just a brief explanation about De Novo Drug Design

1. NAME: MUHAMMAD ‘IZZUDDIN BIN ZAMERY (1217637) PHMC 2122
LECTURER’S NAME: ASSOC. PROF. DR QAMAR U. AHMED
De Novo Design
De novo drug design is a computer-assisted molecular design which supports drug
discovery by suggesting novel chemotypes and compound modifications for lead structure
optimization. Indirectly, this assists in the modification of lead in minimizing its toxicity and side
effects as well as enhancing its desired pharmacological or biological effect. De novo drug
design is an iterative process in which the three-dimensional structure of the receptor is used to
design newer molecules. It involves structure determination of the lead target complexes and the
design of lead modifications using molecular modeling tools. It can also be used to design new
chemical classes of compounds that present similar substituents to the target using a template,
which is chemically distinct from previously characterized leads. The design of the new drugs
structure in the de novo design is based on the structure of the binding site where they are meant
to be interacted. The binding site structure can be identified by performing X-ray
crystallographic study of the target protein containing a bound ligand or inhibitor. The position
of the ligand identifies where the binding site is in the protein and also determines any induced
fit that might have happened due to it binding.
After downloading the 3D structure of the protein-ligand complex into a computer, the
ligand can be eradicated to leave the vacant binding site, and the de novo design can then take
place. By identifying the amino acids that are present in the binding site, it is possible to
determine the binding interaction that is possible within the site. A molecular skeleton can be
designed which would fit the available space. Suitable functional grous can then be incorporated
into the structure to ensure binding interactions with nearby amino acids residue. Eventually, a
new drug will then be synthesized which has correct shape and size to properly fit the space
available as well as contains several required functional groups that can interact with the binding
regions and show desired pharmological effect. In theory, it should be possible to design a drug
for a particular target if one knows the structure of the binding site. However, in reality, de novo
design is not a straightforward as it seems and it is rare to obtain an ideal compound purely by
this technique.
The operator can conduct each of these operations manually or alternatively by using
software packages available which will carry out the procedures automatically. Manual studies
allow operators to have full control over the study and to input their own ideas as an dwhen they
wish. Such studies have been successfully produced novel active compounds, yet they do face
several difficulties and disadvantages. For instance, the novelty of the structures obtained is
inevitably limited to the operators’ own imagination and originality. Furthermore, the manual
deisign is slow and it is really limited to the identification of the single novel structure.
Automatic design is much faster and able to generate large amount of various structures in a brief
period of time. The following are several important points to take into consideration in the de
novo design which are:

2. NAME: MUHAMMAD ‘IZZUDDIN BIN ZAMERY (1217637) PHMC 2122
LECTURER’S NAME: ASSOC. PROF. DR QAMAR U. AHMED
 It is possible that the designed molecule may not bind to the binding site exactly as
predicted. Id the intended fit is too tight, a slight alteration in the binding mode may
prevent the molecule binding at all. It would be better to have a loose-fitting structure in
the first instance and to check whether it binds as desired. If it does not, the loose fit gives
the molecule a chance to fit in an alternative fashion.
 It is worth leaving scope for variation and elaboration in the molecule. This allow fine-
tuning of the molecule’s binding affinity and pharmacokinetics.
 It is pointless designing molecules that are difficult or impossible to synthesize.
 It is pointless designing molecules that need to adopt an unstable conformation in order to
bind.
 Consideration of the energy losses involved in water desolvation should be taken into
account.
 There may be subtle differences in structure between receptors and enzymes from
different species. This is significant if the structure of the binding site used for de novo
design is based on a protein that is not human in origin.
One of the best known de novo software is called LUDI, which works by fitting
molecular fragments to different regions of the binding site then linking the fragments together.
LUDI positions small molecules into clefts of protein structures in such a way that the hydrogen
bonds can be formed with the enzyme and hydrophobic pockets are filled with hydrophobic
groups. The LUDI works in three stages to the process which are:
1. First, it calculates interaction sites, which are unconnected positions in space suitable to
form hydrogen bonds or to fill a hydrophobic pocket.
2. The second step is the fitting of molecular fragments onto the interaction sites.
3. The final step in the present program is the connection of some or all of the fitted
fragments to a single molecule. This is done by brifge fragments.
Several computer software programs have been written which automatically design novel
structured to fit known binding sites. The automated docking procedures described can be used
to screen a variety of different 3D structures to see whether they fit the binding site of a
particular target. This is useful for a pharmaceutical company wishing to screen its own or other
chemical stocks (libraries) for suitable lead compounds.
Reference:
1. Patrick G.L. De Novo Design. Introduction to Medicinal Chemistry 4th Edition. (2009)
Oxford University Press. Page 365-366.
2. De Novo Definition. Retrieved from: http://www.chemistry-dictionary.com/definition/
de+novo+design.php