Drug Design: Discovery, Development and Delivery Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Associate Professor Department of Pharmaceutics KLE University BELGAUM – 590010 E-mail: [email_address] Cell No: 0091 9448716277

Drug Design

Drug Design Drug design is the approach of finding drugs by design, based on their biological targets . Typically a drug target is a key molecule involved in a particular metabolic or signalling pathway that is specific to a disease condition or pathology , or to the infectivity or survival of a microbial pathogen . Other approaches may be to enhance the normal pathway by promoting specific molecules in the normal pathways that may have been affected in the diseased state. In medicine , biotechnology and pharmacology , drug discovery is the process by which drugs are designed

Drug design is the approach of finding drugs by design, based on their biological targets . Typically a drug target is a key molecule involved in a particular metabolic or signalling pathway that is specific to a disease condition or pathology , or to the infectivity or survival of a microbial pathogen .

Other approaches may be to enhance the normal pathway by promoting specific molecules in the normal pathways that may have been affected in the diseased state.

In medicine , biotechnology and pharmacology , drug discovery is the process by which drugs are designed

Drug Design 1. Rational Drug Design 2. Computer-assisted Drug Design (CADD) 3. Neural network in Drug Design

1. Rational Drug Design

2. Computer-assisted Drug Design (CADD)

3. Neural network in Drug Design

Rational Drug Design The industry now has the research tools to pursue rational Drug Design successfully, but a new hurdle is being raised:finding a way to generate data and manage our knowledge of disease that maximizes the value of that knowledge 1. Molecular properties 2. Receptor-Based modeling 3. Numerical methods

The industry now has the research tools to pursue rational Drug Design successfully, but a new hurdle is being raised:finding a way to generate data and manage our knowledge of disease that maximizes the value of that knowledge

1. Molecular properties

2. Receptor-Based modeling

3. Numerical methods

Rational Drug Design Refining the understanding of pathogenesis

Rational Drug Design Investigating complex systems increases knowledge return

Computer-assisted Drug Design (CADD) Drug design is a three-dimensional puzzle where small drug molecules, ligands, are adjusted to the binding site of a protein. The factors which affect the protein-ligand interaction can be characterized by using molecular docking and different quantitative structure-activity relationships (QSAR) methods

Drug design is a three-dimensional puzzle where small drug molecules, ligands, are adjusted to the binding site of a protein.

The factors which affect the protein-ligand interaction can be characterized by using molecular docking and different quantitative structure-activity relationships (QSAR) methods

Computer-assisted Drug Design (CADD) In CoMFA map the colored fields describe how molecular structure can be modified to increase biological activity (CoMFA-Comparative molecular field analysis)

Computer-assisted Drug Design (CADD) The most commonly used tool to model biological system is molecular dynamics The model of a receptor refined with molecular dynamics simulations

The most commonly used tool to model biological system is molecular dynamics

The model of a receptor refined with molecular dynamics simulations

Computer-assisted Drug Design (CADD) 3D models of membrane receptors can be refined and validated in a realistic lipid-water-salt environment using molecular dynamics simulations

Computer-assisted Drug Design (CADD ) Virtual screening is a computational technique to find novel drug candidates. Data from virtual screening can be used to develop predictive models in order to optimize ADMET properties of the candidate molecules. The ultimate goal of this procedure is to find investing lead molecules that are worth for further drug research and synthesis.

Virtual screening is a computational technique to find novel drug candidates.

Data from virtual screening can be used to develop predictive models in order to optimize ADMET properties of the candidate molecules.

The ultimate goal of this procedure is to find investing lead molecules that are worth for further drug research and synthesis.

Computer-assisted Drug Design (CADD) New potent inhibitor for the Human Sirutuin Type 2 enzyme was found using a virtual screening technique

Neural network in Drug Design This is the most latest technique being applied to discover new drugs. It works on the same principles as the neural networks found in the human brain. This technique makes use of Computer Artificial Intelligence, whereby a computer learns by itself, how to approach a target drug molecule and improves its iterations by itself. This technique can be applied to solve complex drug calculations. Desktop computers as well as Super-Computers both are employed for Neural Networks Drug research.

This is the most latest technique being applied to discover new drugs. It works on the same principles as the neural networks found in the human brain.

This technique makes use of Computer Artificial Intelligence, whereby a computer learns by itself, how to approach a target drug molecule and improves its iterations by itself.

This technique can be applied to solve complex drug calculations. Desktop computers as well as Super-Computers both are employed for Neural Networks Drug research.

Applications 1 . Find interesting lead molecules quickly 2. Predicting properties and activities of untested molecules 3. Propose compounds for synthesis 4. Validate models of receptor binding sites 5. Optimize pharmacokinetic properties of compound

1 . Find interesting lead molecules quickly

2. Predicting properties and activities of untested molecules

3. Propose compounds for synthesis

4. Validate models of receptor binding sites

5. Optimize pharmacokinetic properties of compound

Drug Discovery

Drug Discovery In medicine , biotechnology and pharmacology , drug discovery is the process by which drugs are discovered The process of drug discovery involves the identification of candidates, synthesis, characterization, screening, and assays for therapeutic efficacy.

In medicine , biotechnology and pharmacology , drug discovery is the process by which drugs are discovered

The process of drug discovery involves the identification of candidates, synthesis, characterization, screening, and assays for therapeutic efficacy.

Dermatology Inflammatory/ Immune-related Oncology/ Cancer Respiratory Cardiovascular/ Blood Disorder Musculoskeletal Infectious Disease Microbial/Viral Neurological/ Pyschotherapeutic Ophthalmic Metabolic Gastrointestinal Important DRUG Targets Focused Areas of Research

Drug Discovery Pathway Efficacy ADME Toxicology Safety Preformulations Stability Studies Leads Selection of candidate drug Preclinical Studies Primary Screening [Hits] Discovery & Development

1. What is an ideal drug? (Given by mouth and has a beneficial effect {safe & efficacious} in only ~ 50% !) 2. What is a promising drug candidate? (Most site specific with best combination of target affinity, highest bioavailability and lowest toxicity) 3. How is a ‘lead’ drug candidate screened for ideal characteristics? (Study of the in vitro ADME/Tox- drug transport , absorption, metabolism, etc) [Toxicity & pharmacokinetics: In vivo ] Drug Discovery Process

1. What is an ideal drug?

(Given by mouth and has a beneficial effect {safe & efficacious} in only ~ 50% !)

2. What is a promising drug candidate?

(Most site specific with best combination of target affinity, highest bioavailability and lowest toxicity)

3. How is a ‘lead’ drug candidate screened for ideal

characteristics?

(Study of the in vitro ADME/Tox- drug transport , absorption, metabolism, etc)

[Toxicity & pharmacokinetics: In vivo ]

Drug Discovery Pipeline Validated Targets Hot Leads Drug Candidates ADME PK Human Trials H-UHTS Primary Screening Secondary Screening Lead Identification Lead Optimization Pre-clinical Clinical Discovery Development M-HTS Lab & Animal Tests L-MTS Clinical Validation Genome Sequencing SNP Discovery Genotyping Gene Expession Profiling Exploratory Research Genomics Proteomics Drug Discovery Fractionate Protein Mass Spec Combichem Synthesis Natural Compounds Compound Library Pathway Mapping Protein Structure Functional Genomics Protein- protein Interactions Protein Localization Expression Profiling Peptide Mass Fingerprinting Production Diagnostics

Drug Discovery Process Assay Development Discovery Center w/primary & secondary screening & Pre-ADME In vitro & in-vivo ADMET Compound library generation Combichem Clinical Trials & Clinical monitoring Functional and ADMET screening assays becoming more important earlier in the screening process. Exploratory Drug Discovery Drug Development New Drug Target Identification Target Qualification Validation Lead Identification Lead Optimization Preclinical Development Clinical Development NDA

“ Real drug “pipeline ” Drug Targets A – Absorption Solubility Stability Dissolution Drug Transport D - Distribution Plasma Protein Binding assays (PPB) “ Permeability” Drug Drug

Cell Membrane Transport Mechanisms Transcellular Paracellular Active Transport Active Efflux

Membranes are two-dimensional solutions of oriented lipids and globular proteins that are mobile in the plane of the membrane – fluid-mosaic model Membrane transport is mediated by specific integral membrane proteins – ion channels, porins, transporters ( passive ), pumps ( active ) Integral membrane proteins have common structural features – predominantly transmembrane  helices Membrane structure & transport

Membranes are two-dimensional solutions of oriented lipids and globular proteins that are mobile in the plane of the membrane – fluid-mosaic model

Membrane transport is mediated by specific integral membrane proteins – ion channels, porins, transporters ( passive ), pumps ( active )

Integral membrane proteins have common structural features – predominantly transmembrane  helices

Ion channels are membrane spanning proteins

Opening and closing of channels requires conformational change

Extracellular Intracellular Flux of ions through the channels is passive

Drug Development

Drug Development Drug development or preclinical development is defined in many pharmaceutical companies as the process of taking a new chemical lead through the stages necessary to allow it to be tested in human clinical trials , although a broader definition would encompass the entire process of drug discovery and clinical testing of novel drug candidates.

Drug development or preclinical development is defined in many pharmaceutical companies as the process of taking a new chemical lead through the stages necessary to allow it to be tested in human clinical trials , although a broader definition would encompass the entire process of drug discovery and clinical testing of novel drug candidates.

Drug Discovery Pathway Efficacy ADME Toxicology Safety Preformulations Stability Studies Leads Selection of candidate drug Preclinical Studies Primary Screening [Hits] Discovery & Development

Drug Development Process

Reasons for Attrition in Drug Development

Stomach pH2 Intestine pH3-8 PV Blood Kidneys Tissues Cell Target Stability Acidic buffer Stability Acidic enzymatic buffer Solubility pKa Stability CYP3A metabolic stability Permeability Passive P-gp efflux Transportes Log D Liver Phase I and II Metabolic stability Metabolite ID Protein binding RBC uptake Stability Enzymatic Plasma stability Renal Extraction Log D Permeability Passive Transporters Log D Cell Exposure Barriers of Drug Reaching Target

Candidate Selection: Building “Developability” in Preclinical Profiling Lead (active molecule) Metabolism Selectivity Potency LO (optimized molecule) Potency Selectivity Metabolism Physical properties Best leads Physical / chemical properties Biopharmaceutics

Stability in Physiological Conditions Duodenum Stomach Ascending colon Descending colon Jejunum Ileum Small intestine Transverse colon Rectum pH = 1 - 3.5 pH = 5 - 7 pH = 8 Blood = 7.4

Solubility, Permeability, Chemical and Metabolic Stability Affects Oral Bioavailability Solid Drug Drug in Solution Absorbed Drug Dissolution Membrane Transfer Solubility Permeability Systemic Circulation Metabolism Liver Extraction Portal Vein

Physico-chemical profile of NCEs Permeability pKa Stability PPB Log D Polymorphism Lipophilicity Solubility Integrity Profile

Successful Drug = Activity + Property Optimization Activity Pharmacology Property Pharmaceutical Profiling In vitro Solubility Permeability BBB & Pgp Log P & pKa Metabolism P450 Inhibition Stability Pharmacokinetics In vivo Enzyme Receptor Cell-based assay In vitro Animal Model In vivo Redesign

Drug Development Process

Drug Delivery

Drug Delivery Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals Drug Delivery technologies are patent protected formulation technologies that modifies drug release profile, absorption, distribution and elimination for the benefit of improving product efficacy & safety and patient convenience & compliance

Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals

Drug Delivery technologies are patent protected formulation technologies that modifies drug release profile, absorption, distribution and elimination for the benefit of improving product efficacy & safety and patient convenience & compliance

Drug Delivery Most common methods of delivery include the preferred non-invasive peroral (through the mouth), topical (skin), transmucosal ( nasal , buccal / sublingual , vaginal , ocular and rectal ) and inhalation routes

Most common methods of delivery include the preferred non-invasive peroral (through the mouth), topical (skin), transmucosal ( nasal , buccal / sublingual , vaginal , ocular and rectal ) and inhalation routes

Drug Delivery Many medications such as peptide and protein , antibody , vaccine and gene based drugs, in general may not be delivered using these routes because they might be susceptible to enzymatic degradation or can not be absorbed into the systemic circulation efficiently due to molecular size and charge issues to be therapeutically effective protein and peptide drugs have to be delivered by injection .

Many medications such as peptide and protein , antibody , vaccine and gene based drugs, in general may not be delivered using these routes because they might be susceptible to enzymatic degradation or can not be absorbed into the systemic circulation efficiently due to molecular size and charge issues to be therapeutically effective

protein and peptide drugs have to be delivered by injection .

Drug Delivery Current efforts in the area of drug delivery include the development of targeted delivery in which the drug is only active in the target area of the body (for example, in cancerous tissues) and in which the drug is released over a period of time in a controlled manner from a formulate

Current efforts in the area of drug delivery include the development of targeted delivery in which the drug is only active in the target area of the body (for example, in cancerous tissues) and in which the drug is released over a period of time in a controlled manner from a formulate

Context – Drug Delivery

Context – Drug Delivery

Drug Delivery - Markets

Drug Delivery Systems Nano Technology DDS Buccal DDS Rectal DDS Vaginal DDS Pulmonary DDS Nasal DDS Topical DDS Parentral DDS Oral DDS Delivery Systems

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