Computer Aided Drug Design

(Using Comp Chem + ML)

 What is drug design?
• Drug design is the inventive process of finding new medications
based on the knowledge of a biological target.
• Referred to as rational drug design or simply as rational design
• Multi Disciplinary process that includes;
➢ Identification of a Drug target
➢ Bioassays
➢ Structural Biology
➢ Synthetic Medicinal Chemistry
➢ Evaluation of the drug behaviour in the body
• Each of these processes in itself is a complex task and there is a
significant risk of failure at any step on the development path.
• In the most basic sense drug design involves the design of small
molecules that are complementary in shape and charge to the
bimolecular target with which they interact and therefore will bind to
it.
Limitations of conventional drug design
• Only traditional experimentation(in-vivo and in-vitro ) was done for
therapeutic purpose
• Animal and Human models were used
• Laboratory tests were performed for assurance of desired pharma
logical response.
• Very costly
• Time Consuming : Many years 10-25 years needed for the approval of
single drug
Introduction of computer simulation in the
field of drug designing :
• By using Computer aided drug designing (CADD) software (computer
simulations), time and expenses can be saved
Importance of using simulations:
With simulations:
• One can examine a problem that is not often subject to direct
experimentation
• Gain a better understanding of working of a system
• Can identify problems prior to implementation
• Once built the models can run to give realistic results
• Provides a valuable support in making decision on more logical and
scientific basis.
Computer Aided Drug Design (CADD)
• Drug design which relies on computer modelling techniques and
machine learning techniques is referred to as computer aided drug
design
• Computer aided drug design uses computational chemistry + machine
learning to discover, enhance or study drugs and related biologically
active molecules
• The most fundamental goal is to predict whether a given molecule
will bind to a target and if so how strongly
• Overcome the limitations of conventional methods
CADD: Ligand based or the receptor based
Ligand based drug design
• Uses a known set of ligands
• Pharmacophore model that defines the minimum necessary
structural characteristics a molecule must possess in order
to bind to the target.
• A model of the biological target may be built based on the
knowledge of what binds to it, and this model in turn may be
used to design new molecular entities that interact with the
target.
• QSAR in which a correlation between calculated properties of
molecules and their experimentally determined biological
activity, may be derived (Predict the activity of new analogs.
Receptor-based drug design :
• Structure-based drug design (or direct drug design) relies on
knowledge of the three dimensional structure of the biological
target obtained through methods such as x-ray crystallography or
NMR spectroscopy.
• If an experimental structure of a target is not available, it may be
possible to create a homology model of the target based on the
experimental structure of a related protein.
• Using the structure of the biological target, candidate drugs that
are predicted to bind with high affinity and selectivity to the
target may be designed using interactive graphics and the
intuition of a medicinal chemist.
Benefits of CADD Cost savings
• Cost savings
▪ Based on CADD simulations, promising experimental lines of
enquiry followed and experimental dead-ends avoided
• Time to market
▪ By focussing drug research on specific lead candidates companies
can market the drugs quickly
• Insight
▪ Non-quantifiable benefits of CADD
Contributions of machine learning in drug
designing
The ML model was used to search through thousands of approved ligands by the Food and Drug Administration
(FDA) and a million biomolecules in the BindingDB database. From these, insights were obtained for more than
19,000 molecules satisfying the Vina score (i.e. an important physicochemical measure of the therapeutic
process of a molecule that is used to rank molecular conformations and predict free energy of binding)
The Vina scores for the top ligands were further confirmed using docking approaches, resulting in the
identification of 75 FDA-approved and 100 other ligands potentially useful to treat SARS-CoV-2. This study
highlights a reasonable CompChem+ML strategy for making useful suggestions to aid expert biologists and
medical professionals to focus in fewer candidates when performing either robust CompChem efforts or
synthesis and trial experiments.