Rational Drug Design Part 1

What are lipinski rules state (4). Exceptions?

Poor adsoprtion or permation are more likely when?

1. >5 H-bond doners (sum of all OHs and NHs)

2. MW > 500

3. Log P > 5 (or MlogP > 4.15)

4. > 10 H-bond acceptors (sum of all Ns and Os

Exception: substrates for biological transporters

What is Log P? Log D?

Log P = log (compiund orgnanic/compond aqueous). at neutral pH (7.4)

Log D (is at a specific pH). (u have to include the ionized and unionized portions)

How is lipophilicity of a compound commonly estimated

Log P from otactonol/water partitionitong

Lipophilicyt is a major determinant of many ADME/Tox peroetpeis

Why octanol

lenght of the cell memrbnae. thicknes sof the bilayer mickers the thicknes sof hte cell membrnae

What factors affect logP

• Molercular volume

• Dipolarity

• Hydrogen bond acidity

• Hydrogen bond basicity

What is the impact of LogD7.4 on drug-like properties

When Log <1, log = 1 to 3, 3 to 5, > 5?

Solubility

Permeability

Metabolism

Volume of distribution

Oral adsorption and BBB penetration

Renal clearance

How many HBD does NH2 have

2

How many hydrsogen bond acceptors does COO have

2

What happens when u get higher potency

You get worse oral adsorption

What does Vebers rules define

Rules for good bioavilability

<= 10 rotatable bonds

<= 140 A PSA or <= 12 total hydrogen bonds (acceptors + donors)

PSA

Polar surface area

does this compound have good bioavailability according to vebers rules

What are the properties of lead-like compounds

whats template conservation

in order to maintain lead-like compound properties, the researchers apply template conservation. The lead template is conserved during lead optimization

What is the rule of 3

Set of rules for lead like compounds. Guidelines for hte propertie sof molecules used in fragment based screening techniques.

Rank the bonds

What is imatinib mesylate?

Gleevec

Wht are the steps for De novo desing

`1. Interaction sites

2. Fragment fitting

3. Bridging

Anchor and grow algorithm

1. Identify rotatable bonds

2. Identify and dock a rigid anchor

3. Add molecular fragments in layers

Whats happening here?

Ch2Me has no electrostatic interactions but far away, with NH2Me there is electrostatic interaction

Whats happening here

The hydroxyl group is not close to the receptor. but if you take the miror image, we can establish 3 interactions

1) electrostatic

2) hydrogen bonding

3) aromatic hydrophobic grou

If you add an alkyl group → the long chain will not allow the. molecule to dock on the binding site

Perfect fit, the distance is just right