DDD - Chapter 2 - Drug Discovery Process

Molecular drug target in disease

A drug discovery phase should generally start with a/an A. Assured drug approval and market entry from national regulators B. Preexisting accepted clinical principle or use for a natural remedy C. Molecular drug target in disease D. Realistic target market share in clinical practice

Lead finding - Compound sources

Combinatorial synthesis of analogues

Target finding

Defined human molecular targets based on genomics

Lead optimization - Screens

Efficacy in animal models Detailed DMPK analysis

'Validation' of 'hits'

Entail assessment of the structure-activity relationships within the screening library, and whether the hit belongs to a family of compounds - a 'hit series' - which represents a reasonable starting point for further chemistry

High-throughput screening

From hundreds of thousands of compounds, 'hits' are selected using

1. Drug discovery 2. Drug development 3. Commercialization

In the creation of a new drug what are the three main phases?

Inability of pharmacological properties at these stages to predict effect at clinical trials

Incongruent results from drug discovery and preclinical phases with clinical trial manifests A. Poor genetic and pathologic bases between animal models employed at these stages and disease prognosis in human body B. Incompatibility of screening methods to predict effect at clinical trials C. Inability of pharmacological properties at these stages to predict effect at clinical trials D. Stringency of national regulating agencies in approval process for new drugs

Lead identification (or hit-to-lead phase)

Indentify DMPK issues; Preliminary tox, etc.; Assessment of synthetic feasibility, etc

Hit identification

Lipinski's rule of 5 and chemical libraries are features of which stage in the drug discovery process? A. Lead optimization B. Target identification C. Hit identification D. Chemical synthesis

Hit finding - Compound sources

Massive virtual libraries, then focused combinatorial libraries

Lead finding - screens

Medium throughput in vitro screens for target affinity DMPK characteristics Preliminary measurements of DMPK in vivo

Drug candidate

Safety pharmacology In vitro genotoxicity

Lead optimization

Solve DMPK issues; Evaluation of potency, selectivity and DMPK to establish detailed SAR

False

T/F: 'Hits' are products of preliminary pharmacokinetics and toxicology studies while 'leads' come from selectivity and structure activity relationship studies

True

T/F: 'Validation' of hits is, therefore, necessary to eliminate artefacts, and this may involve repeating the screening of the hits, confirming the result in a different assay designed to measure activity on the chosen target, as well as resynthesis and retesting of the hit compounds.

True

T/F: A huge number of 'theoretical' compounds (far too many to be physically accessible) is first 'filtered' in silico to reduce it to a practicable number of compounds that is available, or can be synthesized, in screening libraries.

False. It should be increased

T/F: Decreasing reliance on in silico predictions to generate leads

False. Drug development

T/F: Drug Discovery phase is from molecule to registered product

False. Commercialization

T/F: Drug development is primarily concerned with translating therapeutic application to sales

False. Commercialization

T/F: Drug discovery phase is from product to therapeutic application to sales

True

T/F: Drug discovery phase of a typical project aimed at producing a new synthetic drug.

False. Palclitaxel (Taxol)

T/F: Flecainide (Tambocor) is indicated for ovarian cancer where its mechanism is a natural product inhibitor of tubulin depolymerization

True

T/F: Focus on cloned human targets as starting points

True

T/F: In a typical high-throughput screen more than 99% of compounds will be eliminated, so it is essential that this is done early

False. In vitro genotoxicity

T/F: In high-throughput screen, in contrast, will be found only occasionally, so it would be wasteful to test for this early in the sequence.

True

T/F: In the 'premolecular' drug discovery era, targets were mainly pathophysiological or biochemical mechanisms, such as blood pressure regulation, inflammation or cholesterol metabolism, of which the molecular components were not yet defined.

True

T/F: Increasing reliance on in silico predictions to generate leads

True

T/F: Increasing the emphasis on defined molecular targets as starting points for drug discovery projects would reduce the likelihood of such therapeutic surprises.

False. It originates from natural products, rather than synthetic molecules.

T/F: Many therapeutic agents, particularly anti-infective and anti-tumour drugs, originate from synthetic molecules rather than natural products.

True

T/F: Molecular drug target are typically proteins

False. Flecainide (Tambocor)

T/F: Paclitaxel (Taxol) is indicated for cardiac dysrhythmias where it blocks cardiac Na+ channels

False. 'Lead optimization' stage

T/F: Synthetic chemistry then begins, in the 'lead identification' stage.

False. 3 yrs or less

T/F: The interval from from the start of the project to identification of the compound has now been substantially reduced (3 years or more) once a molecular target has been selected, mainly as a result of (a) high-throughput screening of large compound libraries (including natural product libraries) to identify initial lead compounds

True.

T/F: The main bottlenecks now in drug discovery are in lead optimization and animal testing, areas so far largely untouched by the high-throughput revolution.

True

T/F: The main reasons that compounds fail, apart from lack of efficacy or unexpected side effects, are that they show toxicity, or that they have undesirable pharmacokinetic properties (e.g. poor absorption, too long or too short plasma halflife, unpredictable metabolism, accumulation in tissues, etc.).

True

T/F: The properties required for a drug candidate will vary from project to project, but will invariably include chemical,pharmacological, pharmacokinetic and toxicological aspects of the compound.

False. They are not independent and consecutive stages

T/F: The three main phases for the creation of new drug are independent and each phase can be done wthout the existence of the previous phase.

True

T/F: There is a dire need to incorporate pharmacokinetic and toxicological studies, as well as pharmacological ones, at an earlier stage of the project during the lead optimization to prevent compounds from failing in the preclinical development.

True

T/F: There is an increasing reliance on in-silico predictions to generate lead compounds

False. high-throughput screens for actual compounds, and in silico screens for virtual compounds

T/F: To deal with large - compound libraries, the introduction of in silico screens for actual compounds and high-throughput screens for virtual compounds

False. Lead optimization

T/F: Use of automated synthesis methods to accelerate lead identification

True

T/F: drug discovery and development have become more technology-driven and, hence, expensive, regulatory requirements are much more stringent, and the competition is more intense.

False. Compound screening are the to be analyzed not libraries

T/F: improvements at the lead optimization stage whereby the results of screening libraries are analyzed to reveal the molecular configurations that are associated with biological activity.

Biological

This refers to category of approach in drug discovery aimed at identifying compounds for screening

Chemical

This refers to category of approach in drug discovery aimed at screening available compound libraries

'Lead optimization'' stage

This usually involves parallel synthesis to generate derivatives of the lead series, which are screened and profiled with respect to pharmacology, pharmacokinetics and toxicology, to home in on a small number of 'drug candidates' judged suitable for further development, at which point they are taken into preclinical development.

Evaluation of SAR

Validation of hits may be simply described as A. Statistical design to arrive at a practical number of compounds for screening B. Evaluation of structure activity relationship C. Feasibility of the synthetic chemistry program for the compound D. Progressing of drug candidates for the next stage of preclinical development

Hit finding - screens

Virtual library screened in silico for predicted target affinity 'rule-of-5' compliance, chemical and metabolic stability, toxic groups, etc

I-III-IV-II

What is the proper sequence for the creation of new drug? I. Starts with the choice of disease area and defining the therapeutic need II. followed by the design, testing and fine-tuning of the drug molecule to the point where it is deemed suitable for development III. proceeds to the identification of the biochemical, cellular or pathophysiological mechanism that will be targeted, and, if possible, the identification and validation of a molecular 'drug target' IV. Identification of a lead structure

Drug discovery

What phase is from therapeutic concept to molecule?

Paclitaxel - Anticancer drug from yew tree

Which among these successful drug discovery projects originated from natural products? A. Imatinib B. Flecainide C. Omeprazole D. Paclitaxel

Feasibility of the synthetic chemistry program for the compound

Which of the following depicts activities in the lead identification? A. Determination of pharmacokinetic properties and toxicity of selected compounds B. Statistical design to arrive at a practical number of compounds for screening C. Feasibility of the synthetic chemistry program for the compound D. Progressing of drug candidates for the next stage of preclinical development

Disease pathophysiology

Which of the following discovery pathways was the basis for the development of imatinib and omeprazole? A. Biopharmaceutical molecules B. Structure of existing drugs C. Disease pathophysiology D. Natural products

Structures of existing drugs

Which of the following discovery pathways was the basis forthe development of Flecainide ? A. Biopharmaceutical molecules B. Structure of existing drugs C. Disease pathophysiology D. Natural products

Biopharmaceuticals molecules

Which of the following discovery pathways was the basis forthe development of erythropoietin ? A. Biopharmaceutical molecules B. Structure of existing drugs C. Disease pathophysiology D. Natural products

Natural products

Which of the following discovery pathways was the basis forthe development of paclitaxel ? A. Biopharmaceutical molecules B. Structure of existing drugs C. Disease pathophysiology D. Natural products