Impact of DNA-Encoded Chemical Library Technology on Drug Discovery

DNA-Encoded Chemical Libraries (DELs) have gained momentum over the recent years for the discovery of small-molecule ligands and the technology has been integrated in most of the larger pharmaceutical companies. With this perspective we would like to summarize the development of DEL technology and present some representative DEL-derived hits which may soon enter the pharmaceutical market

Computational methods to analyze and predict the binding mode of inhibitors targeting both human and mushroom tyrosinase

Tyrosinase, a copper-containing enzyme critical in melanin biosynthesis, is a key drug target for hyperpigmentation and melanoma in humans. Testing the inhibitory effects of compounds using tyrosinase from Agaricus bisporus (AbTYR) has been a common practice to identify potential therapeutics from synthetic and natural sources. However, structural diversity among human tyrosinase (hTYR) and AbTYR presents a challenge in developing drugs that are therapeutically effective. In this study, we combined retrospective and computational analyses with experimental data to provide insights into the development of new inhibitors targeting both hTYR and AbTYR. We observed contrasting effects of Thiamidol™ and our 4-(4-hydroxyphenyl)piperazin-1-yl-derivative (6) on both enzymes; based on this finding, we aimed to investigate their binding modes in hTYR and AbTYR to identify residues that significantly improve affinity. All the information led to the discovery of compound [4-(4-hydroxyphenyl)piperazin-1-yl](2-methoxyphenyl)methanone (MehT-3, 7), which showed comparable activity on AbTYR (IC50 = 3.52 μM) and hTYR (IC50 = 5.4 μM). Based on these achievements we propose the exploitation of our computational results to provide relevant structural information for the development of newer dual-targeting molecules, which could be preliminarily tested on AbTYR as a rapid and inexpensive screening procedure before being tested on hTYR

Umweltinformationen: Beschaffung - Verarbeitung - Nutzung

Laufende und umfassende Informationen über den Zustand und die Entwicklung der Umwelt sind unabdingbare Voraussetzungen für einen vorsorglichen Umgang mit unseren natürlichen Lebensgrundlagen. In Baden-Württemberg wurden und werden im Bereich der Umweltverwaltung täglich eine große Menge von Meßdaten, Analysedaten, Verwaltungsdokumenten, statistischen Erhebungen und Berechnungen erzeugt. Diese Informationen zu sammeln, zu sichten, zu bewerten und bedarfsgerecht aufzuarbeiten, ist mit den herkömmlichen Methoden der Verwaltungsarbeit nicht mehr möglich, sondern erfordert neue Methoden insbesondere auch der Informationstechnik. In Baden-Württemberg wird auf Beschluß der Landesregierung seit 1986 (jetzt unter Federführung des Ministeriums für Umwelt und Verkehr - UVM) ein Konzept für ein ressortübergreifendes Umweltinformationssystem des Landes Baden-Württemberg entwickelt und umgesetzt

Ex vivo mass spectrometry-based biodistribution analysis of an antibody-Resiquimod conjugate bearing a protease-cleavable and acid-labile linker

Immune-stimulating antibody conjugates (ISACs) equipped with imidazoquinoline (IMD) payloads can stimulate endogenous immune cells to kill cancer cells, ultimately inducing long-lasting anticancer effects. A novel ISAC was designed, featuring the IMD Resiquimod (R848), a tumor-targeting antibody specific for Carbonic Anhydrase IX (CAIX) and the protease-cleavable Val-Cit-PABC linker. In vitro stability analysis showed not only R848 release in the presence of the protease Cathepsin B but also under acidic conditions. The ex vivo mass spectrometry-based biodistribution data confirmed the low stability of the linker-drug connection while highlighting the selective accumulation of the IgG in tumors and its long circulatory half-life

Macrocyclic DNA-encoded chemical libraries: a historical perspective

While macrocyclic peptides are extensively researched for therapeutically relevant protein targets, DNA-encoded chemical libraries (DELs) are developed at a quick pace to discover novel small molecule binders. The combination of both fields has been explored since 2004 and the number of macrocyclic peptide DELs is steadily increasing. Macrocycles with high affinity and potency were identified for diverse classes of proteins, revealing DEL's huge potential. By giving a historical perspective, we would like to review the methods which permitted the rise of macrocyclic peptide DELs, describe the different DELs which were created and discuss the achievements and challenges of this emerging field

Advancing small-molecule drug discovery by encoded dual-display technologies

DNA-encoded chemical library technology (DECL or DEL) has become an important pillar for small-molecule drug discovery. The technology rapidly identifies small-molecule hits for relevant target proteins at low cost and with a high success rate, including ligands for targeted protein degradation (TPD). More recently, the setup of DNA- or peptide nucleic acid (PNA)-encoded chemical libraries based on the simultaneous display of ligand pairs, termed dual-display, allows for more sophisticated applications which will be reviewed herein. Both stable and dynamic dual-display DEL technologies enable innovative affinity-based selection modalities, even on and in cells. Novel methods for a seamless conversion between single- and double-stranded library formats allow for even more versatility. We present the first candidates emerging from dual-display technologies and discuss the future potential of dual-display for drug discovery.ISSN:0165-6147ISSN:0167-769

Impact of DNA-Encoded Chemical Library Technology on Drug Discovery

DNA-Encoded Chemical Libraries (DELs) have gained momentum over the recent years for the discovery of small molecule ligands and the technology has been integrated in most of the larger pharmaceutical companies. With this perspective we would like to summarize the development of DEL technology and present some representative DEL-derived hits which may soon enter the pharmaceutical market.ISSN:0009-429

How to Calibrate the Scores of Biased Reviewers by Quadratic Programming

Peer reviewing is the key ingredient of evaluating the quality of scientific work. Based on the review scores assigned by the individual reviewers to the submissions, program committees of conferences and journal editors decide which papers to accept for publication and which to reject. However, some reviewers may be more rigorous than others, they may be biased one way or the other, and they often have highly subjective preferences over the papers they review. Moreover, each reviewer usually has only a very local view, as he or she evaluates only a small fraction of the submissions. Despite all these shortcomings, the review scores obtained need to be aggregrated in order to globally rank all submissions and to make the acceptance/rejection decision. A common method is to simply take the average of each submission's review scores, possibly weighted by the reviewers' confidence levels. Unfortunately, the global ranking thus produced often suffers a certain unfairness, as the reviewers' biases and limitations are not taken into account. We propose a method for calibrating the scores of reviewers that are potentially biased and blindfolded by having only partial information. Our method uses a maximum likelihood estimator, which estimates both the bias of each individual reviewer and the unknown "ideal" score of each submission. This yields a quadratic program whose solution transforms the individual review scores into calibrated, globally comparable scores. We argue why our method results in a fairer and more reasonable global ranking than simply taking the average of scores. To show its usefulness, we test our method empirically using real-world data