Drug Discovery Programs Research Articles

Diabetes mellitus drug discovery: insights into targeting feline and human amylin with small molecules

Background Type 2 diabetes (T2D) is a health concern for both humans and cats, with cases rising over the past decade. Around 70% of patients from either species exhibit pancreatic aggregates of islet amyloid polypeptide (IAPP), a protein that proves toxic upon misfolding. These misfolded protein aggregates congregate in the islets of Langerhans of the pancreas, diminishing the capability of β-cells to produce insulin and further perpetuating disease. Objective Our team’s drug discovery program is investigating newly synthesized compounds that could diminish aggregates of both human and feline IAPP, potentially disrupting the progression of T2D. Material and methods We prepared 24 compounds derived from diaryl urea, as ureas have previously demonstrated great potential at reducing accumulations of misfolded proteins. Biophysical methods were employed to analyze the anti-aggregation activity of these compounds at inhibiting and/or disrupting IAPP fibril formation in vitro. Results The results demonstrate that compounds 12 and 24 were most effective at reducing the fibrillization and aggregation of both human and feline IAPP. When compared with the control for each experiment, samples treated with either compound 12 or 24 exhibited fewer accumulations of amyloid-like fibrils. Conclusion Urea-based compounds, such as compounds 12 and 24, may prove crucial in future pre-clinical studies in the search for therapeutics for T2D.

The (pro)renin receptor as a pharmacological target in cardiorenal diseaes.

The (pro)renin receptor ((P)RR) is not only a member of the renin-angiotensin system (RAS) but also exerts several RAS-independent functions due to its multiple signal transductions pathways. In this mini-review, we shortly discuss the molecular functions of this receptor and its pathophysiological significance with a focus on cardiorenal diseases. Finally, we provide a short summary regarding a drug discovery and drug development program on small molecule-based renin/prorenin receptor blockers (RERBs).

Infusion of Magnetic Nanocatalyst to Microwave Propped Synthesis of Bioactive Azaheterocycles

Abstract: Microwave-assisted synthesis is a powerful tool in organic chemistry, providing a rapid and efficient method for the synthesis of bioactive heterocycles. The application of micro-waves significantly reduces reaction times and increases percentage yields with high purity of the final product. To make the synthetic protocol greener, the application of the magnetic nanocata-lyst is a rapidly growing area of interest nowadays. Magnetic nanocatalyst, with its unique fea-tures like magnetic separable facile recovery from the reaction media heterogeneously, makes the overall synthetic strategy cleaner, faster, and cost-effective. Aiming this, in the present review, we will focus on the infusion of Magnetic nanocatalyst to microwave-assisted synthesis of vari-ous classes of azaheterocyclic compounds, including pyridines, pyrimidines, quinolines, and ben-zimidazoles. The synthetic methodologies involved in the preparation of these heterocycles are highlighted, along with their biological activities. Furthermore, in this review, the most recent and advanced strategies to incorporate nanocatalysts in the microwave-assisted synthesis of nat-ural products containing azaheterocyclic moieties in drug discovery programs are elucidated in detail, along with the incoming future scope and challenges.

Structural and Synthetic Aspects of Small Ring Oxa- and Aza-Heterocyclic Ring Systems as Antiviral Activities.

Antiviral properties of different oxa- and aza-heterocycles are identified and properly correlated with their structural features and discussed in this review article. The primary objective is to explore the activity of such ring systems as antiviral agents, as well as their synthetic routes and biological significance. Eventually, the structure-activity relationship (SAR) of the heterocyclic compounds, along with their salient characteristics are exhibited to build a suitable platform for medicinal chemists and biotechnologists. The synergistic conclusions are extremely important for the introduction of a newer tool for the future drug discovery program.

Dearomatization of (Hetero)arenes through Photodriven Interplay between Polysulfide Anions and Formate.

The facile construction of C(sp3 )-rich carbo- and heterocyclic compounds is a pivotal synthetic strategy to foster contemporary drug discovery programs. The downstream dearomatization of readily accessible two-dimensional (2D) planar arenes represents a direct pathway towards accessing three-dimensional (3D) aliphatic scaffolds. Here, we demonstrate that polysulfide anions are capable of catalyzing a dearomatization process of substituted naphthalenes, indoles, and other related heteroaromatic compounds in the presence of potassium formate and methanol under visible light irradiation. The developed protocol exhibits broad functional group tolerance, operational simplicity, scalability, and cost-effectiveness, representing a practical and sustainable synthetic tool for the arene dearomatization.

Dearomatization of (Hetero)arenes through Photodriven Interplay between Polysulfide Anions and Formate**

AbstractThe facile construction of C(sp3)‐rich carbo‐ and heterocyclic compounds is a pivotal synthetic strategy to foster contemporary drug discovery programs. The downstream dearomatization of readily accessible two‐dimensional (2D) planar arenes represents a direct pathway towards accessing three‐dimensional (3D) aliphatic scaffolds. Here, we demonstrate that polysulfide anions are capable of catalyzing a dearomatization process of substituted naphthalenes, indoles, and other related heteroaromatic compounds in the presence of potassium formate and methanol under visible light irradiation. The developed protocol exhibits broad functional group tolerance, operational simplicity, scalability, and cost‐effectiveness, representing a practical and sustainable synthetic tool for the arene dearomatization.

A Hybrid Structure-Based Machine Learning Approach for Predicting Kinase Inhibition by Small Molecules.

Kinases have been the focus of drug discovery programs for three decades leading to over 70 therapeutic kinase inhibitors and biophysical affinity measurements for over 130,000 kinase-compound pairs. Nonetheless, the precise target spectrum for many kinases remains only partly understood. In this study, we describe a computational approach to unlocking qualitative and quantitative kinome-wide binding measurements for structure-based machine learning. Our study has three components: (i) a Kinase Inhibitor Complex (KinCo) data set comprising in silico predicted kinase structures paired with experimental binding constants, (ii) a machine learning loss function that integrates qualitative and quantitative data for model training, and (iii) a structure-based machine learning model trained on KinCo. We show that our approach outperforms methods trained on crystal structures alone in predicting binary and quantitative kinase-compound interaction affinities; relative to structure-free methods, our approach also captures known kinase biochemistry and more successfully generalizes to distant kinase sequences and compound scaffolds.

Developing the Pipeline: A Drug Discovery and Biomedical Research Training Program for Underserved Minority Youth

Developing the Pipeline: A Drug Discovery and Biomedical Research Training Program for Underserved Minority Youth

Synthesis of Squaric Acid Monoamides as Building Blocks for Drug Discovery

AbstractHerein, we present a synthetic compound library comprising of 28 anilino and benzylamino monosquarate-amide derivatives. Members of this library were designed as bioisosteric replacements for groups such as the ubiquitous carboxylic acid moiety. Further to their synthesis, we have shown the potential of these chemical building blocks for the generation of additional novel compounds. This work forms part of our efforts aimed at the assembly of 96-well plates loaded with bioisosteric analogues that may be used to enrich drug discovery programs. The research presented in this work focuses on the chemistry of 3,4-dihydroxycyclobut-3-ene-1,2-dione, a known carboxylic acid bioisostere.

A small animal model of NASH with progressive steatohepatitis -induced by fast food diet and alcohol in C57BL/6J mouse with high human pathophysiological proximity.

Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) both can progress to end-stage liver disease (ESLD). No relevant animal models are available for studying the toxic consequences of concurrent fast food diet and alcohol usage in fibrosing NASH. As a result, dependable and short-term in-vivo models capable of recapitulating human disease pathophysiology are required for deciphering mechanistic insights and preclinical drug discovery programs. The current study aims to develop a mouse model for progressive steatohepatitis employing a fast food (FF) diet with intermittent oral alcohol (EtOH) administration. For eight (8) weeks, C57BL/6J mice were fed standard chow (SC) diet±EtOH or FF±EtOH. EtOH uses enhanced the histological characteristics of FF -induced steatohepatitis and fibrosis. A dysregulated molecular signaling cascade related to oxidative stress, steatosis, fibrosis, DNA damage, and apoptosis was evident at protein and gene expression levels in the FF+EtOH. The results from the in-vivo model were replicated in mouse hepatocyte cultures (AML-12) subjected to palmitic acid (PA)±EtOH exposures. The results of the present study indicate that the clinical hallmarks of human progressive steatohepatitis and fibrosis were achieved in our mice model, showing its suitability for preclinical research.

Investigating the human and non-obese diabetic mouse MHC class II immunopeptidome using protein language modelling.

Identifying peptides associated with the major histocompability complex class II (MHCII) is a central task in the evaluation of the immunoregulatory function of therapeutics and drug prototypes. MHCII-peptide presentation prediction has multiple biopharmaceutical applications, including the safety assessment of biologics and engineered derivatives in silico, or the fast progression of antigen-specific immunomodulatory drug discovery programs in immune disease and cancer. This has resulted in the collection of large-scale data sets on adaptive immune receptor antigenic responses and MHC-associated peptide proteomics. In parallel, recent deep learning algorithmic advances in protein language modelling (PLM) have shown potential in leveraging large collections of sequence data and improve MHC presentation prediction. Here, we train a compact transformer model (AEGIS) on human and mouse MHCII immunopeptidome data, including a preclinical murine model, and evaluate its performance on the peptide presentation prediction task. We show that the transformer performs on par with existing deep learning algorithms and that combining datasets from multiple organisms increases model performance. We trained variants of the model with and without MHCII information. In both alternatives, the inclusion of peptides presented by the I-Ag7 MHC class II molecule expressed by the non-obese diabetic (NOD) mice enabled for the first time the accuratein silico prediction of presented peptides in a preclinical type 1 diabetes model organism, which has promising therapeutic applications. The source code is available at https://github.com/Novartis/AEGIS. Supplementary data are available at Bioinformatics online.

Nexo launches with oncology drug discovery program

Nexo launches with oncology drug discovery program

Drug repurposing: A futuristic approach in drug discovery

Drug repurposing (DR), also known as drug repositioning, is a strategy aimed at identifying new therapeutic uses for existing drugs. It offers an effective approach to discovering or developing drug molecules with novel pharmacological or therapeutic indications. In recent years, pharmaceutical companies have increasingly embraced the drug repurposing strategy in their drug discovery and development programs, leading to the identification of new biological targets. This strategy is highly efficient, time-saving, cost-effective, and carries a lower risk of failure compared to traditional drug discovery methods. By maximizing the therapeutic value of existing drugs, drug repurposing increases the likelihood of success. It serves as a valuable alternative to the lengthy, expensive, and resource-intensive process of finding new molecular entities (NMEs) through traditional or de novo drug discovery approaches. Drug repurposing combines activity-based or experimental methods with in silico-based or computational approaches to rationally develop or identify new uses for drug molecules. It leverages the existing safety data of drugs tested in humans and redirects their application based on valid target molecules. This approach holds great promise, particularly in addressing rare, difficult-to-treat diseases, and neglected diseases. By utilizing the wealth of knowledge and resources available, drug repurposing presents an emerging strategy for optimizing the therapeutic potential of existing medicines. It offers a pathway to rapidly identify effective treatments and repurpose approved drugs for new indications, benefiting patients and healthcare systems alike.

Continuous Flow Chemistry: A Novel Technology for the Synthesis of Marine Drugs.

In this perspective, we showcase the benefits of continuous flow chemistry and photochemistry and how these valuable tools have contributed to the synthesis of organic scaffolds from the marine environment. These technologies have not only facilitated previously described synthetic pathways, but also opened new opportunities in the preparation of novel organic molecules with remarkable pharmacological properties which can be used in drug discovery programs.

Estimating the hydrophobicity extent of molecular fragments using reversed-phase liquid chromatography.

A fast HPLC method was developed to study the hydrophobicity extent of pharmaceutically relevant molecular fragments. By this strategy, the reduced amount of sample available for physico-chemical evaluations in early-phase drug discovery programs does not represent a limiting factor. The sixteen acid fragments investigated were previously synthesized also determining potentiometrically their experimental log D values. For four fragments it was not possible to determine such property since their values were outside of the instrumental working range (2<pKa <12). An RP-HPLC method was therefore optimized. For each scrutinized method, some derived chromatographic indices were calculated, and Pearson's correlation coefficient (r) allowed to select the so-called "φ0 index" as the best correlating with the log D. The was fixed at 3.5 and a modification of some variables [organic modifier (methanol vs. ACN), stationary phase (octyl vs. octadecyl), presence/absence of the additives n-octanol, n-butylamine, and n-octylamine], allowed to select the best correlation conditions, producing a r=0.94 (p<0.001). Importantly, the φ0 index enabled the estimation of log D values for four fragments which were unattainable by potentiometric titration. Moreover, a series of molecular descriptors were calculated to identify the chemical characteristics of the fragments explaining the obtained φ0 . The number of hydrogen bond donors and the index of cohesive interaction correlated with the experimental data.

Chromone Containing Hybrid Analogues: Synthesis and Applications in Medicinal Chemistry.

The use of privileged scaffolds has proven beneficial for generating novel bioactive scaffolds in drug discovery program. Chromone is one such privileged scaffold that has been exploited for designing pharmacologically active analogues. The molecular hybridization technique combines the pharmacophoric features of two or more bioactive compounds to avail a better pharmacological activity in the resultant hybrid analogues. The current review summarizes the rationale and techniques involved in developing hybrid analogues of chromone, which show potential in fields of obesity, diabetes, cancer, Alzheimer's disease and microbial infections. Here the molecular hybrids of chromone with various pharmacologically active analogues or fragments (donepezil, tacrine, pyrimidines, azoles, furanchalcones, hydrazones, quinolines, etc.) are discussed with their structure-activity relationship against above-mentioned diseases. Detailed methodologies for the synthesis of corresponding hybrid analogues have also been described, with suitable synthetic schemes. The current review will shed light on various strategies utilized for the design of hybrid analogues in the field of drug discovery. The importance of hybrid analogues in various disease conditions is also illustrated. Keywords: Bioactive scaffolds, chromone, drug discovery, molecular hybridization, hybrid analogues.

FRAGMENTISE: A user-friendly, cross-platform tool to create and analyze comprehensive small-molecule fragment databases.

The ongoing COVID-19 pandemic, and constant demand for new therapies in unmet clinical needs, necessitates strategies to identify drug candidates for rapid clinical deployment. Over the years, fragment-based drug design (FBDD) has emerged as a mainstream lead discovery strategy in academia, biotechnology start-ups, and large pharma. Chemical building block libraries are the fundamental component of virtually any FBDD campaign. Current trends focus on smaller and smarter libraries that offer synthetically amenable starting points for rational lead generation. Therefore, there remains an ever-increasing need for new methods to generate fragment libraries to seed early-stage drug discovery programs. Here, we present FRAGMENTISE-a new user-friendly, cross-platform tool for user-tunable retrosynthetic small-molecule fragmentation. FRAGMENTISE allows for visualization, similarity search, annotation, and in-depth analysis of the fragment databases in the medicinal chemistry context. FRAGMENTISE is available as standalone software for Linux, Windows, and macOS users, with a graphical interface or command-line version.

Photoinduced Minisci Reaction with Diazines: An Approach Toward Original Fused Heterocycles.

Herein, we developed a photoinduced Minisci reaction on a large panel of diazines with good to excellent yields (28 examples, 44% to 89%). The reaction using 4CzIPN (1 mol%) as photoinitiator was carried out under white LED irradiation and required a slight excess of the acid reagent (1.2 equiv.). Cyclization reactions were then developed to access original N-heterocycles building blocks for drug discovery programs. An extension of the reaction to continuous flow was also reported. Finally, the mechanism of the transformation was studied suggesting a plausible radical chain mechanism.

Target Identification in Anti-Tuberculosis Drug Discovery.

Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis (TB), a disease that, although preventable and curable, remains a global epidemic due to the emergence of resistance and a latent form responsible for a long period of treatment. Drug discovery in TB is a challenging task due to the heterogeneity of the disease, the emergence of resistance, and uncomplete knowledge of the pathophysiology of the disease. The limited permeability of the cell wall and the presence of multiple efflux pumps remain a major barrier to achieve effective intracellular drug accumulation. While the complete genome sequence of Mtb has been determined and several potential protein targets have been validated, the lack of adequate models for in vitro and in vivo studies is a limiting factor in TB drug discovery programs. In current therapeutic regimens, less than 0.5% of bacterial proteins are targeted during the biosynthesis of the cell wall and the energetic metabolism of two of the most important processes exploited for TB chemotherapeutics. This review provides an overview on the current challenges in TB drug discovery and emerging Mtb druggable proteins, and explains how chemical probes for protein profiling enabled the identification of new targets and biomarkers, paving the way to disruptive therapeutic regimens and diagnostic tools.

Discovery and in vitro Characterization of BAY 2686013, an Allosteric Small Molecule Antagonist of the Human PAC1 Receptor.

The human pituitary adenylate cyclase activating polypeptide receptor (hPAC1-R), a class B GPCR identified almost 30 years ago, represents an important pharmacological target in the areas of neuroscience, oncology, and immunology. Despite interest in this target, only a very limited number of small molecule modulators have been reported for this receptor. We herein describe the results of a drug discovery program aiming for the identification of a potent and selective hPAC1-R antagonist. An initial HTS screen of 3.05 million compounds originating from the Bayer screening library failed to identify any tractable hits. A second, completely revised screen using native HEK293 cells yielded a small number of hits exhibiting antagonistic properties (4.2 million compounds screened). BAY 2686013 (1) emerged as a promising compound showing selective antagonistic activity in the sub-micromolar potency range. In depth characterization supported the hypothesis that BAY 2686013 blocks receptor activity in a non-competitive manner. Preclinical, pharmacokinetic profiling indicates that BAY 2686013 is a valuable tool compound for better understanding the signalling and function of hPAC1-R. Significance Statement Although the human PAC1-R is of major significance as a therapeutic target with a well-documented role in pain signaling, only a very limited number of small molecule (SMOL) compounds are known to modulate its activity. We identified and thoroughly characterized a novel, potent and selective SMOL antagonist of hPAC1-R (acting in an allosteric manner). These characteristics make BAY 2686013 an ideal tool for further studies.