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SOP for Assessment of Drug-Likeness Parameters

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SOP for Assessment of Drug-Likeness Parameters

Standard Operating Procedure (SOP) for Assessment of Drug-Likeness Parameters

1) Purpose

The purpose of this Standard Operating Procedure (SOP) is to describe the process for assessing the drug-likeness parameters of compounds during the early stages of drug discovery. Drug-likeness refers to the chemical and pharmacological properties of a compound that are favorable for development as a drug candidate. This SOP ensures that drug-likeness is systematically evaluated using computational and experimental methods to select lead compounds with optimal drug-like characteristics.

2) Scope

This SOP applies to the assessment of drug-likeness parameters for compounds in the early stages of drug discovery. It includes the evaluation of physical, chemical, and pharmacokinetic properties, such as molecular weight, lipophilicity, solubility, and toxicity. The SOP is relevant to all teams involved in the early screening and optimization of drug candidates, including medicinal chemists, computational chemists, and pharmacologists.

3) Responsibilities

  • Medicinal Chemists: Responsible for designing compounds with favorable drug-likeness profiles based on the drug-likeness parameters outlined in this SOP. They collaborate with computational chemists to optimize lead compounds for drug development.
  • Computational Chemists: Perform computational assessments of drug-likeness, including the use of in silico models to predict key parameters such as solubility, lipophilicity, and permeability. They also assess ADMET
(Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of compounds.
  • Pharmacologists: Assist in evaluating the pharmacological aspects of drug-likeness, particularly in terms of bioavailability and metabolic stability. They provide feedback on how pharmacokinetics affect drug-likeness in vivo.
  • Project Managers: Oversee the assessment of drug-likeness parameters, ensuring that the evaluation is conducted systematically and within project timelines. They ensure communication across teams to align compound development efforts.
  • Quality Assurance (QA): Ensure that the drug-likeness assessment process follows internal protocols and regulatory standards. QA verifies the accuracy, consistency, and documentation of all data and assessments.

    • 4) Procedure

    The following steps outline the detailed procedure for assessing drug-likeness parameters:

    1. Step 1: Define Drug-Likeness Criteria
      1. Identify key drug-likeness parameters that need to be assessed, including molecular weight, lipophilicity (logP), solubility, polarity, toxicity, and pharmacokinetic properties.
      2. Determine the ideal ranges for each parameter based on established guidelines for drug candidates (e.g., molecular weight < 500 Da, logP between 2 and 5, high solubility).
      3. Ensure that the defined criteria align with the therapeutic area and the specific target, as different types of drugs may have different requirements for drug-likeness.
    2. Step 2: Computational Assessment of Drug-Likeness
      1. Use computational tools to predict the drug-likeness of lead compounds. Commonly used tools include ChemDraw, ADMET Predictor, and Lipinski’s Rule of Five, which evaluate molecular properties such as solubility, lipophilicity, and polarity.
      2. Calculate key parameters, such as the octanol-water partition coefficient (logP), molecular weight, hydrogen bond donors and acceptors, and topological polar surface area (TPSA).
      3. Use in silico models to predict ADMET properties, including bioavailability, metabolic stability, and plasma protein binding. Tools like the ADMETlab or SwissADME can be used to perform these predictions based on compound structures.
    3. Step 3: Experimental Validation of Drug-Likeness Parameters
      1. Conduct experimental assays to validate the computational predictions of drug-likeness parameters. For example, perform solubility and permeability tests using in vitro models such as Caco-2 cells for absorption and diffusion studies.
      2. Assess the compound’s bioavailability and stability using animal models to confirm its pharmacokinetic properties, including half-life, absorption rate, and plasma concentration.
      3. Perform toxicity studies to evaluate the compound’s safety profile, including cytotoxicity and genotoxicity assays to confirm that the compound does not pose any significant toxic risks.
    4. Step 4: Evaluation Against Lipinski’s Rule of Five
      1. Assess whether the compound adheres to Lipinski’s Rule of Five, which serves as a guideline for drug-likeness based on molecular properties. The compound should have:
        • Mol. weight ≤ 500 Da
        • LogP ≤ 5
        • No more than 5 hydrogen bond donors
        • No more than 10 hydrogen bond acceptors
      2. Check if the compound violates any of the rules and make adjustments to the molecular structure if necessary to improve drug-likeness.
    5. Step 5: Drug-Likeness Optimization
      1. Optimize the compound structure based on the drug-likeness assessment. Modify functional groups, adjust molecular weight, and optimize solubility and lipophilicity to meet ideal parameters for drug development.
      2. Ensure that modifications do not significantly alter the biological activity of the compound. Use structure-activity relationship (SAR) analysis to guide the optimization process.
      3. Iteratively assess drug-likeness after each modification, repeating computational predictions and experimental validation as needed.
    6. Step 6: Documentation and Reporting
      1. Document all steps of the drug-likeness assessment process, including computational predictions, experimental data, and optimization results.
      2. Prepare a Drug-Likeness Assessment Report that includes detailed information on the criteria used, predictions made, experimental validation results, and any modifications to the compound.
      3. Ensure that the report is stored securely and can be accessed for future reference, regulatory compliance, or intellectual property purposes.

    5) Abbreviations

    • ADMET: Absorption, Distribution, Metabolism, Excretion, Toxicity
    • SAR: Structure-Activity Relationship
    • TPSA: Topological Polar Surface Area
    • logP: Octanol-Water Partition Coefficient
    • IC50: Half-Maximal Inhibitory Concentration

    6) Documents

    The following documents should be maintained throughout the drug-likeness assessment process:

    1. Drug-Likeness Assessment Report
    2. Computational Drug-Likeness Data
    3. Experimental Validation Data
    4. Compound Optimization Logs

    7) Reference

    References to regulatory guidelines and scientific literature that support this SOP:

    • FDA Guidance for Industry on Drug Discovery
    • Scientific literature on drug-likeness and Lipinski’s Rule of Five
    • ADMET prediction tools and methodologies in drug discovery

    8) SOP Version

    Version 1.0: Initial version of the SOP.

    See also  SOP for ADME Screening in Early Drug Discovery

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