Bioinformatics and variability in drug response: a protein structural perspective

Abstract

Marketed drugs frequently perform worse in clinical practice than in the clinical trials on which their approval is based. Many therapeutic compounds are ineffective for a large subpopulation of patients to whom they are prescribed; worse, a significant fraction of patients experience adverse effects more severe than anticipated. The unacceptable risk-benefit profile for many drugs mandates a paradigm shift towards personalized medicine. However, prior to adoption of patient-specific approaches, it is useful to understand the molecular details underlying variable drug response among diverse patient populations. Over the past decade, progress in structural genomics led to an explosion of available three-dimensional structures of drug target proteins while efforts in pharmacogenetics offered insights into polymorphisms correlated with differential therapeutic outcomes. Together these advances provide the opportunity to examine how altered protein structures arising from genetic differences affect protein-drug interactions and, ultimately, drug response. In this review, we first summarize structural characteristics of protein targets and common mechanisms of drug interactions. Next, we describe the impact of coding mutations on protein structures and drug response. Finally, we highlight tools for analysing protein structures and protein-drug interactions and discuss their application for understanding altered drug responses associated with protein structural variants.

Figure 1.

Shape complementarity between small molecules and their protein targets. The structure of Brd4 (grey cartoon) with an inhibitor (sticks) shows excellent shape complementarity when viewed looking (a) into and (b) perpendicular to the binding pocket (grey mesh). In contrast, Cdc34 (grey cartoon) bound to an inhibitor (sticks) has imperfect and incomplete shape complementarity, as depicted looking into (c) and perpendicular to (d) the binding pocket (grey mesh). Water molecules represented as red and white spheres. (Brd4, PDB 3MXF [62]; Cdc34, PDB 3RZ3 [63].) (Online version in colour.)

Figure 2.

Drug binding modes. Orthosteric and allosteric ligands bind topographically distinct protein sites to positively or negatively affect target protein function. (a) Orthosteric full, partial or inverse agonism; (b) positive or negative affinity modulation; (c) positive or negative efficacy modulation; (d) allosteric full, partial or inverse agonism; (e) competitive drug binding. Target protein (blue rounded rectangle), endogenous ligand (purple square), orthosteric drug (orange hexagon), and allosteric drug (red circle). Adapted with permission from [70]. (Online version in colour.)

Figure 3.

Mutation of kinase gatekeeper residue confers drug resistance. (a) Overlay of wild-type Abl kinase (light grey cartoon) with bound imatinib (sticks) and T315I variant (dark grey cartoon) shows equivalent global structures. (b) Wild-type Abl binding pocket (yellow mesh) has a threonine gatekeeper residue (grey stick and semitransparent surface) bound to imatinib (yellow sticks). (c) Wild-type Abl binding pocket (yellow mesh) and imatinib (yellow sticks) overlaid on the T315I variant structure shows an inability of the mutant to accommodate the drug owing to protrusion of the isoleucine gatekeeper residue (red stick and semitransparent surface) that sterically prevents drug binding. (Wild-type Abl kinase, PDB 2HYY [105]; Abl kinase T315I, PDB 2Z60 [104].) (Online version in colour.)

Figure 4.

Expansion of AR binding pocket converts antagonist drugs to agonists. (a) Overlay of wild-type AR (light grey cartoon) with bound cyproterone (sticks) and T877A variant (dark grey cartoon) depicts their globally similar structures. (b) Expanded binding pocket of AR T877A variant (red mesh) compared with wild-type (yellow mesh) better accommodates the bulky cyproterone (yellow sticks). (c) Overlay of wild-type AR (light grey cartoon) with bound R-bicalutamide (yellow sticks) and W741L variant (dark grey cartoon) depicts their globally similar structures. (d) Expanded binding pocket of AR W741L variant (red mesh) compared with wild-type (yellow mesh) better accommodates the bulky R-bicalutamide drug (yellow sticks). Substituted sidechains (red sticks and semi-transparent surfaces) compared with wild-type (grey sticks and semi-transparent surfaces) are highlighted. Binding pockets generated using HOLLOW [120]. (Wild-type AR, PDB 2AM9 [121]; AR T877A, PDB 2OZ7 [119]; AR W741L, PDB 1Z95 [117].) (Online version in colour.)

Figure 5.

Mutation of p53 surface residue decreases protein stability. (a) Overlay of wild-type p53 (light grey) and Y220C variant (dark grey) shows high structural similarity. (b) Mutation of Tyr220 (grey stick and semitransparent surface) to Cys (red stick and semitransparent surface) creates a cleft on the surface of mutant p53 (mesh) that destabilizes the protein structure. (Wild-type p53, PDB 1UOL [141]; p53 Y220C, PDB 2J1X [139].) (Online version in colour.)

Figure 6.

CYP2C9 variant displays altered warfarin binding. (a) CYP2C9 (grey) bound to warfarin (yellow sticks) and haem cofactor (blue sticks). (b) Close-up of CYP2C9 warfarin binding pocket and surrounding environment. Structural disturbances in neighbouring residues (cyan sticks and semitransparent surface) resulting from substitution of residue 359 (red stick and semitransparent surface) disrupt the drug binding pocket (yellow mesh). Binding pocket generated using HOLLOW [120]. (Wild-type CYP2C9, PBD 1OG5 [144].) (Online version in colour.)