Olden times of Computers in Pharmaceutical Research and Development: A Brief Review

Dr. Shaikh Siraj N¹*, Jayesh C Chaudhary², Dr. G J Khan², Makrani Shaharukh I², Sandip S Kshirsagar², Magan G Vasave²

¹Associate Professor and Head Department of Pharmaceutics, Ali-Allana College of Pharmacy Akkalkuwa, Nandurbar and Maharashtra, India.

²Ali Allana College of Pharmacy Akkalkuwa, Nandurbar, Maharashtra-425415, India.

*Corresponding Author E-mail: Sirajsk1234@gmail.com

ABSTRACT:

At present-day, computers are so communal in pharmaceutical research and development that it may be rough to visualize a time when there were no computers to help the medicinal chemist or biologist. Nowadays, computers are completely essential for generating, managing, and transmitting information. The primary computers were designed for military and accounting applications, but gradually it became apparent that computers would have a massive number of uses. At modern, computers are so common in pharmaceutical research and development. The purpose of this review is to give a brief description of the historical development in respect applications of computers in Research and Development.

KEYWORDS: Minitab, Fortran, Chemdraw, Eli Lilly, Computational Chemists, IBM.

INTRODUCTION:

At current, computers are so common in pharmaceutical research and development that it may be rough to visualize a time when there were no computers to help the medicinal chemist or biologist. Now, computers are completely essential for generating, managing, and transmitting information. These early computers were usually for the workforce and for accounting, not for science. Pharmaceutical scientists did finally gain access to computers, if not in the company itself, then through promised agreements with nearby educational institutions or other contractors¹.

One vital concept understood by chemists was that chemical structure is related to molecular properties counting biological activity. Biological activity by binding to and inhibiting some biomolecule in the body. This concept stems from Fischer’s famous lock-and-key hypothesis^1-2. Other advance was the development of the theory of quantum mechanics in the 1920s³. This theory connected the distribution of electrons in molecules with observable molecular properties. Inventive research in the 1950s attacked the problem of linking electronic structure and biological activity. The early computers were designed for military and accounting applications, but gradually it became apparent that computers would have a vast number of uses. MMM was one of the first people in the pharmaceutical industry to perceive that computer-aided drug design was something that might be practical and worthy of investigation. He established a sustained, industrial research program to use computers in drug design. After retiring from Eli Lilly and Company in 1986, he became a Visiting Research Scientist and later an Adjunct Professor in the Department of Chemistry, Indiana University, and Bloomington³. Computers in pharmacy are used for the information of drug data, records and files, drug management.⁴

Development - The 1960s:

The students coming from those academic laboratories constituted the main pool of candidates that industry could hire for their initial ventures into using computers for drug discovery. Another pool of chemists educated using computers were X-ray crystallographers.^4,5 Although a wonder at the time, the workplace of the 1960s looks ancient in perception. One of the largest computers then in use by theoretical chemists and crystallographers was the IBM 7094. In the 1960s, drug discovery was by trial and error. A lead compound would be discovered by biological screening or by reading the patent and scientific literature published by competitors at other pharmaceutical companies. The most potent compounds found would become the basis for another round of analog design and synthesis. A structure-activity relationship which in summary would consist of a table of compounds and their activities. The medicinal chemist who invented or could claim authorship of a project team compound would receive kudos from management.^5-6

Achievement a Position - The 1970s:

Lilly management of the 1970s troubled further permanent growth but at least sustained the effort. Other companies such as Merck and Smith Kline and French entered the field a few years later. Unlike Lilly, they hired chemists trained in organic chemistry and computers and with a pedigree traceable back to Prof. E. J. Corey at Harvard and his attempts at computer-aided synthesis planning^7-9. Concerning hardware of the 1970s, pharmaceutical companies invested money from the sale of their products to buy better and better mainframes. Widely used models included members of the IBM 360 and 370 series. For instance, at Lilly an IBM 3278 and a Decwriter II were used by the computational chemistry group. The statistics program MINITAB was one of the programs that ran on the interactive Digital Equipment Corporation machine. Card punches were not yet totally obsolete, but received less and less use. Software was still written primarily in FORTRAN, now mainly FORTRAN IV. Computational chemists in the pharmaceutical industry also expanded from their academic upbringing by acquiring an interest in force field methods, QSAR, and statistics. Computational chemists with responsibility to work on pharmaceuticals came to appreciate the fact that it was too limiting to confine one’s work to just one approach to a problem. It meant using molecular mechanics or QSAR or whatever. Unfortunately, the tension between the computational chemists and the medicinal chemists at pharmaceutical companies did not ease in the 1970s.¹⁰

Thus the 1970s remained a period when the relationship between computational chemists and medicinal chemists was still being worked out. The 1970s were full of small successes such as finding correlations between calculated and experimental properties. Two new computer-based resources were launched in the 1970s.

Progress - The 1980s’:

The 1980s were the Recovery, the Baroque Period, and the Information all rolled into one. The decade of the 1980s was when the various approaches of quantum chemistry, molecular mechanics, molecular simulations, QSAR, and molecular graphics coalesced into modern computational chemistry. In the world of scientific publishing, a seminal event occurred in 1980. Professor Allinger launched his Journal of Computational Chemistry. This helped stamp a name on the field. Before the journal began publishing, the field was variously called theoretical chemistry, calculational chemistry, modeling, etc. Interestingly, Allinger first took his proposal to the business managers for publications of the American Chemical Society (ACS). Nearly 25 years passed before the ACS moved to rectify its mistake, and in 2005 it remolded its Journal of Chemical Information and Computer Sciences (JCICS) in an attempt to meet the needs of today’s computational chemists. JCICS was becoming the most popular venue for computational chemists to publish work on combinatorial library designs several exciting technical advances fostered the improved environment for computer use at pharmaceutical companies in the 1980s. The first was a development of the VAX 11/780 computer by Digital Equipment Corporation (DEC) in 1979. The machine was departmental size, that is, the price, dimensions, and easy care of the machine allowed each department or group to have its own superminicomputer. This was a start toward no centralized control over computing resources. At Lilly, the small-molecule X-ray crystallographers were the first to gain approval for the purchase of a VAX, around 1980. The Apple Macintosh appeared on the scene in 1984. The second important software advance was ChemDraw, which was released first for the Mac in 1986^11-14. This program gave chemists the ability to quickly create two-dimensional chemical diagrams. Every medicinal chemist could appreciate the aesthetics of a neat ChemDraw diagram. The third software advance also had an aesthetic element. This was the technology of computer graphics, or when 3D structures were displayed on the computer screens, molecular graphics.

A few years later, a survey was conducted of 48 pharmaceutical and chemical companies that were using computer-aided molecular design methods and were operating in the United States¹⁵. Between 1975 and 1985, the number of computational chemists employed at these companies increased from less than 30 to about 150, more than doubling every five years.¹⁶ The 1980s saw an important change in the way software was handled. In the 1970s, most of the programs used by computational chemists were exchanged essentially freely through QCPE, exchanged person to person, or developed in-house. But in the 1980s, many of the most popular programs— and some less popular ones—were commercialized. The number of software vendors mushroomed. For example, Pople’s programs for ab initio calculations were withdrawn from QCPE; marketing rights were turned over to a company he help pharmaceutical companies were so wedded to MACCS that there was great inertia against switching their databases to another platform, even if it was cheaper and better suited for some tasks. In 1982, MDL started selling REACCS, a database management system for chemical reactions. Medicinal chemists liked both MACCS and REACCS.

By the mid-1980s, for example, several pharmaceutical companies had acquired the Floating-Point System (FPS) 164. For instance, in 1988 Lilly partnered with the National Center for Supercomputing Applications (NCSA) in Urbana-Champaign, Illinois.

Accomplishment - The 1990s:

The 1990s was a period of achievement because the computer-based drug discovery works of the 1980s yielded a remarkable number of new chemical entities reaching the pharmaceutical marketplace.

A second technique of the 1990s involved designing a computer algorithm to construct a ligand de novo inside a receptor structure. The third technique of the 1990s was virtual screening^18-20. A new approach to drug discovery came to prominence around 1993. Pharmaceutical companies made massive investments in people and machinery to set up the necessary equipment in the 1990s. In 1993, with traditional one-compound-at-a-time chemistry it took one organic chemist on average one week to make one compound for biological testing. Hence by 1993–1994, these technological changes possibly helped save the jobs of many computational chemists at a time when pharmaceutical companies in the United States were downsizing, as we now explain. In 1992–1993 an acute political force impinged on the pharmaceutical industry in the United States. That force was the healthcare reform plan proposed by Hillary and Bill Clinton^21-22. Toward the mid-1990s, a new mode of delivering content came to the fore: the web browser. Information technology engineers and computational chemists help set up intranets at pharmaceutical companies. Use of the open-source Linux operating system spread in the 1990s. Whereas the trend in the 1980s was toward dispersal of computing power to the departments and the individual user, the IT administrators started bringing the PCs under their centralized control in the 1990s. Table 1. lists medicines whose discoverywas aided in some way by computer- Those compounds marked.^18-20

Table 1. Marketed Pharmaceuticals who’s Discovery Was Aided by Computers

Generic Name	Brand Name	Discovery Assisted by	Activity	Year of approved in US
Norfloxacin	Noroxin	QSAR	Antibacterial	1983
Losartan	Cozaar	CADD	Anti-hypertensive	1994
Dorzolamide	Trusopt	CADD/SBDD	Antiglaucoma	1995
Ritonavir	Norvir	CADD	Antiviral	1996
Donepezil	Aricept	QSAR	Anti-Alzheimer’s	1997
Lopinavir	Aluviran	SBDD	Antiviral	2000
Ximelagatran	Exanta	SBDD	Anticoagulant	2004

As seen in Table 1. There were seven compounds meeting this criterion in the period 1994–1997. The computational techniques used to find these seven compounds included QSAR, ab initio molecular orbital calculations, molecular modeling, molecular shape analysis ²³, docking, active analog approach²⁴, molecular mechanics, and SBDD. Therefore, computational chemistry experts play an important role in maximizing the potential benefits of computer based technologies.²⁵

Recent Applications of computers in Pharmacy

· Drug information storage and retrieval,

· Pharmacokinetics, Mathematical model in Drug design,

· Electronic Prescribing and discharge systems,

· Barcode medicine identification and automated dispensing of drugs,

· Mobile technology and adherence monitoring

· Diagnostic System, Lab-diagnostic System, Patient Monitoring System,

· Pharma Information System

· Bioinformatics

· Computers as data analysis in Preclinical development

· The design of new drug molecules using molecular modeling software

· Molecular docking

· Computer-aided formulation development Pharmacodynamics

· Computer Simulations in Pharmacokinetics and

· Artificial Intelligence, Robotics and Computational fluid

· Electronic records and digital

· Pharmaceutical Automation, Computerized system validation^26,27,28

CONCLUSION:

Current article conclude that; Today, computers are absolutely essential for creating, supervision, and conveying information. At modern, computers are so common in pharmaceutical research and development. Regarding hardware of the 1970s, pharmaceutical companies invested money from the sale of their products to buy better and better mainframes. The era of the 1980s was when the various approaches of quantum chemistry, molecular mechanics, molecular simulations, QSAR, and molecular graphics coalesced into modern computational chemistry. At modern, computers are so common in pharmaceutical research and development.

The 1990s was aera of achievement because the computer-based drug discovery work of the 1980s yielded an remarkable number of new chemical entities reaching the pharmaceutical marketplace.

CONFLICT OF INTEREST:

All authors do not have conflict of Interest

REFERENCES:

1. Fischer E. Einfluß der Konfiguration auf die Wirkung der Enzymen. BerDtsch Chem Ges 1894;27: 2985–93.

2. Silverman RB.The organic chemistry of drug design and drug action. San Diego: Academic Press, 1992.

3. Messiah A. Quantum mechanics, Vol. I. (Translated from the French by Temmer GM). New York: Wiley, 1966.

4. Sachin S. Navale, Rajendra R. Patel, Manohar D. Kengar, Priyajit S. Hasabe. History of Computer in Pharmaceuticals Research Development and Education. Vol-31-Issue-47-June-2020: 189=194.

5. Hoffmann R, Lipscomb WN. Theory of polyhedral molecules. I. Physical factorizations of the secular equation. J Chem Phys 1962; 36: 2179–89.

6. Hoffmann, R.An extended Hückel theory. I. Hydrocarbons. J Chem Phys 1963; 39: 1397–412.

7. Corey EJ, Wipke WT, Cramer RD III, Howe WJ. Computer-assisted synthetic analysis. Facile man-machine communication of chemical structure by interactive computer graphics. J Am Chem Soc 1972; 94: 421–30.

8. Corey EJ, Wipke WT, Cramer RD III, Howe WJ. Techniques for perception by a computer of synthetically significant structural features in complex molecules. J Am Chem Soc 1972; 94: 431–9.

9. Wipke, WT, Gund P. Congestion. Conformation-dependent measure of steric environment. Derivation and application in stereoselective addition to unsaturated carbon. J Am Chem Soc 1974; 96: 299–301.

10. Bingham RC, Dewar MJS, Lo DH. Ground states of molecules. XXV. MINDO/3. Improved version of the MINDO semiempirical SCF-MO method. J Am Chem Soc 1975; 97: 1285–93.

11. Corey EJ, Long AK, Rubenstein SD. Computer-assisted analysis in organic synthesis. Science 1985; 228: 408–18.

12. Rubenstein SD. Electronic documents in chemistry, from Chem Draw 1.0 to present. Abstracts of Papers, 228th ACS National Meeting, Philadelphia, PA, August 22–26, 2004.CINF-054.

13. Helson HE. Structure diagram generation. In: Boyd DB, Lipkowitz KB, editors. Reviews in Computational Chemistry, Vol. 13. New York: Wiley-VCH, 1999. p. 313–98.

14. Monmaney T. Robert Langridge: His quest to peer into the essence of life no longer seems so strange. Smithsonian 2005;36 (8):48.

15. Boyd DB. Profile of computer-assisted molecular design in industry. Quantum Chemistry Program Exchange (QCPE) Bulletin 1985; 5: 85–91.

16. Lipkowitz KB, Boyd DB. Improved job market for computational chemists. In: Reviews in Computational Chemistry, Vol. 12. New York: Wiley-VCH, 1998. p. v–xiii.

17. Marshall GR, Barry CD, Bosshard HE, Dammkoehler RA, Dunn DA. The conformational parameter in drug design: The active analog approach. Computer-assisted drug design. ACS Symposium Series 112. Washington DC: American Chemical Society, 1979. p. 205–26.

18. Wold JS. Supercomputing network: A key to U.S. competitiveness in industries based on life-sciences excellence. Testimony before the U.S. Senate, Commerce, Science and Transportation Committee Science, Technology and Space Subcommittee.

19. Lauri G, Bartlett PA. CAVEAT: A program to facilitate the design of organic molecules. J Comput-Aided Mol Des 1994; 8:51–66.

20. Walters WP, Stahl MT, Murcko MA. Virtual screening—An overview. Drug Discovery Today 1998; 3: 160–78.

21. Lewis RA, Pickett SD, Clark DE. Computer-aided molecular diversity analysis and combinatorial library design. In: Lipkowitz KB, Boyd DB, editors. Reviews in Computational Chemistry, Vol. 16. New York: Wiley, 2000. p. 1–51.

22. Boyd DB, Lipkowitz KB, editors. Trends in the job market for computational chemists. Reviews in Computational Chemistry, Vol. 7. New York: VCH, 1996. p. v–xi.

23. Walters DE, Hopfinger AJ. Case studies of the application of molecular shape analysis to elucidate drug action. THEOCHEM 1986 27: 317–23.

24. DePriest SA, Mayer D, Naylor CB, Marshall GR. 3D-QSAR of angiotensin converting enzyme and thermolysin inhibitors: a comparison of CoMFA models based on deduced and experimentally determined active site geometries. J Am Chem Soc 1993; 115: 5372–84.

25. Sean Ekins, Computer applications in Pharmaceutical research and development, Published by John Wiley & Sons, Inc., Hoboken, New Jersey, 2006, p-3-38

26. Computer Applications in Pharmaceutical Research and Development, Sean Ekins, 2006, John Wiley & Sons.

27. Computer-Aided Applications in Pharmaceutical Technology, 1st Edition, Jelena Djuris, Woodhead Publishing

28. Encyclopedia of Pharmaceutical Technology, Vol 13, James Swarbrick, James. G.Boylan, Marcel Dekker Inc, New York, 1996.

Received on 28.09.2020            Modified on 31.12.2020

Accepted on 10.03.2021      ©Asian Pharma Press All Right Reserved

Asian J. Res. Pharm. Sci. 2021; 11(2):109-112.

DOI: 10.52711/2231-5659.2021-11-2-3