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Molecular Modeling in Drug
Discovery: an Overview
Nanjie Deng
Drug development is a long and expensive process
Early stage drug discovery
Preclinical safety
Phase I, II, III
Hit /Lead
• It takes > 10 years and > 1 billion dollars of investment to develop a new drug
•Molecular modeling tools has been widely used in drug development projects to
help reduce the time/cost in early stages of drug discovery.
The goal of early stage drug discovery: to identify hits
and leads compounds
• Most drugs work by interacting with a protein/DNA at a specific
target site.
• Drug molecules need to
(1) bind tightly to the target site (affinity) and exert the desired activity
(2) have minimal off-target binding (side effects/toxicity)
(3 ) can get to the target site and can be removed from the body by
metabolism and excretion pathways. (ADME properties)
• Three key steps in early stages of drug discovery:
Discover hits: molecules showing some activity.
Discover leads: a series of related molecules that show some variation in
activities as the structure is modified.
Optimize Leads: further optimization resulting in drug candidates with the
desired potency and good ADME/T properties.
Computer-aided drug discovery
• Molecular modeling are used at the
following stages of drug discovery
(1) hit identification using structureor ligand-based design.
(2) hit-to-lead optimization of affinity
and selectivity (structure-based
design, QSAR, etc.)
(3) lead optimization of other
pharmaceutical properties like
ADMET while maintaining affinity
Two main approaches to computer-aided drug
• Ligand-based
relies on knowledge of known molecules that bind to the biological
target. These existing molecules are used to derive a pharmacophore
model that defines the minimum necessary structural characteristics a
molecule must possess in order to bind to the target.
• Structure-based
- uses the knowledge of the 3D-structure of the target to design and
predict candidate drugs that bind with high affinity and selectivity to
the target.
Methods used in structure-based drug
• Virtual screening
identification of new ligands for a given receptor by
searching large databases of small molecules to find
those fitting the binding pocket of the receptor using
fast approximate docking programs.
• De novo ligand design
ligand molecules are built up within the binding pocket
by assembling small molecular fragments. The
method allows novel structures to be designed.
Development of allosteric inhibitors targeting the LEDGF site of HIV
Integrase (IN): a case study using virtual screening
Viral DNA
LEDGF site
Host DNA
HIV-IN is responsible for the integration of viral the genome into the
host genome.
The human LEDGF protein links HIV-IN to the human chromosome.
Development of inhibitors targeting the LEDGF-site of IN could lead to
novel HIV therapies.
Discovery of HIV-1 Integrase inhibitors: a virtual
screening workflow
A commercial library of
200,000 compounds
160,000 compounds
200 molecules
Generation of
25 molecules
for testing
Compound 1 was found to
inhibit IN/LEDGF binding at
100 mM.
Christ et al., Nature. Med. Chem., 2010