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

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that one CETP inhibitor, Torcetrapib, has deadly off-target effects as a result of hypertension, and hence it has been withdrawn from phase III clinical trials.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

The Cell Adhesion Molecule “CAR” and Sialic Acid on Human Erythrocytes Influence Adenovirus In Vivo Biodistribution

Although it has been known for 50 years that adenoviruses (Ads) interact with erythrocytes ex vivo, the molecular and structural basis for this interaction, which has been serendipitously exploited for diagnostic tests, is unknown. In this study, we characterized the interaction between erythrocytes and unrelated Ad serotypes, human 5 (HAd5) and 37 (HAd37), and canine 2 (CAV-2). While these serotypes agglutinate human erythrocytes, they use different receptors, have different tropisms and/or infect different species. Using molecular, biochemical, structural and transgenic animal-based analyses, we found that the primary erythrocyte interaction domain for HAd37 is its sialic acid binding site, while CAV-2 binding depends on at least three factors: electrostatic interactions, sialic acid binding and, unexpectedly, binding to the coxsackievirus and adenovirus receptor (CAR) on human erythrocytes. We show that the presence of CAR on erythrocytes leads to prolonged in vivo blood half-life and significantly reduced liver infection when a CAR-tropic Ad is injected intravenously. This study provides i) a molecular and structural rationale for Ad–erythrocyte interactions, ii) a basis to improve vector-mediated gene transfer and iii) a mechanism that may explain the biodistribution and pathogenic inconsistencies found between human and animal models

Identification of Potential Solid-State Li-Ion Conductors with Semi-Supervised Learning

Despite ongoing efforts to identify high-performance electrolytes for solid-state Li-ion batteries, thousands of prospective Li-containing structures remain unexplored. Here, we employ a semi-supervised learning approach to expedite identification of ionic conductors. We screen 180 unique descriptor representations and use agglomerative clustering to cluster ~26,000 Li-containing structures. The clusters are then labeled with experimental ionic conductivity data to assess the fitness of the descriptors. By inspecting clusters containing the highest conductivity labels, we identify 212 promising structures that are further screened using bond valence site energy and nudged elastic band calculations. Li3BS3 is identified as a potential high-conductivity material and selected for experimental characterization. With sufficient defect engineering, we show that Li3BS3 is a superionic conductor with room temperature ionic conductivity greater than 1 mS cm-1. While the semi-supervised method shows promise for identification of superionic conductors, the results illustrate a continued need for descriptors that explicitly encode for defects

Potential-sensing electrochemical atomic force microscopy for in operando analysis of water-splitting catalysts and interfaces

Heterogeneous electrochemical phenomena, such as (photo)electrochemical water splitting to generate hydrogen using semiconductors and/or electrocatalysts, are driven by the accumulated charge carriers and thus the interfacial electrochemical potential gradients that promote charge transfer. However, measurements of the “surface” electrochemical potential during operation are not generally possible using conventional electrochemical techniques, which measure/control the potential of a conducting electrode substrate. Here we show that the nanoscale conducting tip of an atomic force microscope cantilever can sense the surface electrochemical potential of electrocatalysts in operando. To demonstrate utility, we measure the potential-dependent and thickness-dependent electronic properties of cobalt (oxy)hydroxide phosphate (CoPi). We then show that CoPi, when deposited on illuminated haematite (α-Fe2O3) photoelectrodes, acts as both a hole collector and an oxygen evolution catalyst. We demonstrate the versatility of the technique by comparing surface potentials of CoPi-decorated planar and mesoporous haematite and discuss viability for broader application in the study of electrochemical phenomena

Domain Structures of Ni and NiFe (Oxy)Hydroxide Oxygen-Evolution Catalysts from X‑ray Pair Distribution Function Analysis

Ni–Fe (oxy)­hydroxides, Ni_{(1–<i>z</i>)}Fe_<i>z</i>O_<i>x</i>H_<i>y</i>, are among the fastest-known water oxidation catalysts in alkaline media on a per-cation basis. At current densities relevant for electrolysis (e.g., >0.5 A/cm^–2), mass and electron transport through catalyst films with high mass loading are critical and depend substantially on the extended and intermediate catalyst architecture. Here we use X-ray pair distribution function (PDF) analysis to determine the intermediate nanostructures of electrodeposited Ni_{(1–<i>z</i>)}Fe_<i>z</i>O_<i>x</i>H_<i>y</i> films. We report the effects of electrodeposition technique (pulsed versus continuous), electrochemical cycling, and Fe content on the structure of the catalyst film. The PDF patterns for Ni_{(1–<i>z</i>)}Fe_<i>z</i>O_<i>x</i>H_<i>y</i> films are best simulated by model structures consisting of brucite-like β-Ni­(OH)₂ fragments 1 to 3 layers in thickness. Only the oxidation state of the film significantly affects the intralayer scattering behavior (i.e., metal–oxygen bond distance). The interlayer interactions, however, are affected by Fe content and deposition conditions. The domain size of many of the systems are similar, extending to ∼5 nm, which are best modeled by sheets containing upward of ∼250 metal cations. Smaller domains were found for films deposited through a larger number of electrochemical cathodic current pulses. Films can be cycled between as-deposited, oxidized, and reduced states, with minimal loss of intrasheet coherence, indicating a degree of structural stability. We estimate heterogeneity in the domain structures by modeling the PDF data to linear combinations of oxyhydroxide fragments with different sizes and numbers of layers

Direct in Situ Measurement of Charge Transfer Processes During Photoelectrochemical Water Oxidation on Catalyzed Hematite

Electrocatalysts improve the efficiency of light-absorbing semiconductor photoanodes driving the oxygen evolution reaction, but the precise function(s) of the electrocatalysts remains unclear. We directly measure, for the first time, the interface carrier transport properties of a prototypical visible-light-absorbing semiconductor, α-Fe₂O₃, in contact with one of the fastest known water oxidation catalysts, Ni_0.8Fe_0.2O_<i>x</i>, by directly measuring/controlling the current and/or voltage at the Ni_0.8Fe_0.2O_<i>x</i> catalyst layer using a second working electrode. The measurements demonstrate that the majority of photogenerated holes in α-Fe₂O₃ directly transfer to the catalyst film over a wide range of conditions and that the Ni_0.8Fe_0.2O_<i>x</i> is oxidized by photoholes to an operating potential sufficient to drive water oxidation at rates that match the photocurrent generated by the α-Fe₂O₃. The Ni_0.8Fe_0.2O_<i>x</i> therefore acts as both a hole-collecting contact and a catalyst for the photoelectrochemical water oxidation process. Separate measurements show that the illuminated junction photovoltage across the α-Fe₂O₃|Ni_0.8Fe_0.2O_<i>x</i> interface is significantly decreased by the oxidation of Ni²⁺ to Ni³⁺ and the associated increase in the Ni_0.8Fe_0.2O_<i>x</i> electrical conductivity. In sum, the results illustrate the underlying operative charge-transfer and photovoltage generation mechanisms of catalyzed photoelectrodes, thus guiding their continued improvement

Catalyst Deposition on Photoanodes: The Roles of Intrinsic Catalytic Activity, Catalyst Electrical Conductivity, and Semiconductor Morphology

Semiconducting oxide photoanodes are used to drive the oxygen evolution reaction (OER) in water-splitting systems. The highest-performing systems use nanostructured semiconductors coated with water-oxidation catalysts. Despite much work, the design principles governing the integration of catalysts with semiconductors are poorly understood. Using hematite as a model system, we show how semiconductor morphology and electrical conductivity of the catalyst affect the system photoresponse. Electrically conductive catalysts can introduce substantial “shunt” recombination currents if they contact both the semiconductor surface and the underlying conducting-glass substrate, leading to poor performance. This recombination can be largely eliminated by using pinhole-free semiconductors, using selective photoassisted electrodeposition of thin catalyst layers on the semiconductor surface, using electrically insulating catalyst layers, or adding an intermediate insulating oxide layer. The results of this study are used to clarify the mechanisms behind several important results reported in the literature