Science Pool

This article forms a book chapter in Artificial Intelligence in Drug Design.

In this review article, we provide the latest insights into de novo design approaches based on  artificial intelligence (AI) algorithms with a specific focus on ligand-based methods.

It includes:

• a background to de novo design approaches developed prior to the use of AI
• an overview of AI and commonly employed neural network architectures used in ligand based de novo design
• a list of more than 100 deep generative models reported in the literature from 2017-2020
• current applications of deep generative approaches in the drug discovery context
• an insight into future applications of deep generative models in de novo drug design 

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Transient Receptor Potential Melastatin 5 (TRPM5) is an intracellular calcium-activated cation-selective ion channel which is expressed in a variety of cells and tissues. Dysfunction of the TRPM5 channel has been linked to a number of pathological conditions including diabetes, inflammatory responses, enteric infections and parasitic infections. Identifying sufficiently selective agonists or positive modulators of the TRPM5 channel has, to date, proved challenging which has limited its potential as a drug target.   

In this publication, we focus on:

• the development of a high throughput screen using a fluorescent membrane potential assay for primary hit identification screening and selectivity assessment of TRPM5 channel positive modulators 
• use of medium and high throughput electrophysiology assays (QPatch HTX and SyncroPatch 384PE) as follow-up screens to confirm activity and selectivity of identified hits
• the SyncroPatch 384PE assay for structure-activity relationship (SAR) expansion of the identified chemical series

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Loss of heart myocardium is considered to be an irreversible process which can eventually lead to heart failure. Adult cardiomyocytes divide at a rate of less than 1% per year and no cardiac stem or progenitor cell type contribute significantly to the replacement of lost myocytes. One approach being pursued to replace lost heart muscle and regenerate the heart is the use of stem cell-derived cardiomyocytes.

In this publication, we focus on an in-depth review of the use of human pluripotent stem-cell derived cardiomyocytes in heart regeneration including:

• a background to cardiac regeneration and the approaches used to address this
• preclinical research and achievements in the use of cell therapy and stem cell-derived cardiomyocytes for the replacement of lost heart muscle 
• an overview of existing open questions such as how the technology works, the duration of effect, patient selection, immunological issues and how to reduce risk
• a summary of the clinical trials currently ongoing in this field

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P2X3 receptors play an important role in the sensitisation of nerve fibres and pain pathways. Involvement in pathways triggering cough and contribution to the pathophysiology of endometriosis and overactive bladder have also been reported. Development of P2X antagonists have been hampered by off‑target effects which include severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer.  

In this publication, we focus on:

• how eliapixant (BAY 1817080), a P2X3 receptor antagonist, is both highly potent and selective for P2X3 over other P2X subtypes in vitro including P2X2/3
• how eliapixant reduces inflammatory pain in relevant animal models
• experimental evidence that P2X3 antagonism reduces neurogenic inflammation and vaginal pain, and demonstration of the potential use of eliapixant in endometriosis

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The key to de-risking and expediting the development and approval of new antimicrobials lies in the detailed understanding of the PK/PD relationship. Understanding this relationship informs the development of optimal human dosing, maximising efficacy while minimising the potential to antimicrobial resistance.

This white paper describes and appraises today's most versatile in vitro system for the determination of in vitro PK/PD relationships between antimicrobial compounds and bacteria, fungi and viruses - the Hollow Fibre Infection Model (HFIM)

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Mass spectrometry (MS)-based ubiquitinomics allows a system-level understanding of ubiquitin signalling. 

In this publication, we focus on:

• a background to ubiquitinome profiling
• presentation of a scalable and robust workflow for deep and precise in vivo ubiquitinome profiling using DIA-MS (data-independent acquisition mass spectrometry) and neural network based data processing
• comprehensive mapping of substrates of deubiquitinase USP7, an anticancer drug target known to regulate tumour suppressor p53
• application of the method including rapid mode of action profiling of candidate drugs targeting deubiquitinases or ubiquitin ligases 

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Alastair Parkes, Ph.D, Group Leader, Discovery Chemistry, Evotec UK

As part of our ongoing efforts at Evotec to tackle AMR through the design of novel antibiotics we have been working with Boston-based X-Biotix in a collaboration focussed on targeting priority Gram-negative pathogens. We are now able to share the story of our work on inhibitors of UDP-N-Acetylglucosamine Acyltransferase (LpxA), a key enzyme in the biosynthetic pathway of the outer membrane lipopolysaccharide of Gram-negative bacteria. Building on hit-finding work at X-Biotix we put together a multi-disciplinary team including Medicinal Chemistry, Computational Chemistry, Structural Biology and DMPK at our Abingdon UK site, in vitro and in vivo Microbiology and PK at our Alderley Park UK site, and in vitro Biology at our site in Hamburg, Germany. Through structure and property-based optimisation we were able to design highly potent inhibitors of Pseudomonas aeruginosa LpxA that were active against multi-drug resistant clinical isolates. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa bacteria. In our paper in the Journal of Medicinal Chemistry we share the optimisation story, along with a significant quantity of activity data that we hope will be useful for other teams working on small molecule strategies to tackle P. aeruginosa and other Gram-negative bacteria.

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Arthralgia (persistent pain or stiffness of the joints) is a common symptom of chikungunya virus infection which can persist for many months following the disease. This condition is associated with significant disability and reduced quality of life. In order to manage individual clinical expectations and long term burden on the population following a chikungunya virus infection epidemic, it is critical to know the expected duration of the post infection arthralgia. 

In this publication, we focus on:

• a background to chikungunya virus and its symptoms including arthralgia
• a literature review of published cohort studies which have tracked the symptoms of chikungunya virus over time after infection with the virus
• using simple statistical models to estimate the average arthralgia resolution rate

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Following chikungunya virus infection, chronic rheumatological symptoms are similar to those observed with rheumatoid arthritis. To further evaluate this, a comparison was made between the relevance of joint counts and symptoms between the two conditions.

In this publication, we focus on:

• a background to chikungunya virus and its various symptoms including chronic joint pain and inflammation
• a cross sectional study of 40 patients with chronic chikungunya arthralgia and 40 patients with rheumatoid arthritis in order to compare symptoms
• an assessment of the relevance of joint counts in both conditions and their relationship with disability

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Mutant huntingtin (mHTT) protein has been implicated in neuronal degeneration in Huntington's Disease.

In this publication, we focus on:

• a background to the inherited neurodegenerative disorder, Huntington's Disease, including the impact of the mutant huntingtin (mHTT) gene
• a discussion of the use of positron emission tomography (PET) to monitor disease progression
• the identification of a novel ligand CHDI-626 which binds to mHTT aggregates

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