1.
Structure-based Drug Design
(Direct drug design)
❖The explosion of genomic, proteomic, and
structural information has provided hundreds of
new targets and opportunities for future drug-lead
discovery.
❖ SBDD proceeds through multiple steps before an
optimized lead enters phase I clinical trials.
Detailed steps for SBDD
1. The ideal target macromolecule is closely linked to human
disease. The target molecule usually has a well-defined
binding pocket.
❖The goal in developing drugs against human targets is often to
modulate the function of the human protein.
❖The goal in developing drugs against pathogenic organisms is total
inhibition.
❖Cancer targets can be difficult because the targets are very similar to
the normal cell targets.
2. Once a target has been identified, it is necessary to obtain
accurate structural information. Purification and structure
determination of the target macromolecule (protein or
nucleic acid)
• Crystal structures are the most common source of structural
information for drug design, since structures with high resolution
may be available.
• The crystal structures of the targets are often deposited in the
Protein Data Bank (PDB).
• The PDB is an archive of experimentally determined 3D structures of
proteins, nucleic acids, and other biological macromolecules.
• The data, is typically obtained by X-ray crystallography (XRC), NMR,
or, cryo-electron microscopy.
❖The data submitted by biologists and biochemists from around
the world, are freely accessible on the Internet via the websites
([Link]
❖If no experimentally determined structure is available, a
homology model can be used for drug design.
3. Using the structural information obtained through
the above techniques, the structure is then
prepared for drug design programs by:
a. Adding hydrogen (H) atoms
b. Protonation state of residues.
c. Small molecules, such as ions and water molecules, can
be included during the lead generation phase in cases
where they play structural roles crucial for the
conformation of the target, otherwise, they are usually
removed to allow any potential lead to occupy their
positions.
3. Identification of a potential ligand binding site on the target
molecule.
➢ The target site is a pocket with various potential hydrogen
bond donors and acceptors, hydrophobic characteristics,
and sizes of molecular surfaces.
➢ Using computer algorithms, compounds from a database
are positioned into a selected region of the structure.
Molecular Docking
➢ Docking is a mathematical technique that anticipates the preferable
orientation of one molecule (ligand) relative to another (target) when
they are linked together to create a stable complex to manage the
small molecule’s affinity and activity.
➢ Programs for Docking Small Molecules or Fragments against a Target
include:
➢ Glide
➢ Autodock
➢ SPROUT
➢ Gold
❖ These compounds are docked, scored and ranked
based on their steric and electrostatic interactions with
the target site,
❖The best compounds are tested with biochemical
assays.
Types of Molecular Docking
There are two distinct forms of docking:
1. Rigid docking
Assuming the compounds are inflexible, we are seeking a rearrangement of
one of the compounds in 3D space that results in the best match to the
other compounds in the parameters of a scoring system.
2. Flexible docking
We evaluate molecular flexibility to identify conformations for the receptor
and ligand molecules as they exist in the complex.
Applications of molecular docking
I. Hit identification: Docking enables rapid screening of vast databases of
possible medications in silico to find compounds that are capable of
binding to a particular target of interest.
II. Lead optimization: Docking can be used to anticipate the ligand’s
binding mode. This data can be utilized to develop more powerful and
selective analogs.
III. Determine the specificity of a proposed medication against homologous
proteins.
IV. Identify enzymes and their mode of action (MOA).
Receptor
Ligand
De novo drug design
➢ De novo drug design involves the design of novel structures based on the
structure of the binding site with which they are meant to interact.
➢ The structure of the binding site can be identified from an X-ray
crystallographic study of the target protein containing (co-crystallized) a
bound ligand or inhibitor.
➢ Once the structure of the protein-ligand complex has been downloaded
onto a computer, the ligand can be removed to leave the empty binding
site.
➢ Several software packages will carry out the process automatically. One of
the best-known de novo software programs is called LUDI.
Receptor-Ligand Complex Ligand removed from the binding site
➢ By identifying the amino acids that are present in the binding
site, it is possible to identify the binding interactions that are
possible within the site.
➢ A structure can then be designed which will have the correct
size and shape to fit the space available, and will also have the
required functional groups to interact with the binding
region.
➢ Small fragments of molecules, such as benzene rings, carbonyl
groups, amino groups, etc., are Fitted (positioned) in the
binding site, scored, and linked fragments together in silico.
➢ The final compounds, created in silico from the linked
fragments, then must be synthesized in the laboratory.
Important notes about De novo drug design
➢ Designing a molecule that can easily be synthesized is an
important points to take into consideration in de novo design.
➢ De novo drug design does not identify whether the structures
identified will have favorable pharmacokinetic properties or
acceptable safety profiles.