Computer modelling

1. Computers in Pharmaceutical
Research and Development
Dr. Lakshmi
M. Pharm., Ph.D.

2. History of computers in pharmaceutical
research and development.
History of Computers in Pharmaceutical Research
Origin of Computers in Pharmaceutical Research
Mid 19th Century
Early 1960s
Early 1970s
Between 1975 and 1985
The 1990s

3. Introduction
Today computers becomes so ubiquitous in pharmaceutical research and
development that it may be hard to imagine a time when there were no
computers to assist the medicinal chemist or biologist.
A quarter-century ago, the presence of a computer on the desk of every
scientist and company manager was not even contemplated.
But nowadays, computers becomes absolutely essential for generating,
managing, and transmitting the information.
The journey of computers in pharmaceutical companies starts in the
early 1940s.

4. Contd…
There were several scientific and engineering advances that made it
possible to design and develop a molecule through a computational
approach.
With the advancement of science medicinal chemists starts
understanding the relationship between the chemical structure of a
molecule with its molecular and biological activity (SAR).
Therefore if someone could predict the molecular properties by
doing calculations, then he/she might be able to predict which
structures should be investigated in the laboratory.

5. Contd…
At the same time Fischer’s proposed the hypothesis of lock and key
concepts to understand how a drug molecule exerts its
pharmacological/biological activity through binding to and/or
inhibiting some biomolecule/ receptor in the body.
Upto 1950s, the Pioneering research in the field of Quantum
mechanics attacked the problem of linking the relationship between
electronic structure and biological activity.
These developments leads to the introduction to QSAR (Quantitative
Structure Activity Relationships) which basically assigned molecular
descriptors in describing biological activity

6. Contd…
Molecular descriptors are the calculated or experimental numerical
value that describes the chemical structure of that molecule.
A good part of this work was published in the 1963 book by Bernard
and Alberte Pullman of Paris, France, which fired the imagination
of what might be possible with calculations on biomolecules.
Therefore gradually computer became a tool for scientific
innovation, which was initially designed for accounting applications.

7. Contd…
Earlier up to the 1960s, drug discovery was carried out through Random Drug
Design i.e. by “trial and error”.
The medicinal chemists manually collect and read the literature related to
patented products and used their creativity and expertise to synthesize
therapeutically active compounds.
The synthesized compounds were then tested by in/out house
microbiologists/biochemists for their biological potential along with another
related bioactivity for which research was being conducted at that time.
The most potent compound discovered led to a series of other structures which
leads to the creation of a table comparing the potency and activity, which finally
led to one compound (drug) and after development known as a pharmaceutical
product.

8. Contd…
However, Random drug Design involved time and cost and sometime
were inaccurate.
Today computational biology plays a central role in innovation
which remarkably reduced the time interval for finding potential drug
candidates by matching molecular structure databases against target
molecules and finding an appropriate match thus generating a lead
molecule.
This will lead to a Rational Drug Design approach.

9. Computational Chemistry: The Beginnings at Lilly
In the early 1940s, the first computers to have stored programs of
scientific interest were acquired.
One of these was an IBM 650; it had a rotating magnetic drum memory
consisting of 2000 accessible registers.
The programs, the data input, and the output were all in the form of
IBM punched cards.
Apart from lilly other MNC groups like Abbott, Upjohn and Dow
Chemical’s also took the initiative to explore using computers for drug
discovery. These initiatives involved either adding resources with
computer proficiency or training in-house scientists on the new
methodology.

10. Contd…
 It was carried out by Lilly’s research statistics group under Dr. Edgar
King.
It was not until 1968, when Don Boyd joined the second theoretical
chemist in the group, that the computers at Lilly started to reach a
level of size, speed, and sophistication to be able to handle some of the
computational requirements of various evaluation and design efforts.
The first breakthrough in computational drug discovery was at Lilly
which revealed the relationship between the calculated electronic
structure of beta-lactam ring of cephalosporins and antibacterial
activity.

11. Germination: The 1960s
 Other MNCs also initiated these efforts, however, some of these
companies lost out and quit due to lack of management support. It was
Lilly, whose persistence paid off as it established its base in such
expertise.
 The companies at that time invested in hardware and software from the
money they gained from the sale of their products. The computer models
used at that time were the IBM360 and the 370 series and input methods
slowly advanced from punch cards to dumb terminals (terminals or PCs
that had no local processing capability).
 The industry hired computational chemists from academia for their
initial ventures into using computers for drug discovery.

12. Contd…
In addition, the other chemists educated using computers were the X-
ray crystallographers.
One of the largest computers then in use by theoretical chemists and
crystallographers was the IBM 7094. Support staff operated the tape
readers, card readers, and printers.
Programs were still written in FORTRAN, followed by the well-
known MMPI program used for molecular mechanics.
Finally in regard to software, one program that came from the realm
of crystallography to overcome the tedious task of restoring the deck
and replacing the unused torn cards.

13. Contd…
This program was ORTEP (Oak Ridge Thermal Ellipsoid Program),
which was the first widely used program for (non-interactive) molecular
graphics.
With these developments the pharmaceutical industry began transitioning to
using molecular mechanics, QSAR, and statistics rather than restricting
to quantum mechanics.
However, on the other hand, this will lead to a war situation between the
medicinal and computational chemists. For the computational chemists, it
was quite easier to change a nitrogen atom to carbon or any other element or
to attach a subsistent at any position in whatever stereochemistry would make
the compound more active. Computationally, it was easy to change a six-
member ring to a five-member ring and so on.

14. Gaining a Foothold: The 1970s
Lilly management took a positive step in 1970s, by opening communication
channels between the two groups and organizing a series of workshops for
medicinal chemists to operate computational programs to perform
calculations on molecules.
The same activity was followed by Merck and Smith Kline group which
conducted a similar workshop. However, despite these initiatives, the
medicinal chemists were slow to accept this computational approach
because sometimes the computational methods failed to predict the
biologically active compounds and therefore medicinal chemists would start
dismissing the idea of computational chemistry as a whole.

15. Contd…
 In the 1970s two new computer resources were launched namely the
Cambridge Structural Database (CSD) and the PDB (Protein Data
Bank). Both of these were found as a boon for Computational
chemists because these databases would yield more therapeutically
active compounds as more compounds were deposited into them.
 Placing more powerful in-house machines (IBM 360 and 370 series)
made it easier and more secure to submit jobs and retrieve output. But
output was still in the form of long printouts.

16. Growth: The 1980s
The decade of the 1980s was when the pharmaceutical companies noted the
development of the IBM personal computer (PC) for application of
various modern computational chemistry approaches like quantum
chemistry, molecular mechanics, molecular simulations, QSAR, statistics and
molecular graphics etc.
The first technical advances computer was development as VAX 11/780
computer by Digital Equipment Corporation (DEC) in 1979. Later in 1984,
the Apple Macintosh introduced a set of new standard of user friendliness to
the computer. These machines were great at word processing, graphics and
managing small laboratory databases and suddenly all medicinal chemists
took a liking to it.

17. Fruition: the 1990s
In addition, the advancements of software front also made most
medicinal chemists enthusiastic about computers. The important ones
are electronic mail, networking capability advancement,
ChemDraw, and molecular graphics for 3D molecular structures.
The 1990s was a decade of fruition because the computer- based drug
discovery work of the 1980s yielded a large number of NCEs (new
chemical entities) reaching the pharmaceutical marketplace.

18. Contd…
During this time the Apple Macintoshes were well liked by scientists.
However, in 1994 Apple lost its lawsuit against Microsoft regarding
the similarities of the Windows graphical user interface (GUI) to
Apple’s desktop design.
 With the advancement of computational drug discovery, the attitude
towards the computational chemists changed, and therefore CADD
become an indispensable factor in the process of drug discovery and
development ever since for providing assistance to the medicinal
chemist.

21. Applications of Computers in pharmacy
 Right now computers and pharmacy go hand in hand.
 Drug and patient database management.
 Order entry systems, billing; purchasing.
 Drug information.
 Automated dispensing units.
 Used in various studies i.e. PK/PD
 Today we can exchange health information and provide services across
geographic, time and social boundaries.

22. Computer & Medical Education
 Computers have revolutionized the wayeducation is handled in today’s world.
 In medical education, computers are particularly useful because there is such a
need for learning and presenting large amounts of data, getting and
comparing accurate study and test results, and effectively monitoring
patients.

23. Health informatics
 Health care informatics or medical informatics is the intersection of
information science, computer science, and health care. It deals with the
resources, devices, and methods required to optimize the acquisition (gaining),
storage, retrieval, and use of information in health and biomedicine.
 Health informatics tools include not only computers but also clinical
guidelines, formal medical terminologies, and information and
communication systems. It is applied to the areas of nursing, clinical care,
dentistry, pharmacy, public health, and biomedical research

24. Computer-aided design of drugs
 A further refinement of new drug design and production was provided by the
process of computer-aided design (CAD).
 With the availability of powerful computers and sophisticated graphics
software, it is possible for the medicinal chemist to design new molecules and
evaluate their effectiveness.

25. Presentations
 The field of medicine often relies on complex definitions of conditions and
procedural techniques.
 If you are an educator, use the computer to show your medical students PowerPoint
presentations that simplify the large amounts of text often needed in medical science.
 Stick to the basics in visual presentations. You also may use computers to present
video data of medical policies or procedures, or for slide shows of diseases or traumas
and their treatments.

26. Research Papers
 If you are doing a medical research study, you can use the computer to write
your findings, format a paper for publication, find relevant studies on the
Internet or print posters for medical conferences.
 If you use the Internet, stick to reputable information sources such as
electronic versions of medical journals.
 Being able to write these kinds of papers is crucial in establishing your
credibility as a medical professional because they show that you have an
understanding of one or more medical topics and are able to conduct
research and present information.

27. Simulations
 Because medicine involves hands-on work, medical students need to practice
procedures before they do the procedure for real on a patient.
 Use computer programs that simulate surgery and other procedures to meet
this need.

29. Instrumentations
 Instruments play a vital role in the analysis of various samples.
 Various software are designed running of instruments.
 Examples:
 UV-visible spectroscopy by UV Probe.
 FTIR by IR Solution
 HPTLC by Wincats
 HPLC by Empower

30. Informational Storage
 Computers can store massive amounts of data.
 Use a computer or personal digital assistant to take and store notes on any
patients you may see as you go on supervised rounds.
 This makes it much easier to find the medical information you need when
discussing the patient and reduces the physical amount of papers and texts you
need to carry with you.
 This is very important in medicine, since efficiency and ease of referencing
medical information impacts the speed and accuracy of patient treatment.

31. Testing and Self Evaluation
 Use computers to take tests on medical subjects or to quiz yourself on
medical data.
 The advantage of this is that you can get immediate feedback and do not
need to depend on your instructor to review information or to find out how
well you have learned.
 If you use this method, keep your tests or reviews short and use them often
rather than having huge long tests and reviews.
 You are more likely to retain information if you use it frequently, and in
medicine, you'll also be called on to pull many medical facts daily from
memory.

32. Drug Information Services
 Pharmaceutical companies are responsible for providing updated, relevant
information on the efficacy, safety, and quality of drugs to medical
professionals and finally to patients.
 To fulfill this responsibility, they developed a drug information database
system to manage various information generated during the development of
new products and after the launch of the products.
 This system is incorporated into an online network system and can be directly
accessed by thousands of people all over the world.

33. Information System in The Pharmaceutical Industry
 An information system (IS) is any combination of information technology
and people's activities using that technology to support operations,
management, and decision-making.
 Advanced pharmaceutical companies are realizing that the implementation of
information management technologies in their operations can greatly enhance
their chances for success by reducing their time-to-market and enhancing
efficiency in their production runs.

34. 3D Printing in Medicine &Formulation
 Three-dimensional printing (3DP) technology relies on computer aided
designs to achieve unparalleled flexibility, time-saving, and exceptional
manufacturing capability of pharmaceutical drug products. The process
involves 3D proto-typing of layer-by-layer fabrication (via computer-aided
design models) to formulate drug materials into the desired dosage form.
 3DP in pharmaceutical drug delivery is anticipated to excel tremendously in
the area of personalized medicines.

36. Packaging and Labeling
 Computers play a vital role in packaging and designing of creative labels.
 Packaging takes 2D designs and transforms them into printed, tactile 3D
creations—it’s an incredibly effective way of bringing a strong branded look to a
product, or helping the consumer to commit to purchasing.