Computer aided drug design

1. DE NOVO DRUG
DESIGN
Submitted To- Submitted By-
Prof. Narasimhan B. Mayank
Department Of Pharmaceutical Sciences M.pharm-2nd sem.
M.D.U. Rohtak

2. INTRODUCTION
• De Novo is a latin expression meaning “from the beginning”. Or “ start
afresh” .
• It is an iterative process which involves the design of novel structure based on
structure of binding site with which they are meant to interact.
• It is mainly used when the receptor structure is known but ligand or drug is
unknown.
• Receptor structure can be identified from an X-ray crystallography.
• Once the structure of protein-ligand complex has been downloaded into
computer, the ligand can be removed to leave the empty site and then de novo
design takes place.

3. ALGORITHM OF DE NOVO DRUG DESIGN
• 1. Outside-in method- Here binding site is first analysed to determine where
specific functional groups bind tightly.These groups are connected together
to give molecular skelton which are then converted into real molecules.
• 2. Inside-out method- Molecules are grown within binding site under the
control of appropriate search algorithm with each suggestion being evaluated
and energy function

4. DE NOVO DRUG DESIGN METHODS
ACTIVE SITE ANALYSIS METHOD
This method of analysis do not construct ligands but properties of active site are analysed and favorable
binding location for individual atoms are analysed.
ADVANTAGES
• Small number of well placed fragments can provide significant binding.
• Diversity of reasonable fragments may yield a molecule which can be synthesizable.
DISADVANTAGES
• Do not propose ligands for testing and requires additional work to convert fragments into a complete ligand.
• Programs used- GRID,HINT.

5. WHOLE MOLECULE METHODS
• Based on fitting of ligand into receptor site using shape complementarity
alone or coupled with electrostatic fitting.
ADVANTAGES-
• Any hit produced may readily be tested.
• Known or synthesizable compounds are generally studied.
DISADVANTAGES- Time consuming.
Program used- AUTODOCK

6. SITE POINT CONNECTION METHOD
• A site point is a point in space at which a suitable ligand atom can make favorable
interactions with one or more enzyme atoms.
ADVANATGES- Very fast and reliable method.
DISADVANTAGES- If site point needs to be matched properly most of the fragments
will miss those points and be rejected.
Lack of flexibility of individual fragments.
Program used- CLIX, LUDI

8. FRAGEMENT CONNECTION METHOD
• In this method, isolated fragment which have been selected in variety of ways, are
connected using a linker.
ADVANTAGES-
• Information about favorable fragment locations may be obtained from any source.
• If one has a set of fragments placed in active site, they can be quickly stitched.
DISADANTAGES-
• Molecules suggested by these methods are generally complicated and thus
impractical for the medicinal chemists.
Program used- NEWLEAD, PRO_LIGAND

9. SEQUENTIAL BUILDUP METHOD
• It is based on philosophy ligands can be constructed piece by piece.
• Construction can’t be linear each piece can be added anywhere on existing ligand.
ADVANTAGES
• Ligands suggested by these methods are smaller and more efficient.
• Each piece is added sequentially which make it possible to perform more
conformational analyses, leading to few misses.
DISADVANTAGES
• Problem of crossing “Dead zones’ i.e. open spaces of the active site where
few enzymes contacts are possible.
• PROGRAM USED- Grow mol , Grow , Group-Build , Sprout

10. RANDOM CONNECTION AND
DISCONNECTION METHOD
• Inclusion of method for altering the connectivity of ligand as they are being
constructed.
ADVANTAGES-
• This method explores drug space superior to other methods and generate more
diverse set of suggestions.
Program used- Genetic algorithm

11. REFERENCES
• https://www.ijpsonline.com/abstract/de-novo-drug-design--an-overview-741.html