Drug Discovery Training Course - A Step By Step Introduction

Welcome and Introduction

The Drug Discovery Landscape

Typical drug discovery considerations:

• Essential elements
• Typical Milestones, decision points and pipeline
• Drug Discovery strategies
• Drug Discovery costs and drug revenues
• Reducing attrition
• Nomenclature
• Scientific skills base required (Medicinal Chemistry, Biology, Molecular Biology, ADMET/DMPK, Informatics/Artificial Intelligence)
• Small Molecules v. Biologics as drugs

Project Initiation

Best practice:

• Generating a TPP (Target Product Profile)
•  Selecting a viable Project

Target Protein Selection

How to select the right protein drug target for the disease:

• Target Validation/Hypothesis generation
• Genomics and Proteomics in Target selection
•  Drug action at the cellular level

Target Protein Selection (continued)

• Target tractability.
• Major classes of Target proteins for existing small molecule drugs:
  • G-Protein-Coupled Receptors, Ion Channels, Nuclear Receptors, Kinases 

Lead / Lead Series Identification

The path to obtaining a lead or lead series with the quality attributes to become a clinical candidate. An outline of the key scientific tools of drug discovery:

• Bioactivity assays of compounds, Low/Medium throughput screening, Bioactivity assay formats, Transformed cells, Stem cells, Organoids
• Potency quantification - key constants and parameters
• Targeted Protein Degradation
• Selectivity Analysis
•  Biostructural Analysis of the compound–protein target structure (X-Ray diffraction, Cryo-electron Microscopy, Google AlphaFold).
• E-Docking

Recap of Day One

Lead / Lead Series Identification (continued)

•  High Throughput Screening (HTS)
•  Company compound library
• Virtual company compound library and its e-screening

In vitro ADMET methodologies and their application:

• Compound absorption at the gut and blood-brain barrier, bioavailability
•  Drug Metabolism: Cyp 450 / drug-drug interactions / Glucuronidation / P-glycoprotein / Metabolic stability measurement/ The Prodrug Strategy  
• Protein binding of compounds

Lead / Lead Series Identification (continued)

Medicinal chemistry:

• Multidimensional Optimisation (MDO) of compounds
• Compound Synthesis and automation
• Chemical and physical properties of drug-like compounds
• Drug-Protein Target bonding chemistry
• Drug design physical/chemical parameters (e.g. Lipinski/Schultz ‘rules’)

Lead / Lead Series Identification (continued)

• Animal model studies
• Efficacy in animal models of disease, examples:
  • Inflammation
  • Cancer
  • HIV-AIDS
  • Essential attributes of a Lead Compound
  • Phasing of Scientific activities in Lead Identification for small molecules

Clinical Candidate Identification

Final ‘polishing’ of the lead with a view to its nomination to enter Pre-clinical and Preclinical Development:

• Essential attributes of a clinical candidate
•  Manufacture
• Formulation
• Pharmacokinetics (PK) and Pharmacodynamics (PD)

Clinical Candidate Identification (continued)

• Toxicology and Toxicology Assays in vitro and in vivo / hERG.
• Allometric Scaling.
• Entry into Human Enabling Development stage.

Q & A

The course will include a number of interactive exercises throughout the two days