FROM HIT TO LEAD: SUMMARY OF COMPOUND OPTIMIZATION IN DRUG DISCOVERY

Optimization Studies

5.4 FROM HIT TO LEAD: SUMMARY OF COMPOUND OPTIMIZATION IN DRUG DISCOVERY

at various points in the product lifecycle. However, there are still concerns associated with the management of enormous data generated through anal- ysis of multiple large databases simultaneously, placing a special demand for software, hardware, and behavior developments. Before the inception of bioinformatics and cheminformatics, handling of large individual databases remained a daunting task, which currently is being addressed through the informatics technologies, although the challenges of efficient correlation of such diversified information still exist [67].

The United States National Center for Biotechnology Information has been responsible for keeping databases for genome projects. GenBank, an international collaboration of three databases between the United States, the European Molecular Biology Institute, and the DNA Data Bank of Japan, constantly engages in interchange of database information. This has resulted in problems requiring continual update of records in the old data- base regarding the use of terms and tags that are not consistent with the new format. Private companies are building web interfaces for their database offerings. Celera and Incyte offer web subscriptions to their proprietary databases and customized analysis tools. It appears that the bioinformatics child will continue to speak the web language.

Bank It is a web submission program that includes the top 100 most- accessed information. Sequin is GenBank’s submission program, running on several platforms, with complicated entries and the ability to locate errors such as missing organism information, incorrect coding region lengths, mis- matched amino acids, or internal stop codons in coding regions, and more.

Information exchange in drug discovery would have been more con- strained if it were not for the increasing application of informatics [68].

5.4 FROM HIT TO LEAD: SUMMARY OF COMPOUND

Social Aspects of Drug Discovery, Development and Commercialization 124

Once a drug hit shows a possibility with its target, series of further chemical modifications take place to ensure in vivo compliance and ad- equate functionality. Multiple chemical series are generated based on the structural framework of the hit molecules, leading to an enormous number of compounds with wide chemical and structural diversity. The classical medicinal chemistry approach is used to build a SAR by modifying sub- stituents on a structural scaffold using mostly biochemical knowledge to obtain the desired affinity for the target. Most chemical libraries focus on the chemical series that contain many variations on the same molecular scaffold or molecular backbone. Medicinal chemists utilize many strategies like combinatorial chemistry to introduce structural changes in order to improve a compound’s pharmacodynamics properties.

Combinatorial chemistry involves preparation of diverse compounds and structures by synthesis methods. It could be simply defined as a tech- nology involved in the creation of large diversity libraries, speeding up the production of a wide combination of reactive chemical entities. It has aided the construction the chemicals in a way that improve the biological proper- ties that are determined through bioassays (Figure 5.2). Together with HTS it is expected to provide more biological data in the same proportion with the efficiency of the technique used.

As the chemical series are being evaluated, the pharmacological profile further narrows the series and helps to prioritize the hit compounds. Paral- lel models in drug compound optimization seek to synchronize biological

Figure 5.2 Iterative Process of Compound Design, Synthesis, and Testing.

with chemical studies that increasingly transform the drug compounds to become more drug-like for future clinical application. Successive screenings of the drug molecules lead to a more extended HTS of arrayed targets and ligands (Figure 5.3).

The newly found pharmacologically active moieties might not pos- sess the drug-like properties. Thus, as the bioassays are being conducted, the medicinal chemists use relevant robust data as a foundation for deci- sion making on the chemical modification (Figure 5.3), which gives rise to drug-like qualities. Molecular modification often involves adapting the molecular structure into one that has improved drug qualities, which would exhibit properties like potency, minimized side effects, bioactivity, and im- proved PK. Such data would be used to identify the undesirable activities and to determine SARs at the molecular targets to aid drug design while excluding the undesirable attributes from the chemical series. The modified versions of the lead compound could be synthesized in order to reduce side effects, enhance affinity for one receptor over another, and/or improve activity.

The iterative screening and optimization schemes have taken varied for- mats, where the building knowledge enables the development process, result- ing in a lead compound optimized for potency, selectivity, and PK qualities.

When the selectivity profile has been established, and pharmacology attri- butes and druggability have been duly confirmed for a particular drug, the drug development cycle progresses to the preclinical phase.

Figure 5.3 The Pathway Leading to Compound Optimization in Drug Discovery.

Social Aspects of Drug Discovery, Development and Commercialization 126

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