Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Drugs: Targets:
Natural sources Synthetic sources
Discovering and Developing the
One Drug
Profile of Todays Pharmaceutical Business
Time to market: 10-12 years. By contrast, a chemist develops a
new adhesive in 3 months! Why? (Biochemical, animal, human
trials; scaleup; approvals from FDA, EPA, OSHA)
Pharmaceutical R&D
A Multi-Disciplinary Team
Administrative Support Analytical Chemistry Animal Health Anti-infective Disease Bacteriology
Behavioral Sciences Biochemistry Biology Biometrics Cardiology Cardiovascular Science Clinical Research
Over 100
Communication Computer Science Cytogenetics Developmental Planning DNA Sequencing Diabetology
Document Preparation Dosage Form Development Drug Absorption Drug Degradation Drug Delivery
Electrical Engineering Electron Microscopy Electrophysiology Environmental Health & Safety Employee Resources
Different
Endocrinology Enzymology Facilities Maintenance Fermentation Finance Formulation
Gastroenterology Graphic Design Histomorphology Intestinal Permeability Law Library Science Medical Services
Disciplines
Mechanical Engineering Medicinal Chemistry Molecular Biology Molecular Genetics Molecular Models
Working Together
Physical Chemistry Physiology Phytochemistry Planning Powder Flow Process Development
Technical Information Toxicology Transdermal Drug Delivery Veterinary Science Virology X-ray Spectroscopy
Medicinal chemists today are facing a
serious challenge because of the
increased cost and enormous amount of
time taken to discover a new drug, and
also because of fierce competition
amongst different drug companies
Drug Discovery & Development
Identify disease Drug Design
- Molecular Modeling
- Virtual Screening
Find a drug effective
against disease protein
Isolate protein (2-5 years)
involved in Scale-up
disease (2-5 years)
Preclinical testing
(1-3 years) Human clinical trials
(2-10 years)
Formulation
FDA approval
(2-3 years)
Technology is impacting this process
GENOMICS, PROTEOMICS & BIOPHARM.
Potentially producing many more targets
and personalized targets
COMBINATORIAL CHEMISTRY
Rapidly producing vast numbers Find drug
of compounds
MOLECULAR MODELING
Computer graphics & models help improve activity
Preclinical testing
IN VITRO & IN SILICO ADME MODELS
Tissue and computer models begin to replace animal testing
History of Drug Discovery.
1909 - First rational drug design.
Goal: safer syphilis treatment than Atoxyl.
Paul Erhlich and Sacachiro Hata wanted to maximize toxicity to
pathogen and minimize toxicity to human (therapeutic index).
They found Salvarsan (which was replaced by penicillin in the
1940s)
HO O
ClH.H 2N NH2 .HCl
As
O
HO As As OH
H 2N Na+
Atoxyl
Salvarsan
1960 - First successful attempt to relate chemical structure to
biological action quantitatively (QSAR = Quantitative structure-
activity relationships). Hansch and Fujita
History of Drug Discovery
Mid to late 20th century
- understand disease states, biological structures, processes,
drug transport, distribution, metabolism.
Medicinal chemists use this knowledge to modify chemical
structure to influence a drugs activity, stability, etc.
O O
H 2N OCH2CH2N(C2H5 )2 H 2N NHCH2CH 2N(C 2H5) 2
Procaine Procainamide
Drug Discovery overview
P.A.B.A. SULFANILAMIDE
HO O
NALORPHINE
Chemical Modification.
Traditional method.
An analog of a known, active compound is synthesized with a
minor modification, that will lead to improved Biological Activity.
Drug can then be designed to effectively bind these targets & disrupt
the disease process
Target
Identification and Validation Lead
Compounds
Evaluation
Chemical Libraries,
Combichem, Clinical Trials
Natural Products
New Targets
Total Druggable
Genome genes
Includes biological Space
BIOLOGY
CHEMISTRY
SCREENING TECHNOLOGY
INFORMATICS
BOTTLENECKS
Data mining
Virtual Screening
Model construction
Molecular mechanics
QM, MM methods Homology modeling
Conformational searches
Molecular dynamics
F ma H
When Quantum Chemistry Starts to Move...
Mixed
Traditional QC Classical MD
Quantum- Simulations
Methods
Classical
First-Principles
Car-Parrinello
MD
Mixed Quantum-Classical
in a complex environment - QM/MM
Main idea
Partitioning the system into
Classical MM
Main idea
Partitioning the system into
Classical MM
Receptor Structure
Unknown Known
QSAR
- Distance Geometry
Selection of Descriptors
alignment
Steric Electrostatic
COMSIA studies on imidazole derivatives
alignment
Electrostatic
steric
Hydrophobic/
hydrophilic
Features selection
Conformation Generation
Validation
Considerations/Assumptions
Training Set Molecules should be
- Diverse in structure
- Contain maximum structural information.
- Most potent within series.
1. Chemical function
2. Location and orientation in 3D space
3. Tolerance in location
4. Weight
Pharmacophore Generation
Input
SAR Data
Structures
Conformational
Generate model
Modelling
Evaluate
Hypothesis
Training set
N
N N
N N
N N
N N
N O
O H N
N N N
O N
O N N N N
O O N
S N
N HO
N
H
OH
O O
N
O N N
Cl N N
N N N
O COOH
OH
N N N N N N
N N N N N
N N N N
N
Scoring
Docking compounds into
proteins computationally
De Novo Drug Design
Build compounds that are complementary to a target binding site
on a protein via random combination of small molecular
fragments to make complete molecule with better binding profile.
Can pursue both receptor and pharmacophore-based approaches
independently
If the binding mode of the ligand and target is known,
information from each approach can be used to help the other
- VIRTUAL SCREENING
- Compounds have been in vitro screened and found various new scaffolds
Virtual Screening
Build a computational model of activity for a particular
target
Use model to score compounds from virtual or real
libraries
Use scores to decide which to make and pass through a
real screen
Solubility
Permeability
Absorption
Cytochrome p450 metabolism
Toxicity
MeO N SO2NH 2
N N
S S
HN Et
MeO O2
norfloxacin (1983) donepezil (1996) dorzolamide [Trusopt] (1994)
antibiotic Alzheimer's treatment glaucoma treatment
first of the 6-fluoroquinolones acetylcholinesterase inhibitor carbonic anhydrase inhibitor
QSAR studies shape analysis and docking studies SBLD and ab initio calcs
HO N NH O H
N N NH N
Cl N O
N H NMe 2
Bu
H H
SPh O N Ph O N
Me O O
H
HO N
N N N
H H H H
OH O OH
H CONH 2
H
Dr. C. Dutt
Dr. Sunil Nadkarni
Dr. Vijay Chauthaiwale
Dr .Deepa Joshi
Dr. R.C. Gupta
Mr. Davinder Tuli
Dr. Pankaj Sharma
THANK YOU