Third lecture 13/10/2008

By the end ofthe lecture and tutorial you should be able to:
1- Recognize the role of mol.modeling in simulating the real drug-receptor interactions and thereby helping the medicinal chemist in designing more rationale ligands.
2- understand that the main target of mol.modeling is to maximize the output of active drugs after a reasonable laboratory work, time, and cost.
3- know the two types of CALD (structure-based and lignd-based; differences??).
4- Differentiate beween a ligand and a drug; lowest energy conformation of a drug and its bioactive conformation; pharmacophore identificaton in structure-based and lignd-based dug design)
5- Docking or fitting is judged according to the calculated binding energies that are compared to a reference drug. It is all computerized process.
6- The importance of docking validation.
7- Imagine how small is the binding site of a receptor or enzyme compared to the whole receptor or enzyme protein.
8- Understand that the pharmacophore of the binding site is a 3D arrangement of a group of aminoacids to which complementary groups in the ligand molecule will bind.
9- Understand that the conformation of the binding site acquired after drug-receptor interaction determines the kind of action (agonist or antagonist) and that each biological action is elicited by a certain characteristic conformation (bioactive conformation of the receptor). Therefore, the 3D pharmacophore of the receptor I work on (obtained from PDB) should be that of the biological action I design a drug for.

Here are some T/F questions:
1- In all cases, results of virtual screening using CAMM match those obtained from biological screening.
2- Hypothetical receptor site model is generated whenever the biological target is unknown.
3- The bioactive conformation of a drug is sometimes different from its lowest energy conformation.
4- A 3D pharmacophore represents the relative positions of the important binding groups connected in a defined skeleton.
5- Recognition of the binding site of an enzyme is done by co-crystallization of the enzyme with its specific substrate.
6- In direct drug design, pharmacophore triangles are developed as templates for comparison with candidate drug.
7- DISCO is a computer software used for predicting molecular superimposition.
8- Docking occurs when the new drug molecule interacts optimally with the target protein structure.
The answers are F,T,T,F,T,F,T,T.

Here are links to RCSB proteindata bank:
http://pdbbeta.rcsb.org/pdb/home/home.do;jsessionid=A6C94FB066E4EDC56AB051093D03D871

and to Arguslab (a free molecular modeling software):
http://www.arguslab.com/