Drug Discovery Using Chemical Systems Biology: Identification of the Protein-Ligand Binding Network To Explain the Side Effects of CETP Inhibitors

Abstract

Systematic identification of protein-drug interaction networks is crucial to correlate complex modes of drug action to clinical indications. We introduce a novel computational strategy to identify protein-ligand binding profiles on a genome-wide scale and apply it to elucidating the molecular mechanisms associated with the adverse drug effects of Cholesteryl Ester Transfer Protein (CETP) inhibitors. CETP inhibitors are a new class of preventive therapies for the treatment of cardiovascular disease. However, clinical studies indicated that one CETP inhibitor, Torcetrapib, has deadly off-target effects as a result of hypertension, and hence it has been withdrawn from phase III clinical trials. We have identified a panel of off-targets for Torcetrapib and other CETP inhibitors from the human structural genome and map those targets to biological pathways via the literature. The predicted protein-ligand network is consistent with experimental results from multiple sources and reveals that the side-effect of CETP inhibitors is modulated through the combinatorial control of multiple interconnected pathways. Given that combinatorial control is a common phenomenon observed in many biological processes, our findings suggest that adverse drug effects might be minimized by fine-tuning multiple off-target interactions using single or multiple therapies. This work extends the scope of chemogenomics approaches and exemplifies the role that systems biology has in the future of drug discovery.

Cholesteryl Ester-Transfer Protein Inhibitors Stimulate Aldosterone Biosynthesis in Adipocytes through Nox-Dependent Processes

“…Second, CETP inhibitors are lipid soluble and accumulate, to variable degrees, in adipocytes (Dalvie et al, 2008;Gotto et al, 2014). Third, by computational analysis, these drugs were found to bind to several endogenous proteins related to adipogenesis, such as PPARa, PPARb, PPARg, and LXR (Xie et al, 2009). We studied human and mouse adipocytes and found similar responses in both cell types, indicating that CETP inhibitor-induced adipocyte aldosterone production is independent of CETP, since mice lack the CETP gene.…”

When evolution is the solution to pollution: Key principles, and lessons from rapid repeated adaptation of killifish (Fundulus heteroclitus) populations

“…Population genomics scans help reveal both directly adaptive and compensatory loci, and quantitative trait locus (QTL) mapping may further clarify those directly associated with specific adaptive phenotypes. Further clarifying compensatory loci is more challenging; systems biology may help to predict the unintended side effects of chemicals or adaptive evolution through modeling of how perturbation of specific molecular receptors and pathways may influence the function of interacting proteins and pathways (Xie, Li, Xie, & Bourne, 2009). One could then generate hypotheses about the genes likely to be subject to compensatory adaptive fine‐tuning.…”

Causal Assessment of Pharmaceutical Treatments: Why Standards of Evidence Should not be the Same for Benefits and Harms?

“…This is particularly detrimental in the case of harm assessment considering that much knowledge of the drug behaviour may be inferred analogically from same-class molecules. Furthermore, most compounds are characterised by promiscuity, meaning that they bear some affinity to off-target proteins: this is at the origin of most adverse reactions at the clinical level and integrating information about biochemical constraints, molecular mechanisms and biological pathways at the systems level considerably enhances the predictability of drug-organism interactions [38]. More generally, theoretical knowledge at different levels may be fruitfully combined (and amalgamated with available empirical evidence) to anticipate risk [39] …”