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 (DGobs) associated with complex formation are all additive (DGobs = DGbind + DGsol + DGothers). DGbind and DGsol are the intrinsic binding interaction free-energy of a ligand with a protein, and the solvation free-energy change associated with complex formation, respectively. DGothers, the sum of free-energy terms other than representative free-energy terms, DGbind and DGsol, is assumed to be linear with that of representative free-energy terms (DGothers = β (DGbind + DGsol) + 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). DGsol is replaceable by its dominant polar contribution DGsolpol, and most of DGsolpol comes from the enthalpic contribution. Combining the above three equations yields the following concise expression,
DGobs = g (DEbind + DGsolpol) + const [g = (1 – a) (1 + b)]
where DEbind is computable using ab initio MO calculations such as FMO and ONIOM, and DGsolpol 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 DGobs 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 DGsolpol and (2) dispersion−corrected Hartree-Fock method (HF−D) for DEbind.