Drug Discovery and Molecular Docking

Flashcards about drug discovery and molecular docking

What is a 'hit' in drug discovery?

Any compound confirmed to have biological activity in a biological assay, typically from a High-Throughput Screen (HTS).

What is a binding affinity curve?

A graph showing the binding of a molecule, allowing calculation of experimental parameters related to binding affinity.

What is the typical activity range of a hit molecule?

Micromolar activity range, indicating a weak binding affinity.

What is the main goal in the hit to lead process?

To improve potency/affinity by increasing binding affinity to reach low nanomolar volume

How can potency/affinity be improved in drug discovery?

Structural modification and optimization of the hit molecule.

What characteristics should be improved for a potential drug candidate?

To improve potency, affinity, safety, and other characteristics related to the structure of the molecules

What is considered when looking at agonist and antagonist capability?

Assessing the ligand's capability to induce a biological response.

What is the initial focus when considering binding affinity?

To determine if a hit or lead compound can bind to an enzyme or receptor surface.

What is important in the biological response of a lead compound?

Biological response, particularly the signal via a receptor or enzyme inhibition.

What type of assay is implemented for receptors to assess lead modulation

Functional assay to assess the lead modulation on a target

What parameters are measured from the response curves?

Efficacy (height of the curve) and potency (EC50).

What are the three major classes of enzyme inhibitors?

Competitive, non-competitive, and un-competitive inhibitors.

What is the purpose of the plot derived from the Michaelis-Menten equation?

Used to determine important values related to the Michaelis-Menten equation and classify enzyme inhibitors.

How do competitive enzyme inhibitors work?

They compete with the substrate for the active site.

Which part of the enzyme-substrate reaction is affected by competitive inhibitors?

The formation of a complex between the enzyme and the substrate

How do uncompetitive inhibitors work?

They bind to a different position on the enzyme, available only after the substrate binds.

What kind of complex is induced by uncompetitive inhibitors?

They induce a complex of enzyme, substrate, and inhibitor, preventing the catalytic active complex.

What is the effect of uncompetitive inhibitors on Km and Vmax values?

Decrease both Km and Vmax values.

How do non-competitive inhibitors work?

They bind to an allosteric site, promoting conformational changes in the enzyme's active site.

What kinetic parameter is mainly affected by allosteric inhibitors?

It can affect the Vmax.

How do irreversible inhibitors work?

They form a covalent bond with the active site, irreversibly inhibiting the enzyme.

What is IC50?

The concentration of inhibitor required to reduce the enzyme activity by 50%.

What computational tools are used to improve lead optimization when the target structure is available?

Structure-Based Methods represented by Protein Ligand Docking (molecular docking).

What is molecular docking?

A theoretical approach to predict the binding of a ligand into a protein.

What information is given by molecular docking?

The conformation and binding mode of the ligand that is important to bind to the receptor.

What is one of the primary aplications of docking in drug discovery?

To virtually screen collections of compounds to estimate binding affinity.

What contribution does docking give to SAR analysis?

Analyzing a library of tested compounds to understand how chemical modifications affect biological activity.

What is the 'lock and key' theory in molecular docking?

The idea that a protein has a cavity with a specific shape, so only ligands with a complementary shape can bind.

What type of docking calculation is performed when there are no hints about the active site?

Blind docking, which explores the entire protein surface to locate potential binding sites.

What are the two aspects of molecular docking software that should be considered?

Binding pose and scoring, with pose related to the docking algorithm and scoring estimating the free energy of binding.