Quantum Mechanical Concepts for Epistructural Drug Design

Abstract

In this chapter we show that a quantum mechanics (QM) approach to the epistructural physics of ligand-target association significantly broadens the technological base of the wrapping technology for drug design. We specifically incorporate electron correlation effects to empower the paradigmatic concept of “dehydron-wrapping drug”. The QM approach provides the required scientific grounds for the incorporation of halogens as wrapping groups in the chemical scaffold of the drug exploited for molecular targeted therapy. The chapter explores the possibility that the group that wraps exogenously a dehydron upon drug binding may also effectively interact through quantum mechanical forces with the carbonyl oxygen paired by the preformed dehydron in the target protein. This type of interaction involves dispersion forces that induce an anisotropic electron distribution on the halogen sigma orbital named “sigma hole”. This electron anisotropy promotes the formation of a halogen bond with the carbonyl oxygen in the target protein. Thus, the intermolecular halogen bond is coupled to the dehydron-wrapping interaction, and the wrapping group is a halogen with significant electron polarizability (Cl < Br < I), capable of inducing a significant dispersion force through QM displacement of electron density within the sigma orbital. This novel modality of ligand association involves two coupled drug-target interactions branching from the same drug substituent. The inclusion of polarizable halogens as wrappers is likely to significantly empower drug design as it reinforces the dehydronic drag exerted on the drug through favorable electron-correlation effects. The QM-based epistructural design is illustrated by modifying the chemotype of anticancer drug imatinib to incorporate a wrapping halogen in order to overcome drug resistance due to mutation in the imatinib target c-Kit kinase.