Unit - Università degli Studi di Perugia

Study of the main physico-chemical and ADME properties for drug-like compounds, and of the Structure-Properties and Structure-Activity relationships (SPR and SAR). Methods for the study of SPR and SAR applied to drug-design

Reference texts

Drug-like Properties: Concepts, Structure Design and Methods. From ADME to Toxicity Optimization”, Edward H. Kerns and Li Di, Elsevier Inc., 2008. Additional material will be provided.

Educational objectives

This course aims at providing the concepts for the application of the physical organic chemistry to drug discovery. In particular, the main physical chemical and ADME properties of drugs or potential drugs will be discussed, to learn how to modulate them through the modulation of their chemical structure.

Main knowledge acquired will be:

1) Basic concepts of the drug discovery and drug development processes

2) Knowledge of the main aspects of absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs

3) Knowledge of experimental and in silico methods for the determination of acid-base properties, lipophilicity, permeability and solubility

4) Knowledge of the main chemical strategies for ADME optimization

5) Knowledge of methods for structure-activity relationship studies

The main competence will be:

1) Ability to predict the possible physical chemical and ADME properties from the chemical structure

2) Ability to define synthetic strategies for drug candidate optimization.

3) Comprehension and use of novel methods for ADME properties determination.

Prerequisites

In order to be able to understand and to know how to tackle the course, students must have the basic notions of organic chemistry and analytical chemistry.

Teaching methods

The course is organized as follows:
- Lectures on all subjects of the course
- Classroom exercises at the end of each new topic.
- Simulation of the exam, in which the student will have the opportunity to answer the kind of questions expected for the oral examination, but in the form of a written test. Discussion of the answers will follow
- Visit to the LC/MS facility to attend a Metabolite ID study practical presentation.

Other information

contacts
email: [email protected]
phone: (+39) 0755855632

Learning verification modality

The exam consists of an oral test. The aim is evaluating the capability to apply the course’s contents to specific cases, using open-ended questions. The simulation of ADME properties optimization processes is requested, using methods applied in pharmaceutical companies. For other questions the capability of the student to summarize specific topics or techniques about the use of physical organic chemistry to drug discovery will be evaluated. The oral exam (about 40 min) will also test the student communication skills and his autonomy in the organization and exposure of the theoretical topics.
In summary, the assessment of the exam will take into account the following aspects: correctness and adequacy of responses, processing skills and conceptual connection, mastery and language skills, according to the following percentages: 60%, 30%, 10%.

For info on facilities for special needs students visit: https://www.unipg.it/en/international-students/general-information/facilities-for-special-needs-students

Extended program

Introduction to the Drug Discovery. Identification of a lead compound. History of Drug Discovery. Definition of "Drug-like" property of a chemical compound. Drug Discovery and Drug Development. Exposure of drugs to biological barriers in vivo. Organic compounds and permeability of the blood-brain barrier (BBB): Properties of the BBB. Structure-activity relationship studies in BBB penetration. Strategies to improve the BBB penetration. Hydrogen bonding effect. Charge effect. Lipophilicity effect.

Types of drug absorption. Physico-chemical properties of drug-like compounds. Relationship between biological barriers and pKa, solubility, lipophilicity, permeability. Role of metabolism in the elimination of a xenobiotic. Role of protein binding in drug’s activity. Importance of drug-like properties in drug design.

Acid-base properties. Determination of the percentage of neutral, protonated or deprotonated form for a drug in the human body. Modulation of acid-base properties by structure modification. Acid-based properties of drugs acting on the central nervous system. The pKa effect on permeability, solubility and metabolism. Effect of pKa on activity. Impact of pKa in the use of in silico methods for drug discovery (docking, virtual screening). Methods for low-throughput and high-throughput determination of pKa.

Lipophilicity. LogP and LogD of a chemical compound. Modulation of lipophilicity by structure modification. Methods for low-throughput and high-throughput determination of lipophilicity.

Solubility. Definition of apparent solubility and intrinsic solubility. Equation of Yalkowsky-Banerjee. Definition of kinetic and thermodynamic solubility, and their applications in drug discovery and drug development. Modulation of solubility by structure modification. Methods for low-throughput and high-throughput determination of solubility.

Permeability. Modulation of permeability by structure modification. Methods for low-throughput and high-throughput determination of active and passive permeability.

Drug-design and modulation of drug like properties. Rules of thumb and in silico models to estimate drug-like properties from chemical structure. The Lipinski rule of five: applicability and exceptions. From the chemical space to the protein space.
Prodrugs. Definition. Chemical strategies the design of prodrugs. Use of prodrugs to increase the solubility. Phosphates, phosphonates and phosphinates as prodrugs. Prodrugs to increase the passive permeability. Prodrugs using mediated transport. Prodrugs able to reduce drug metabolism. Definition of soft-drug.

Isosteric and bioisosteric groups. Background. Commonly used isosteric and bioisosteric groups.

Metabolic stability of a drug. Pathways of activation and elimination of a drug. Strategies to increase the metabolic stability by structure modification.

Drugs as enzymatic inhibitors. Overview of the main mechanisms of inhibition. Definition of "drug resistance" and "drug synergism." Difference between drug resistance and tolerance. Drug design strategies for the identification of novel inhibitors.

Drug toxicity. Introduction. On-target and off-target toxicity. Drug-Drug Interaction. Reactive metabolites and toxicity. Drug design strategies to reduce toxicity risk.

Obiettivi Agenda 2030 per lo sviluppo sostenibile

Learning how to design better and safer drugs will reduce overal costs and time needed for drug discovery (Goal n°3)

Piazza Università, 1
06123 Perugia

+39 0755851

C.F./P.Iva 00448820548

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