century has passed since Drs. Hansch and Fujita proposed a general approach to the formulation of QSAR in 1961. Their approach (Hansch-Fujita analysis) has provided a new perspective for chemical-biological interactions as well as a number of successes in drug discovery. Now it is time to develop a new and promising approach based on their QSAR with the aid of modern, powerful molecular calculations.

We have proposed a novel QSAR procedure called Linear Expression by Representative Energy terms (LERE)-QSAR involving molecular calculations such as an ab initio fragment molecular orbital (FMO) and QM/MM (ONIOM) ones. The first assumption made in formulating the LERE-QSAR equationis that the free-energy terms comprising the overall free-energy change (DG_obs) associated with complex formation are all additive (DG_obs = DG_bind + DG_sol + DG_others). DG_bind and DG_sol are the intrinsic binding interaction free-energy of a ligand with a protein, and the solvation free-energy change associated with complex formation, respectively. DG_others, the sum of free-energy terms other than representative free-energy terms, DG_bind and DG_sol, is assumed to be linear with that of representative free-energy terms (DG_others = β (DG_bind + DG_sol) + const, b < 0). The third assumption is an empirical relation between entropic and enthalpic energy changes accompanied with complex formation (TΔS = α DH + const, a > 0). DG_sol is replaceable by its dominant polar contribution DG_sol^pol, and most of DG_sol^pol comes from the enthalpic contribution. Combining the above three equations yields the following concise expression,

DG_obs = g (DE_bind + DG_sol^pol) + const [g = (1 – a) (1 + b)]

where DE_bind is computable using ab initio MO calculations such as FMO and ONIOM, and DG_sol^pol is with continuum solvation models such as GB (generalized Born), PB (Poisson−Boltzmann), and PCM (polarizable continuum model).

We have demonstrated that the LERE-QSAR procedure can excellently reproduce DG_obs associated with complex formation of a series of ligands with a protein (carbonic anhydrase, MMP, influenza and human neuraminidases).

We will also discuss newly introduced two approaches for estimating the representative energy terms; (1) hybrid estimation of PCM and GB/PB for DG_sol^pol and (2) dispersion−corrected Hartree-Fock method (HF−D) for DE_bind.

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