A community challenge for a pancancer drug mechanism of action inference from perturbational profile data

The Columbia Cancer Target Discovery and Development (CTD2) Center is developing PANACEA, a resource comprising dose-responses and RNA sequencing (RNA-seq) profiles of 25 cell lines perturbed with similar to 400 clinical oncology drugs, to study a tumor-specific drug mechanism of action. Here, this resource serves as the basis for a DREAM Challenge assessing the accuracy and sensitivity of computational algorithms for de novo drug polypharmacology predictions. Dose-response and perturbational profiles for 32 kinase inhibitors are provided to 21 teams who are blind to the identity of the compounds. The teams are asked to predict high-affinity binding targets of each compound among similar to 1,300 targets cataloged in DrugBank. The best performing methods leverage gene expression profile similarity analysis as well as deep-learning methodologies trained on individual datasets. This study lays the foundation for future integrative analyses of pharmacogenomic data, reconciliation of polypharmacology effects in different tumor contexts, and insights into network-based assessments of drug mechanisms of action.Peer reviewe

Synthesis and Quantitative Testing of Electrochemical and Optical Sensors in Surface Formats

A series of ionophore and fluoroionophore terminated compounds have been synthesized to be used in the formation of organic thin-films on gold electrodes via self-assembly. These SAMs' bulk optical and electrochemical behavior has been shown to change in the presence of target analytes and calibration curves and thermodynamic binding parameters have been determined. The sensor response, however, has proven highly variable and recently a great deal of this work has focused on fully characterizing and correcting the sources of this variability

Energy viability of solar hydrogen

Hydrogen has received a great deal of attention as a potential clean, alternative energy source. Unfortunately current methods of producing hydrogen consume more fossil fuels per unit energy utilized than would direct use of those same fuels. Photocatalytically produced hydrogen, is here examined as a potential clean and renewable alternative energy source. Its viability as a fuel is examined in terms of payback-time and energy yield estimates derived from a review of the life-cycle literature for comparable photovoltaics

A comprehensive kinetic model for ternary complex catalysis

Ternary-complex directed enzyme catalysis underlies a vast array of biological processes and several clinical therapies including growth hormones, interferon, and heparin. Recently, interest in ternary catalysis drugs has increased significantly with the rapid expansion of research new technologies such as bispecific antibodies and proteolysis targeting chimeras (PROTAC’s). Here, we derive a general model for ternary complex catalysis that defines the timescales of these diverse processes in familiar terms from classical enzyme theory. This was accomplished by solving for the maximum velocity (Vmax) and adapting an under-appreciated strategy within Michaels and Menten’s original publication: integration of the velocity equation. Critically, these equations are simple, conceptually accessible, and enables rapid estimation timescales that are consistent with a wide range of published literature. Finally, we have combined these equations with “big data” from new thermodynamic and kinetic databases to build interactive online tools that enable non-computational investigators to graphically simulate their own systems: • https://douglasslab.com/Btmax_kinetics/ Overall, this work is part of a general trend to reconceptualize pharmacodynamics from classical binding equilibria (e.g. Langmuir-Hill equation) to a kinetic processes with a characteristic timescale

A “Turn-On” Fluorescent Sensor for Methylglyoxal

Methylglyoxal (MGO), a dicarbonyl metabolite produced by all living cells, has been associated with a number of human diseases. However, studies of the role(s) MGO plays biologically have been handicapped by a lack of direct methods for its monitoring and detection. To address this limitation, we have developed a fluorescent sensor (methyl diaminobenzene-BODIPY, or “MBo”) that can detect MGO under physiological conditions. We show that MBo is selective for MGO over other biologically relevant dicarbonyls and is suitable for detecting MGO in complex environments, including that of living cells. In addition, we demonstrate MBo’s utility in estimating plasma concentrations of MGO. The results reported herein have the potential to advance both clinical and basic science research and practice

A Comprehensive Mathematical Model for Three-Body Binding Equilibria

Three-component systems are often more complex than their two-component counterparts. Although the reversible association of three components in solution is critical for a vast array of chemical and biological processes, no general physical picture of such systems has emerged. Here we have developed a general, comprehensive framework for understanding ternary complex equilibria, which relates directly to familiar concepts such as EC₅₀ and IC₅₀ from simpler (binary complex) equilibria. Importantly, application of our model to data from the published literature has enabled us to achieve new insights into complex systems ranging from coagulation to therapeutic dosing regimens for monoclonal antibodies. We also provide an Excel spreadsheet to assist readers in both conceptualizing and applying our models. Overall, our analysis has the potential to render complex three-component systemswhich have previously been characterized as “analytically intractable”readily comprehensible to theoreticians and experimentalists alike

Exploring Binding and Effector Functions of Natural Human Antibodies Using Synthetic Immunomodulators

The ability to profile the prevalence and functional activity of endogenous antibodies is of vast clinical and diagnostic importance. Serum antibodies are an important class of biomarkers and are also crucial elements of immune responses elicited by natural disease-causing agents as well as vaccines. In particular, materials for manipulating and/or enhancing immune responses toward disease-causing cells or viruses have exhibited significant promise for therapeutic applications. Antibody-recruiting molecules (ARMs), bifunctional organic molecules that redirect endogenous antibodies to pathological targets, thereby increasing their recognition and clearance by the immune system, have proven particularly interesting. Notably, although ARMs capable of hijacking antibodies against oligosaccharides and electron-poor aromatics have proven efficacious, systematic comparisons of the prevalence and effectiveness of natural anti-hapten antibody populations have not appeared in the literature. Herein we report head-to-head comparisons of three chemically simple antigens, which are known ligands for endogenous antibodies. Thus, we have chemically synthesized bifunctional molecules containing 2,4-dinitrophenyl (DNP), phosphorylcholine (PC), and rhamnose. We have then used a combination of ELISA, flow cytometry, and cell-viability assays to compare these antigens in terms of their abilities both to recruit natural antibody from human serum and also to direct serum-dependent cytotoxicity against target cells. These studies have revealed rhamnose to be the most efficacious of the synthetic antigens examined. Furthermore, analysis of 122 individual serum samples has afforded comprehensive insights into population-wide prevalence and isotype distributions of distinct anti-hapten antibody populations. In addition to providing a general platform for comparing and studying anti-hapten antibodies, these studies serve as a useful starting point for the optimization of antibody-recruiting molecules and other synthetic strategies for modulating human immunity

Chemically Synthesized Molecules with the Targeting and Effector Functions of Antibodies

This article reports the design, synthesis, and evaluation of a novel class of molecules of intermediate size (approximately 7000 Da), which possess both the targeting and effector functions of antibodies. These compoundscalled synthetic antibody mimics targeting prostate cancer (SyAM-Ps)bind simultaneously to prostate-specific membrane antigen and Fc gamma receptor I, thus eliciting highly selective cancer cell phagocytosis. SyAMs have the potential to combine the advantages of both small-molecule and biologic therapies, and may address many drawbacks associated with available treatments for cancer and other diseases