Chemistry Reference
In-Depth Information
CHAPTER 1
Current State-of-the-art for Quantum Mechanics-based Methods in Drug
Design
Carlton Anthony Taft
1
and Carlos Henrique Tomich de Paula da Silva
2
1
Brazilian Center for Physics Research, Rua Dr. Xavier Sigaud, 150, Urca, 22290-180, Rio de Janeiro, Brazil and
2
School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Monte Alegre,
14040-903, Ribeirão Preto, São Paulo, Brazil
Abstract:
We review the current state of the art for quantum mechanics-based methods in drug design and
selected applications to various diseases. We present a brief introduction and give current trends for each section.
We review bioisosterims and quantum chemical topology (shape, conformation, multipole moments, hydrogen
bonding, fingerprint, charge distributions), free energy simulations (equilibrium, non-equilibrium), Molecular
Interaction Fields (grids, hotspots, fingerprints), solvation (MD/MM-PBSA-GBSA, FEP/TI/LIE, COSMO,
PCM/DFT), docking (algorithms, scoring, new approaches), summary of quantum mechanics approximations
focusing on density functional methods (AM1, HF, Post-HF, MP, QM/MM), DFT(GGA, Meta-GGA, pure τ
functionals, DHDF, MO6, vW-D, Hybrids)) and weak interactions (hydrogen, van der Waals, carbohydrate-
aromatic, halogen, environmental electron densities). Using these models we present selected applications of our
work during the last decade in which we proposed novel inhibitors for Cancer, Aids, Alzheimer, Parkinson and
other diseases.
INTRODUCTION
With the tools of quantum mechanics and computational chemistry it is possible to characterize structure,
energetics and dynamics of the interactions of atoms and molecules with their biological counterparts. The
desired effect of drugs on humans is a result of the molecular recognition between drug and target (proteins). The
type of binding, spatial arrangement and molecular electronic structure will determine the effectiveness and
activity of the drug at its site of action. Although inexpensive approaches such as those based on molecular
mechanics (MM) can aid in novel lead discoveries, QM-based approaches would be fundamental if quantum
physical-chemistry effects are important, i.e charge transfer, polarization, forming/breaking, describing bonds,
weak interactions, solvation and enthalpic/entropic effects.
In drug design, historically, QM-based tools were used for development of quantum descriptors for structure-
activity correlations in QSAR experiments. Semi empirical level QM calculations have also been used for
development of descriptors and structure-activity correlations. However, problems in which molecular mechanics
(MM) and semi-emprical models have failed are nowadays solved by QM-based methods. Some of these
problems involve ligand-binding affinities, transition metal complexes, charge transfer effects, weak interactions,
bond forming/breaking, enzymatic reactions by biological systems of pharmacological relevance, transition state
configurations, solvation effects and accurate determination of free energies. QM-based approaches can also be
used in developing tools for other fields such as quantum chemical topology in drug design and force fields for
molecular mechanics and dynamics.
We discuss bioisosterism and quantum chemical topology in drug design involving quantum chemical descriptors such
as shape, conformation, charge, electronic distribution, fingerprints, multipole moments, polarity and hydrogen
bonding. We present free energy simulations tools FEP / REFEP / TI / FDTI /RTI/LIE / OS / ADuMWHAM / PT /
PTTI / λ-dynamics / non-equilibrium methods. Docking techniques are discussed. The effects of flexibility, water, large
databases, efficiency of scoring algorithms, importance of benchmarking, multiple protein structures, hybrids involving
molecular dynamics (MD), Monte Carlo (MC) and DFT are discussed. The emphasis is, however, on new approaches
and current trends. Molecular Interaction Fields are discussed. Basic quantum mechanical tools are summarized, i.e
