DAIKON: A Data Acquisition, Integration, and Knowledge Capture Web Application for Target-Based Drug Discovery.

Primitive data organization practices struggle to deliver at the scale and consistency required to meet multidisciplinary collaborations in drug discovery. For effective data sharing and coordination, a unified platform that can collect and analyze scientific information is essential. We present DAIKON, an open-source framework that integrates targets, screens, hits, and manages projects within a target-based drug discovery portfolio. Its knowledge capture components enable teams to record subsequent molecules as their properties improve, facilitate team collaboration through discussion threads, and include modules that visually illustrate the progress of each target as it advances through the pipeline. It serves as a repository for scientists sourcing data from Mycobrowser, UniProt, PDB. The goal is to globalize several variations of the drug-discovery program without compromising local aspects of specific workflows. DAIKON is modularized by abstracting the database and creating separate layers for entities, business logic, infrastructure, APIs, and frontend, with each tier allowing for extensions. Using Docker, the framework is packaged into two solutions: daikon-server-core and daikon-client. Organizations may deploy the project to on-premises servers or VPC. Active-Directory/SSO is supported for user administration. End users can access the application with a web browser. Currently, DAIKON is implemented in the TB Drug Accelerator program (TBDA).

Identification of ß-Lactams Active against Mycobacterium tuberculosis by a Consortium of Pharmaceutical Companies and Academic Institutions.

Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of ß-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen ∼8900 ß-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of ß-lactams screened were active against Mtb, many without a ß-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents.

Identification of RO4597014, a Glucokinase Activator Studied in the Clinic for the Treatment of Type 2 Diabetes.

To resolve the metabolite redox cycling associated with our earlier clinical compound 2, we carried out lead optimization of lead molecule 1. Compound 4 showed improved lipophilic ligand efficiency and demonstrated robust glucose lowering in diet-induced obese mice without a liability in predictive preclinical drug safety studies. Thus, it was selected as a clinical candidate and further studied in type 2 diabetic patients. Clinical data suggests no evidence of metabolite cycling, which is consistent with the preclinical profiling of metabolism.

7-Phenyl-pyrido[2,3-d]pyrimidine-2,4-diamines: novel and highly selective protein tyrosine phosphatase 1B inhibitors.

High throughput screening of the Roche compound collection led to the identification of diaminopyrroloquinazoline series as a novel class of PTP1B inhibitors. Structural modification of diaminopyrroloquinazoline series resulted in pyrido[2,3-d]pyrimidine-2,4-diamine series which was further optimized to give compounds 5 and 24 as potent, selective (except T-cell phosphatase) PTP1B inhibitors with good mouse PK properties.

Research and development of glucokinase activators for diabetes therapy: theoretical and practical aspects.

Glucokinase Glucokinase (GK GK ; EC 2.7.1.1.) phosphorylates and regulates glucose metabolism in insulin-producing pancreatic beta-cells, hepatocytes, and certain cells of the endocrine and nervous systems allowing it to play a central role in glucose homeostasis glucose homeostasis . Most importantly, it serves as glucose sensor glucose sensor in pancreatic beta-cells mediating glucose-stimulated insulin biosynthesis and release and it governs the capacity of the liver to convert glucose to glycogen. Activating and inactivating mutations of the glucokinase gene cause autosomal dominant hyperinsulinemic hypoglycemia and hypoinsulinemic hyperglycemia in humans, respectively, illustrating the preeminent role of glucokinase in the regulation of blood glucose and also identifying the enzyme as a potential target for developing antidiabetic drugs antidiabetic drugs . Small molecules called glucokinase activators (GKAs) glucokinase activators (GKAs) which bind to an allosteric activator allosteric activator site of the enzyme have indeed been discovered and hold great promise as new antidiabetic agents. GKAs increase the enzyme's affinity for glucose and also its maximal catalytic rate. Consequently, they stimulate insulin biosynthesis and secretion, enhance hepatic glucose uptake, and augment glucose metabolism and related processes in other glucokinase-expressing cells. Manifestations of these effects, most prominently a lowering of blood glucose, are observed in normal laboratory animals and man but also in animal models of diabetes and patients with type 2 diabetes mellitus (T2DM T2DM ) type 2 diabetes mellitus (T2DM) . These compelling concepts and results sustain a strong R&D effort by many pharmaceutical companies to generate GKAs with characteristics allowing for a novel drug treatment of T2DM.

Intuitive patent Markush structure visualization tool for medicinal chemists.

A Markush, or generic structure, is a widely used convention in chemical and pharmaceutical patents. The flexibility and complexity of this format, however, preclude an easy understanding and analysis of chemical space. In this paper, an application package called MarVis (Markush Visualization) is introduced to help chemists visualize Markush structures in chemical patents. MarVis can output a report with the Markush structure showing the query substructure and also an R-group table of all the possible R-groups described in the patent. MarVis also has a unique interactive interface that allows chemists to explore and zoom in the chemical space to find a subset of interest. SMILES, with minimal extensions, was used to facilitate a variety of patent Markush structure studies.

Novel glucokinase activators: a patent review (2008 - 2010).

IMPORTANCE OF THE FIELD: Small molecule glucokinase activators (GKAs) continue to represent a potential strategy to treat type 2 diabetes (T2D). Glucokinase (GK) primarily exerts its effect through modulatory actions in pancreatic ß-cells and hepatocytes. It couples insulin secretion in the pancreas with plasma glucose concentration and improves glucose utilization in the liver, thus, affecting two key aspects of glucose homeostasis. There has been an intense interest in GKAs within the pharmaceutical industry ever since the first report of a low molecular mass activator in 2003. The key drivers for this interest are the robust glucose lowering activity observed with GKAs in preclinical T2D animal models and early reports of efficacy in T2D patients. AREAS COVERED IN THIS REVIEW: The objective is to review GKA structures disclosed during the 2008 - 2010 period and classify them based on key structural features. For this purpose, only compound data from patent disclosures were used. WHAT THE READER WILL GAIN: The reader would gain a detailed view of structural diversity of the GKA field disclosed during the review period. TAKE HOME MESSAGE: There continues to be a high level of interest within the pharmaceutical industry in novel GKAs. Several new and highly potent structure types were reported for the first time in the past 3 years. Common features of all of them include a hydrogen bond donor-acceptor pair that makes contact with the backbone CO- and NH- bonds of Arg 63 residue on GK and two hydrophobic groups. During this review period, several GKAs progressed to Phase II clinical testing and the data on their safety and efficacy profiles are eagerly awaited.

Potent, selective MCH-1 receptor antagonists.

This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.

Identification of phenyl-pyridine-2-carboxylic acid derivatives as novel cell cycle inhibitors with increased selectivity for cancer cells.

Ro 41-4439, a phenyl-pyridine-2-carboxylic acid derivative, was identified by a cell-based screening approach that exploits the differences between normal and cancer cells in their sensitivity to cytotoxic agents. This compound showed low micromolar antiproliferative activity and cytotoxicity against a broad panel of human cancer cell lines in vitro, and over 10-fold selectivity to cancer cells when tested in parallel with a panel of proliferating normal human cells. Cytotoxicity of Ro 41-4439 is due to arrest of cell cycle progression in mitosis followed by induction of apoptosis. Four-week treatment of nude mice bearing established mammary tumor xenografts (MDA-MB-435) with well-tolerated doses of the compound showed 73% inhibition of tumor growth. Limited exploration of structure-activity relationships involving side chain length, and aryl and pyridine rings allowed for the identification of more potent analogs.