Drug Discovery, Design & Development Part 1

Vocabulary-style flashcards covering the fundamentals of drug discovery, lead compound identification, assay types, and a case study on malaria based on the lecture by Dr. Wenyi Li.

Drug Discovery

The phase of drug development focused on finding a lead compound.

Drug Design

The phase of drug development focused on obtaining a drug candidate.

Drug Development

The phase focused on getting a drug on the market.

Lead Compound

A compound that shows desired activity (even if slight), may have side effects, and is used as a starting point for further development.

Ischaemic heart disease

The leading cause of death globally in 2021 according to the WHO.

Selective drugs

Drugs that only affect the desired molecular target with minimal interaction with other biomolecules, resulting in minimal side effects or off-set targets.

Proteins

Represent the major molecular target of currently available drugs, making up approximately $17\%$ of body weight.

Orphan receptors

Receptors whose endogenous ligands are unknown, which may change the distribution of drug targets in the future.

Isozymes

Different family members or subtypes of a target within a species that can be selectively inhibited, such as PDE4 inhibited by Roflumilast vs. PDE5 inhibited by Sildenafil.

In vitro assays

Assays conducted "within glass" using cells, bacteria, enzymes, receptors, or isolated tissues to measure interactions with a target.

In vivo assays

Assays conducted "within life" using whole animals to evaluate pharmacological activity and side effects.

$$IC_{50}$$

The concentration of drug required to inhibit enzyme activity by $50\%$, used as a measure of potency.

$$EC_{50}$$

The concentration of a drug that gives half-maximal response in receptor-based assays.

MTT assay

A colorimetric assay for assessing cell metabolic activity and cytotoxicity using NAD(P)H-dependent cellular oxidoreductase enzymes.

Scintillation Proximity Assay (SPA)

An assay where the target is immobilized on beads coated with scintillant, and the disruption of binding by a ligand labeled with $^{125}I$ is measured.

Exogenous natural products

Natural materials with biological activity from sources like microorganisms (e.g., Penicillium mold), marine life, plant life, or animal life.

Endogenous ligands

Substrates, products, and modulators found in the body, such as neurotransmitters or hormones, used as leads for agonists or antagonists.

Combinatorial synthesis

An automated solid-phase synthetic method used to generate new synthetic compound libraries of many different structures.

Fragment-based discovery

A strategy to find small molecule "epitopes" that bind specific sites, which are then linked together to increase activity.

High Throughout Screening (HTS)

Automated and miniaturized in vitro assays used to test large numbers of compounds from libraries.

Surface Plasmon Resonance (SPR)

A screening method, such as BIAcore, that measures a decrease in reflected light caused by an evanescent wave interacting with plasmons in a gold film when a ligand binds a target.

Computer aided drug design (CADD)

The use of molecular modeling to design molecules that fit into a target binding site based on X-ray crystal or NMR structures.

In silico

Refers to electronic database mining or virtual screening of compounds using computational technology.

Drug repurposing

The deliberate screening of approved drugs against new diseases, utilizing serendipity or unexpected effects.

Plasmodium falciparum

The unicellular parasite that causes malaria, used in the case study for drug discovery.

Protein Kinase A (PfPKA)

A novel antimalarial target that phosphorylates Apical Membrane Antigen 1 (AMA1) to facilitate erythrocyte invasion.

Antimicrobial peptides (AMPs)

Peptides being researched for antibacterial mechanisms, including cell wall synthesis inhibition and cytoplasmic membrane modification.