THE FUTURE OF
DRUG
DISCOVERY:
COMPUTATIONAL
CHEMISTRY
Zakaria Almansour
HOW IS A NEW DRUG DISCOVERED FROM
SCRATCH?
01
How Is a New Drug Discovered from Scratch?
Target Identification:
Finding the “lock” (protein/pathway) in the body
linked to the disease.
01
How Is a New Drug Discovered from Scratch?
Target Identification: Lead Discovery
Finding the “lock” (protein/pathway) in the body Designing or screening small “key” molecules that
linked to the disease. might fit the “lock”.
01
How Is a New Drug Discovered from Scratch?
Target Identification: Lead Discovery
Finding the “lock” (protein/pathway) in the body Designing or screening small “key” molecules that
linked to the disease. might fit the “lock”.
Lead Optimization
Tweaking the best “keys” to improve fit, solubility,
stability.
01
How Is a New Drug Discovered from Scratch?
Target Identification: Lead Discovery
Finding the “lock” (protein/pathway) in the body Designing or screening small “key” molecules that
linked to the disease. might fit the “lock”.
Lead Optimization Preclinical Testing
Tweaking the best “keys” to improve fit, solubility, Testing the “keys” in cells/animals for safety and
stability. basic efficacy.
01
How Is a New Drug Discovered from Scratch?
Target Identification: Lead Discovery
Finding the “lock” (protein/pathway) in the body Designing or screening small “key” molecules that
linked to the disease. might fit the “lock”.
Lead Optimization Preclinical Testing
Tweaking the best “keys” to improve fit, solubility, Testing the “keys” in cells/animals for safety and
stability. basic efficacy.
Clinical Trials & Approval
Human testing (Phases I–III) and regulatory review
before pharmacy.
01
THE TRADITIONAL DRUG DISCOVERY
PROCESS
analog
design
02
THE TRADITIONAL DRUG DISCOVERY
PROCESS
analog Chemical
design Synthesis
02
THE TRADITIONAL DRUG DISCOVERY
PROCESS
analog Chemical Library
design Synthesis Preparation
02
THE TRADITIONAL DRUG DISCOVERY
PROCESS
analog Chemical Library Biological
design Synthesis Preparation Testing
02
COMPUTER MODELS FOR DRUG
DISCOVERY
De novo
Molecular
Design
AI proposes entirely new
structures for your target
03
COMPUTER MODELS FOR DRUG
DISCOVERY
density
De novo
functional
Molecular
theory (dft)
Design
AI proposes entirely new Quantum calculations to predict
structures for your target electron clouds and binding
energies
03
COMPUTER MODELS FOR DRUG
DISCOVERY
density
De novo Molecular
functional
Molecular Docking
theory (dft)
Design
AI proposes entirely new Quantum calculations to predict Virtually fits each molecule into
structures for your target electron clouds and binding the protein pocket and scores it
energies
03
COMPUTER MODELS FOR DRUG
DISCOVERY
density
De novo Molecular Molecular
functional
Molecular Docking dynamics
theory (dft)
Design simulation
AI proposes entirely new Quantum calculations to predict Virtually fits each molecule into Animates atoms over time to test
structures for your target electron clouds and binding the protein pocket and scores it complex stability
energies
03
TRADITIONAL VS COMPUTATIONAL
COMPARISON
Aspect Traditional Computational
Basis
Molecules tested
Time per cycle
Cost per candidate
Outputs
04
TRADITIONAL VS COMPUTATIONAL
COMPARISON
Aspect Traditional Computational
Basis Chemist intuition
Molecules tested
Time per cycle
Cost per candidate
Outputs
04
TRADITIONAL VS COMPUTATIONAL
COMPARISON
Aspect Traditional Computational
Basis Chemist intuition Physics models & data
Molecules tested
Time per cycle
Cost per candidate
Outputs
04
TRADITIONAL VS COMPUTATIONAL
COMPARISON
Aspect Traditional Computational
Basis Chemist intuition Physics models & data
Molecules tested Dozens–hundreds (lab)
Time per cycle
Cost per candidate
Outputs
04
TRADITIONAL VS COMPUTATIONAL
COMPARISON
Aspect Traditional Computational
Basis Chemist intuition Physics models & data
Molecules tested Dozens–hundreds (lab) Thousands–millions (in silico)
Time per cycle
Cost per candidate
Outputs
04
TRADITIONAL VS COMPUTATIONAL
COMPARISON
Aspect Traditional Computational
Basis Chemist intuition Physics models & data
Molecules tested Dozens–hundreds (lab) Thousands–millions (in silico)
Time per cycle Weeks–months
Cost per candidate
Outputs
04
TRADITIONAL VS COMPUTATIONAL
COMPARISON
Aspect Traditional Computational
Basis Chemist intuition Physics models & data
Molecules tested Dozens–hundreds (lab) Thousands–millions (in silico)
Time per cycle Weeks–months Hours–days
Cost per candidate
Outputs
04
TRADITIONAL VS COMPUTATIONAL
COMPARISON
Aspect Traditional Computational
Basis Chemist intuition Physics models & data
Molecules tested Dozens–hundreds (lab) Thousands–millions (in silico)
Time per cycle Weeks–months Hours–days
Cost per candidate High
Outputs
04
TRADITIONAL VS COMPUTATIONAL
COMPARISON
Aspect Traditional Computational
Basis Chemist intuition Physics models & data
Molecules tested Dozens–hundreds (lab) Thousands–millions (in silico)
Time per cycle Weeks–months Hours–days
Cost per candidate High Low
Outputs
04
TRADITIONAL VS COMPUTATIONAL
COMPARISON
Aspect Traditional Computational
Basis Chemist intuition Physics models & data
Molecules tested Dozens–hundreds (lab) Thousands–millions (in silico)
Time per cycle Weeks–months Hours–days
Cost per candidate High Low
Outputs Empirical assay data
04
TRADITIONAL VS COMPUTATIONAL
COMPARISON
Aspect Traditional Computational
Basis Chemist intuition Physics models & data
Molecules tested Dozens–hundreds (lab) Thousands–millions (in silico)
Time per cycle Weeks–months Hours–days
Cost per candidate High Low
Outputs Empirical assay data Binding poses, energies, dynamics
04
CASE STUDY – SCUTELLAREIN DERIVATIVES AS
POTENTIAL ANTI-CANCER AGENTS
05
MATERIALS
• Researchers designed 10 new derivatives based on
Scutellarein, a natural compunds.
• The aim was to discover molecules that bind better and
stabilize key cancer-related proteins.
06
MATERIALS
• Researchers designed 10 new derivatives based on
Scutellarein, a natural compunds. Target proteins:
1.Human CK2 alpha kinase (PDB ID: 7L1X)
• The aim was to discover molecules that bind better and
stabilize key cancer-related proteins. 2.TNBC receptor (Triple-Negative Breast Cancer, PDB ID:
5HA9)
06
DENSITY FUNCTIONAL THEORY (DFT)
OPTIMIZATION
Before docking, all designed derivatives were optimized using Density Functional Theory
(DFT) methods to:
1. To obtain the most stable and realistic structure for each molecule.
2. To ensure accurate docking results by minimizing structural errors.
07
MOLECULAR DOCKING PROCESS
This image shows how different drug molecules (like DM03, DM04, etc.) stick to two
important proteins:
1. Human CK2 alpha kinase (important in cancer)
08
2. TNBC receptor (Triple-Negative Breast Cancer)
MOLECULAR DOCKING RESULTS
Binding affinity was evaluated in kcal/mol. Key findings:
1. DM03 and DM04 exhibited the strongest binding affinities (approximately -11.0 kcal/mol).
2. These compounds formed multiple hydrogen bonds and extensive hydrophobic interactions.
3. Their binding profiles were superior to Capecitabine, the standard reference drug.
09
MOLECULAR DYNAMICS (MD) SIMULATION
RESULTS
Molecular dynamics simulations were conducted to assess the stability of the drug-protein complexes over time.
Key findings:
Complexes with DM03 and DM04 displayed lower RMSD and lower RMSF values compared to Capecitabine.
Lower fluctuations indicated that DM03 and DM04 maintained greater structural stability during the simulation.
10
CONCLUSION
DM03 and DM04 emerged as promising candidates for further development as anti-cancer agents.
Their high binding affinity and stability suggest potential effectiveness against Human CK2 alpha kinase and
TNBC receptor targets.
Future steps include in vitro and in vivo experimental validation.
11
References
(1) Lin, X.; Li, X.; Lin, X. A Review on Applications
of Computational Methods in Drug Screening and
Design. Molecules2020, 25 (6), 1375.
https://doi.org/10.3390/molecules25061375.
(2) Sadybekov, A. V.; Katritch, V. Computational
Approaches Streamlining Drug Discovery. Nature
2023, 616 (7958), 673–685.
https://doi.org/10.1038/s41586-023-05905-z.
(3) Akash, S.; Aovi, F. I.; Azad, M. A. K.; Kumer, A.;
Chakma, U.; Islam, M. R.; Mukerjee, N.; Rahman, M.
M.; Bayıl, I.; Rashid, S.; Sharma, R. A Drug Design
Strategy Based on Molecular Docking and Molecular
Dynamics Simulations Applied to Development of
Inhibitor against Triple-Negative Breast Cancer by
Scutellarein Derivatives. PLoS One 2023, 18 (10),
e0283271.
https://doi.org/10.1371/journal.pone.0283271.
THANK YOU
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