Drug Discovery and Development Notes

Introduction: Rational Approach to Drug Design

Intended Learning Outcomes

• Describe traditional drug design and its methods.

• Describe rational drug design and its methods.

• Method of Variation

• Case Study - Method of Variation through Disjunction

• Case Study - Method of Variation through Conjunction

Traditional Drug Designing

• Involves the origin of drug discovery that evolved from natural sources and accidental events.

• Was not target-based and less systematized than modern approaches.

• Advancements in pharmaceutical science and technology have led to a more systematized modern drug discovery.

Methods:

1.  Random Screening
2.  Trial & Error Method
3.  Ethnopharmacology Approach
4.  Serendipity Method
5.  Classical Pharmacology

Rational Drug Designing

• Broadly divided into two categories:

  • Development of molecules with desired properties for targets with known structure and function.

  • Development of molecules with predefined properties for targets whose structural information may or may not be known; unknown target information can be found by Global gene expression data.

Methods:

• Two major types:

  1. Ligand-Based Drug Designing

     • QSAR (Quantitative Structure-Activity Relationship)

     • Pharmacophore Perception

  2. Structure-Based Drug Designing

     • Docking

     • De novo drug design

Understanding the Drug Target

Target Identification

• Identify the specific biomolecule, such as a protein or enzyme, involved in the disease process and can be modulated by a drug.

Target Validation

• Confirm that the selected target is biologically relevant and plays a crucial role in the disease.

• Establish the causal relationship between the target and the disease.

Target Structure

• Analyze the three-dimensional structure of the target to understand its function, binding sites, and potential interactions with drug molecules.

Identifying Lead Compounds

• Screening large chemical libraries to identify promising drug candidates with desired biological activities.

• Utilizing high-throughput screening techniques to rapidly test thousands of compounds against a specific target.

• Applying computational methods like virtual screening to narrow down the candidate pool before experimental validation.

Structural Analysis and Optimization

• Structural analysis involves understanding the 3D structure of the drug target (typically a protein) and how potential drug molecules may interact with it.

• Optimization aims to refine the structure of lead compounds to enhance their binding affinity, selectivity, and pharmacokinetic properties, ultimately improving their therapeutic potential.

In Silico Drug Design

• In silico drug design leverages computational methods to model and analyze the interactions between potential drug compounds and their biological targets.

• This allows for rapid virtual screening of chemical libraries to identify promising lead compounds.

• Advanced in silico techniques like molecular docking, pharmacophore modeling, and quantitative structure-activity relationship (QSAR) analysis can accelerate the drug discovery process by predicting binding affinities, ADME properties, and other key characteristics.

High-Throughput Screening

Library Preparation

• Assemble a diverse chemical library of potential drug candidates for automated high-throughput screening.

Robotic Automation

• Use robotic pipetting systems to rapidly test thousands of compounds against the drug target in parallel.

Data Analysis

• Leverage advanced algorithms and machine learning to identify the most promising lead compounds from the screening results.

Pharmacokinetics and Pharmacodynamics

Drug Absorption

• Understanding how a drug is absorbed into the body, including factors like the route of administration, drug solubility, and membrane permeability.

Drug Distribution

• Analyzing how the drug is transported and distributed throughout the body, influenced by factors like protein binding and tissue penetration.

Drug Metabolism

• Examining the chemical transformation of the drug by the body, including the role of enzymes and the formation of active/inactive metabolites.

Drug Excretion

• Evaluating how the drug and its metabolites are eliminated from the body, often through the kidneys or liver.

Preclinical Testing and Evaluation

Target Validation

• Confirm the drug target's role in the disease.

Compound Profiling

• Assess the lead compound's potency, selectivity, and pharmacokinetics.

Safety Assessment

• Evaluate potential toxicity through in vitro and in vivo studies.

• After identifying promising lead compounds, the next critical step is preclinical testing and evaluation.

• This involves rigorously validating the drug target, profiling the lead compound's properties, and thoroughly assessing its safety through extensive in vitro and in vivo studies.

• Only once these preclinical hurdles are cleared can the compound advance to clinical trials.

Clinical Trials and Regulatory Approval

• Once a promising drug candidate has been identified, it must undergo rigorous clinical trials to evaluate its safety and efficacy.

• This multi-phase process involves testing the drug on human volunteers and closely monitoring its effects.

Phase I

• Establishes initial safety and tolerability in healthy volunteers.

Phase II

• Assesses the drug's efficacy and further evaluates safety in a larger patient population.

Phase III

• Compares the drug's performance to the current standard of care in a large, diverse patient group.

• If the clinical trials are successful, the drug must then obtain regulatory approval, typically from agencies like the FDA or EMA, before it can be marketed and prescribed to patients.

Challenges and Future Directions in Rational Drug Design

1. Complexity of Biological Systems

   • The human body is an intricate network of interconnected pathways, making it challenging to predict off-target effects and unintended consequences of new drugs.

2. Identifying Effective Leads

   • Discovering potent and selective lead compounds that can be optimized into viable drug candidates remains a significant obstacle in rational drug design.

3. Advancing In Silico Methods

   • Improving computational models and simulations to better predict pharmacokinetics, pharmacodynamics, and toxicity will enhance the efficiency of the drug discovery process.

4. Personalized Medicine

   • Integrating genomic and patient data to develop tailored treatments that account for individual differences in drug response is a promising future direction.

Case Study: The Method of Variation

Drug Design: The Method of Variation

• Under this method, a new drug molecule is developed from a biologically active prototype.

Advantages:

• At least one new compound of known activity is found.

• The new structural analogues, even if not superior, may be more economical.

• Identical chemical procedures are adopted, hence considerable economy of time, library, and laboratory facilities.

• Screening of a series of congeners (i.e., members of the same gene) gives basic information with regard to pharmacological activity.

• Similar pharmacological techniques for specific screening may be used effectively.

Cardinal Objectives of the Method of Variation

• To improve potency

• To modify specificity of action

• To improve duration of action

• To reduce toxicity

• To effect ease of application or administration or handling

• To improve stability

• To reduce cost of production

Application of the Method of Variation

• The application of the method of variation is exploited in two different manners to evolve a better drug.

• The two main approaches for this goal can be indicated as:

  • Drug design through disjunction

  • Drug design through conjunction

Drug Design Through Disjunction

• Disjunction comes in where there is the systematic formulation of analogues of a prototype agent, in general, toward structurally simpler products, which may be viewed as partial or quasi-replicas of the prototype agent.

• The method of disjunction is usually employed in three different manners, namely:

  • Unjoining of certain bonds.

  • Substitution of an aromatic cyclic system for saturated bonds.

  • Diminution of the size of the hydrocarbon portion of the parent molecule.

Example

• The extensive study on the estrogenic activity of oestradiol via drug design through disjunction ultimately rewarded in the crowning success of the synthesis and evaluation of trans-diethylstilbesterol.

Observations regarding estrogen design from oestradiol

• Various steps in the design of II to III to IV designate nothing but successive simplification through total elimination of the rings B and C in oestradiol (I).

• The above manner of drug design finally led to successively less active products (i.e., II, III, IV).

• Upon plotting estrogenic activity against various structures (I to VII), it was quite evident that the maximal activity in this series was attributed to trans-diethylstilbesterol.

• In the following three different possible structures of diethylstilbesterol analogues, the estrogenic potency decreases substantially as the distance ‘D’ between the two hydroxyl groups decreases.

Drug Design Through Conjunction

• This is known as the systematic formulation of analogues of a prototype agent, in general, toward structurally more complex products, which may be viewed as structures embodying certain moieties of the features of the prototype.

• In this type of drug design, the main principle involved is the ‘principle of mixed moieties.’

• A drug molecule is essentially made up with two or more pharmacophoric moieties embedded into a single molecule.

Example

• Ganglionic blocking agent—its development is based on the principle of mixed moieties.

• The principle of mixed moieties actually involves the conjunction of two or more different types of pharmacophoric moieties within a single molecule.

• Acetylcholine is an effective postganglionic parasympathetic stimulant in doses that afford no appreciable changes in the ganglionic function; whereas hexamethonium possesses only a slight action at postganglionic parasympathetic endings in doses that produce a high degree of ganglionic blockade.

Factors

$(where Sv1 = steric factor 1 ; Sv2 = steric factor 2 ; Sv3 = steric factor 3 ; Sd = steric distance factor ; P1 = polarity factor 1 and P2 = polarity factor 2)$.

• The moiety requirements for postganglionic parasympathetic stimulant action (muscarinic moiety) have been duly summarized for convenience to the above structure of acetylcholine wherein the various operating factors have been highlighted.

• The foregoing generalization of the muscarinic moiety on being studied in relation to the particular bisquaternary type of structure, e.g., hexamethonium, promptly suggests the following proposed design, thus embodying the ganglionic moiety and the muscarinic moiety.

• The ‘internitrogen distance’ essentially constitutes an important factor in many series of bisquaternary salts that possess ganglionic blocking activity.

• This distance is almost similar to that present in hexamethonium in its most extended configuration.

• The actual synthesis and pharmacological evaluation of the above hexamethyl analogue reveal the presence of both muscarinic stimulant and ganglionic blocking actions.

• Interestingly, the corresponding hexaethyl analogue possesses a ganglionic blocking effect and a weak muscarinic stimulant action.

Rational Drug Designing Methods

1) Ligand Based Drug Designing
a) QSAR
b) Pharmacophore Perception
2) Structure Based Drug Designing
a) Docking
b) De novo drug design