Pharmacist Need to know——- The Basic of Drug Design

“Latepost”

Guys, long time no see again. You must be wondering where I was gone lately..??

Actually I am a little bit excess with my activity as a wife, a mother and as a student. I stop to write this blog for a long time and it is not as easy as I thought to be able to do anything that you wish. But it doesn’t means all that activity make you become un-capable to do anything!!

So let me start to tell you my story..

I am still doing my study in Shizuoka University as a master student under Prof. Enoch. Y Park as my supervisor. He accepting me as his student among other 25 students that doing their research under his laboratory. I am very grateful for what Allah ta`ala already bless to me. You know why, because not everyone has the same opportunity as I am. You can click this link for the detail information about Prof. Enoch Y Park and his laboratories here (http://www.green.shizuoka.ac.jp/ and http://www.agr.shizuoka.ac.jp/c/biotech/park/en/index.html).

Now I am doing my 2nd semester until the end of this month. I take several subject which are Advanced organic chemistry of natural product, Advanced lecture on environmental bioethics and seminar in applied biological chemistry III. The last 2 subject were finish, but the first one “Advanced organic chemistry of natural product” isn’t finish yet. I still need to study about 2 kind of topic, which are Intermolecular Interactions and Conformations of molecular shape. These are the basis of “drug design”, to create novel chemicals to probe the living systems and to develop medicines and agrochemicals, such as herbicides, pesticides and fungicides.

It is difficult to understand and I am very regret that I didn`t study well about Organic chemistry when I was conduct my Bachelor degree..hehe..:) That`s why I should write about this, so I can remember better for what I have been studied.

I would like to tell about the first topic “Intermolecular Interactions”. There are 4 interactions that we will discuss about:

  1. Electrostatic interactions

  2. Hydrogen binds

  3. Van der waals interactions

  4. Hydrophobic interactions

 

Electrostatic interactions

This is an attractive force between charges, in the case of cations and anions of metals. For organic molecules, instead of point charges, the dipole-dipole interactions are dominant. In metal chelating agents, we can see the charge-dipole interactions. The energy of electrostatic interactions are -1 to -10 kcal/mol.

1

For proteins in aqueous solutions, hydrophobic pockets inside the protein has a lower dielectric constant than an outer solvent. The solvent with a high dielectric constant disrupts electrostatic interactions between molecules, so electrostatic interactions between proteins and ligands are more effective in a hydrophobic pocket than in an outer surfaces.

Here the practical example of electrostatic interactions. This is PYR1 protein, one of the plant hormone Abscisic acid (ABA) receptors. ABA is a plant hormone that acts as a stress messenger of plant. When plants are exposed to especially, dry, cold, and osmotic stresses, adaptive responses to these stresses are mediated by ABA. We have just developed an inhibitor of ABA receptors, AS6. This is a complex of PYR1 bound AS6. The most important interaction is this, a carboxylate of AS6 and an ammonium group of lysin reside of PYR1. Zoom up this:

3

You can see a salt bridge between a carboxylate anion with a negative charge and an ammonium cation with a positive charge. These specific interactions are responsible for the specific recognition between proteins and ligands. 

Hydrogen binds

The second interaction is hydrogen bonds. This is the typical hydrogen bonds, as you know well, between XH and Y, where X and Y are atoms with a large electronegativity, O, N, S, F, Cl, Br, and I. We call this type of typical hydrogen bonds as “conventional hydrogen bonds”. The energy is -1 to -5 kcal/mol.

When an unoccupied orbital and an occupied orbital interacts, a new, more stable orbital is generated. This stabilizes the molecular complex. The best orbital interaction requires a large overlapping area of two orbitals. Thus, the angle is very important. When the angle XHY is 180 degree, the two orbitals is able to interact on the stragiht to overlap effectively.

A practical example of conventional hydrogen bonds. In this case also, I take up ABA receptors. This complex is a PYR1-ABA-HAB1 complex. HAB1 is a protein phosphatase which inactivates ABA signalling. The ABA receptor, PYR1 and ABA complex acts as an inhibitor of this phosphatase, thereby, ABA signaling is activated. Zoom up this area.

There are 2 kind of Hydrogen bonds:

Conventional:

  • Hydrogen bond via a water molecules and
  • HOMO-LUMO interactions.

Non-conventional:

  • XH- pai hydrogen bonds( where X: C, O, N, S)
  • HOMO-LUMO interactions

 

Van der Waals interactions.

The van der waals interactions are formed by two forces: one is attractive forces derived from dispersion forces, the other is repulsive forces derived from Pauli exclusion principle. The energy is about -0.5 kcal/mol, which is smaller than conventional electrostatic interactions and hydrogen bonds.

 Dispersion forces, or called as London forces, are electrostatic interactions between induced dipoles. Generally, only polar molecules have dipoles, and non-polar molecules have no dipoles. Nevertheless, when you see a non-polar molecule with a much small time scale, an instantaneous dipole caused by instantaneous deviation of electrons can be observed. An instantaneous dipole occured in one molecule induces a new dipole for the neighboring molecule. This positive charge attracts electrons of an adjacent molecule, so this molecule has a dipole. This is an “induced dipole.

On the other hand, the repulsive term. You must know very well Pauli excusion principle. This is a very important principle for determining electron configulation of atoms. Generally, this principle is described by the explanation that electrons occupying an identical orbital=space must have the opposite spin.(one orbital 2 opposite direction)

 

Hydrophobic interactions

The last term of intermolecular interactions is “hydrophobic interactions”. This work only in aqueous solution. This is very important. This interactions never work in vaccuum or in non-polar solvents. In the separating funnel, water and hexane are mixed and shaked, but then hexane is not mixed with water. The two solvents are separated. Why?

A hydrophobic molecule is surrounded by water molecules. These water molecules are called as hydrated water. The hydrated water molecules are unable to move freely. The move restriction results in low entropy of the system. I will discuss about entropy later.

If hydrophobic molecules assemble, a few hydrated water molecules are released into bulk water. The released waters are not restricted, so the entropy increases. That is, hydrophobic interactions are derived by an increase in entropy, which is derived by the release of the hydrated water molecules.

 I think this is the end of my write about my lesson. Oh god my head become so hot and some smoke came out from it..hihi..:P

Next time I hope the author or the lecturer whoever they are they should present this subject attractively and easier to understand!!! Its time to say good bye my friends..Thank you for reading..and take a good rest…:)

PS. I already got my record for this subject and I have no regret for making this note since its really proper with the score..:)

3 thoughts on “Pharmacist Need to know——- The Basic of Drug Design

  1. ASSALAMMUMAIKUM WBT MDM Nurmilasari,

    i am helmy from faculty of forestry, university putra malaysia, Malaysia. I will be at faculty of agriculture, University of Shizouka from 24 of September until 3rd of october 2015. I was scheduled arrived at shizouka on 23rd of september 2015. I will be joining the field lecture in temperate forest ecosystems around Mt. Fuji 2015 which going to be held at faculty of agriculture, University of Shizouka. oh yes, i am a post graduate student too and i am doing a master of science in forestry.

    i really hope u can give an idea how the environment over there, and how about muslim food.
    tq

    • Waalaikumsalam wr wb
      Hello Helmy,nice to know you. I went to UPM previously. The people in Shizuoka are very nice,you dont need to worry. I think you will not be the only one who attend the lecture,so i think you will be fine. The only problem for us muslim is the Halal food. It is difficult or almost impossible to get halal food in the seminar or party. I suggest you to bring some halal instant food for a couple of days or maybe you can eat at vegetarian restaurant. Regarding for praying you can do it in the university,agriculture building 1st floor. You can ask some others muslim student from Indonesia or bangladesh. Since I will not be in Shizuoka during your present in here, I am not able to guide you. I hope this informtion will help you. If there still I can help just let me know..

      • Assalammualaikum….
        Thank you very much for that informations. I would like to know about Internet Connection. How to get the internet at Shizuoka?

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s