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Linear Expression by Representative Energy Terms: A Novel QSAR Procedure Using Theoretical Computations on Protein-Ligand Complexes

Monday, 24 March 2014 15:45
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Hiroshi Chuman
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.

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.

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