Computational Modelling for Drug Design - Detailed Study Notes

Computational Modelling for Drug Design

Lecture 3 - Structure- and Ligand-Based Design

Modelling in Drug Development

  • Stages: Drug development can be divided into three broad stages:

    • Discovery: Initial identification of compounds and understanding their interactions.

    • Development: Optimization of lead compounds and preclinical testing.

    • Commercialization: Marketing and distribution of approved drugs.

  • Application of Modelling: Most applications of computational modelling occur in the discovery stage of drug development.

Design - Make - Test - Analyse (DMTA)

  • Overview: Early-stage medicinal chemistry follows a cycle of Design, Make, Test, and Analyze to identify and develop drug compounds.

  • Key Aims:

    1. Identify hit compounds.

    2. Improve the hit properties including:

    • Potency

    • Solubility

    • Toxicity

    • Bioavailability

    1. Identify lead candidate(s) for preclinical development.

  • Hit-Lead Development Cycle: The process involves:

    • Design: Creation of a library of compounds.

    • Make: Synthesis of these compounds.

    • Test: Evaluation of compound efficacy and safety.

    • Analyze: Assessing data to improve activity and other properties until a clinical candidate emerges.

  • Compound Testing: Typically, a small molecule drug development program synthesizes and tests hundreds to thousands of compounds to identify a clinical candidate that proceeds to human trials.

Approaches to Small Molecule Drug Design

  • Variability in Drug Development Approaches: Depends on the knowledge of the target:

    • Phenotypic Drug Development (PDD):

    • The actual biological target is unknown; development observed through drug effects on phenotype.

    • Assays utilize various biological samples such as tissues, organs, or cells.

    • Historically, early drug development was solely based on PDD, as targets were not well understood.

    • Further covered in BPS2022.

    • Target-Based Drug Development (TDD):

    • The target, typically a protein, is known.

    • Assays can directly use isolated targets alongside other biological samples.

    • This method has become the most common approach in contemporary drug development.

    • Ligand-Based Drug Design:

    • Relies solely on structural information derived from the ligands.

    • Applicable in both PDD and TDD scenarios.

    • This is the only viable approach when the target structure is unknown.

    • Structure-Based Drug Design (SBDD):

    • Additional structural information is available from knowledge of the target structure or ligand-target complexes.

    • Combines ligand- and structure-based methods to enhance drug development techniques.

Example of Ligand-Based Drug Design

  • Journal Reference: Ferrins, L., et al., J. Med. Chem., 2024, 67, 13985-14006.

  • Case Study Overview:

    • Target disease: Human African Trypanosomiasis (HAT) caused by the protozoan Trypanosoma brucei.

    • Current treatments for HAT possess limitations; thus, alternative strategies are considered.

    • Utilized human kinase inhibitor chemotypes to find substituted 4-aminoazaindoles as potential inhibitors.

    • Identified 4s as a promising candidate for inhibiting Trypanosoma brucei growth, exhibiting rapid action in vitro but failing to eradicate infection in an animal model.

  • Mechanism of Action Exploration: Initial findings indicated the involvement of arginine kinase, though not the sole target.

  • Comprehensive Drug Discovery Approach: Incorporated cheminformatics, structure-potency, and structure-property analyses, along with pharmacophore identification in this study.

  • Key Metrics:

    • T. brucei pEC50 values varied (7.4 for 4s and 8.7 for a secondary compound).

    • HepG2 PTC50 values showed 4.4 and 4.3, respectively.

    • BBB Score: 3.2 for initial compound and 3.9 for secondary compound.

    • Inhibition percentage against HSROCK1: 2.2% noted.

Inhibitors of Trypanosoma brucei

  • Pathogen Characteristics: Trypanosoma brucei is the causative agent of HAT, which is fatal if untreated.

  • Development Challenges: Approximately 75 compounds were synthesized to vary the hit compound, evaluated against cultured T. brucei.

  • Evaluation of Lead Compounds: Tested compounds in mice infected with T. brucei, although the infection was not cleared, leading to project cessation.

Pharmacophore Model

  • Definition: Pharmacophore – derived from Greek:

    • phármakon meaning remedy or poison.

    • phoros translates to bearer or carrier.

  • Function: Represents the part of a molecule that is essential for its biological activity.

  • Model Development: Ferrins et al. developed a 3D pharmacophore model structured from known inhibitors to identify potential hydrogen bond donors and acceptors and evaluate the volume occupied by the receptor (Details will be discussed next week).

Example of Structure-Based Drug Design

  • Case Example: SARS-CoV2 Protease

    • The 3C-like protease (3CLpro) or main protease (Mpro) is crucial for SARS-CoV2 viral replication.

    • Proteases function by binding to and cleaving extended protein strands.

    • Crystallization of 3CLpro with bound ligands allows observation of protein-ligand interactions through X-ray crystallography.

    • Reference: Jiang et al., Nature Communications (2023) 14:6463.

SBDD Project Overview

  • Initial Compound: Development began with boceprevir, a known inhibitor of another viral protease.

  • Testing Protocols: Compounds synthesized were tested in vitro against SARS-CoV2 infected cells.

  • Structural Data Acquisition: Findings were confirmed through X-ray crystallography leading to the approval of Simnotrelvir in China in 2023.

  • Crystal Structure Information: The crystal structure reference associated with this project is 8IGX according to Jiang et al.

Key Questions Addressed

  • Application of Molecular Modelling: Where is it most often applied in drug design?

  • Understanding the DMTA Cycle: What does it involve in drug development?

  • Clarification of Design Types: What constitutes structure- and ligand-based drug design?

  • Requirements for SBDD: What are the essential components?

  • Application of Ligand-Based Design: Where would these methods be appropriate?

  • Comparison of Design Methods: Are structure-based and ligand-based methods mutually exclusive?