Fourth lecture 20/10/2008

You have to point out the following:
1- Structure of the drug molecule affects the biological ativity in two ways: first, it affects its affinity to the receptor; second, it affects its physicochemical properties and hence its pharmacokinetics.
2- The relation between structure and physicochemical properties (PCP) can be quantified ((QSAR)) through the Hansch equation.
3- The relation between activity and partition coefficient (PC) is parabolic and not linear.Why?
4- π and σ are descriptors of the hydrophobic and electronic effects of substituents. They can have either +ve or -ve values. What is the significace of π and σ values?
5- Topliss scheme is generated through interactive SAR studies. It indicates whether activity favours increased or decreased lipophilicity; favours electron withdrawing or electron donating groups. The various chemical groups are arranged in what is called Craig plot (a 2 dimensional plot) to easily locate the π and σ values of groups.
6- Steric factors can be measured by two experimental methods and one computational method.
7- Experimental determination of π depends on the fact that the sum of π values of the groups constituting the molecule represents the PC.
8- Experimental determination of σ value depends on the effect of electron withdrawing or electron donating properties of a given group on the acidity (pKa) of benzoic acid.
9- Experimental determination of Es depends on the effect of a given group (larger than methyl) on the rate of hydrolysis (K) of substituted methylacetate.

The Hansch equation relating π, σ and Es is:
Log 1/C= -K π2+K’ π+ σρ+K’’Es+K’’’

Molar refractivity MR=

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/