Addressing Selective Polypharmacology of Antipsychotic Drugs Targeting the Bioaminergic Receptors through Receptor Dynamic Conformational Ensembles

Abstract

Selective polypharmacology, where a drug acts on multiple rather than a single molecular target involved in a disease, emerges to develop a structure-based system biology approach to design drugs selectively targeting a disease-active protein network. We focus on the bioaminergic receptors that belong to the group of G-protein-coupled receptors (GPCRs) and represent targets for therapeutic agents against schizophrenia and depression. Among them, it has been shown that the serotonin (5-HT(2A) and 5-HT₆) and dopamine (D₂ and D₃) receptors induce a cognition-enhancing effect (group 1), while the histamine (H₁) and serotonin (5-HT(2C)) receptors lead to metabolic side effects and the 5-HT(2B) serotonin receptor causes pulmonary hypertension (group 2). Thus, the problem arises to develop an approach that allows identifying drugs targeting only the disease-active receptors, i.e. group 1. The recent release of several crystal structures of the bioaminergic receptors, involving the D₃ and H₁ receptors, provides the possibility to model the structures of all receptors and initiate a study of the structural and dynamic context of selective polypharmacology. In this work, we use molecular dynamics simulations to generate a conformational space of the receptors and subsequently characterize its binding properties applying molecular probe mapping. All-against-all comparison of the generated probe maps of the selected diverse conformations of all receptors with the Tanimoto similarity coefficient (Tc) enable the separation of the receptors of group 1 from group 2. The pharmacophore built based on the Tc-selected receptor conformations, using the multiple probe maps discovers structural features that can be used to design molecules selective toward the receptors of group 1. The importance of several predicted residues to ligand selectivity is supported by the available mutagenesis and ligand structure-activity relationship studies. In addition, the Tc-selected conformations of the receptors for group 1 show good performance in isolation of known ligands from a random decoy. Our computational structure-based protocol to tackle selective polypharmacology of antipsychotic drugs could be applied for other diseases involving multiple drug targets, such as oncologic and infectious disorders.

Selection of protein conformations for structure-based polypharmacology studies

“…A variety of protein-centered approaches might represent efficient tools to identify suitable protein conformations for polypharmacology studies [9,18,25,45]. In fact, the shape and properties of a binding site are mostly dependent on amino acid rearrangements, switches between active and inactive protein states, and the presence and chemical nature of the bound ligand.…”

“…In particular, in a recent study of Selvam B. and coworkers, an application of MD simulations with Desmond [69] and probe mapping with the "multifragment" search module of the MOE2011.10 program [70] was used to address ligand selectivity [45]. In this study, the authors generated the conformational space of a set of similar bioaminergic G-protein-coupled receptors through MD, allowing the identification of common and distinct interaction "hot-spots" that were used to investigate selectivity and side effects.…”

“…These features could be useful to guide the design of molecules able to circumvent metabolic side effects and pulmonary hypertension, which are commonly associated with antipsychotic drugs targeting bioaminergic receptors. Then, they performed retrospective docking screenings (with Glide) on a set of conformations of the different proteins that allowed to discriminate known ligands from decoys [28,45]. Despite its utility in single target drug design [67], MD has not been thoroughly explored for selecting protein conformations for polypharmacology studies.…”

GPCR structure, function, drug discovery and crystallography: report from Academia-Industry International Conference (UK Royal Society) Chicheley Hall, 1–2 September 2014

“…Recent pharmacological studies revealed that clinically effective antipsychotic agents act by binding to several bioamine receptors (Roth et al 2004 ). In particular, the interaction with the serotonin (5-HT 2A and 5-HT 6 ) and dopamine (D 2 and D 3 ) receptors ( group 1 ) induces cognition-enhancing effects, while the histamine (H 1 ), 5-HT 2C and 5-HT 2B receptors (group 2) modulation causes unwanted side effects (Selvam et al 2013 ). Due to the complex pharmacological profile of CNS disorders, the attempts to develop drugs based on the one-target-one-disease paradigm have been limited (Allen and Roth 2011 ).…”

“…In academia, this approach has been undertaken with some promising results. For example, in the Tikhonova group, a computational protocol combining concepts from statistical mechanics and chemoinformatics have been developed to explore the flexibility of the bioamine receptors and identify geometrical and physicochemical properties that characterised the conformational space of the bioamine receptor family (Selvam et al 2013 ). Figure 11 illustrates the molecular modelling steps undertaken to identify the unique pharmacophoric features of disease-active receptors.…”