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Chapter 1 Introduction 1.1. Background In this report, Medicinal Chemistry for Drug Discovery: Significance of Recent Trends, we present a thorough description and analysis of recent trends in medicinal chemistry and evaluate their significance for contributing to progress and improving the productivity of drug discovery research. For a variety of reasons mainly traceable to the biological revolution triggered by the Human Genome Project and associated technological advances, combined with strategic shifts in the kinds of diseases and disorders given high priority in the pharmaceutical industry, drug researchers in the past decade or so have been faced with the need to discover and validate new drug targets. Given the relative scarcity of basic research supporting the potential medical utility of many of these targets, they represent relatively risky bets, especially from the perspective of toxicity and efficacy of the drugs developed to modulate their function. Yet given this uncertainty, the job of the medicinal chemist has not changed much over the years in one sense, in that it is still to design and synthesize compounds to modulate the function of these targets in the desired direction while maintaining appropriate levels of target selectivity and pharmacokinetics. Achieving these goals is a highly complex task, which requires that chemists make a great many decisions about the kinds of structures to select for primary screening, hit-to-lead elaboration, and lead optimization. Computer-aided drug design modalities, based both on actual structures of targets and endogenous ligands together with 2D or 3D structures of candidate compounds, are increasingly coming to the aid of chemists in • www.InsightPharmaReports.com • Reproduction prohibited 1 Organic and Medicinal Chemistry Technologies for Drug Discovery IPR: So once you get some hits and perform some hit-to-lead work, you can then use structure-based methodologies to begin to outline pharmacophores and do some scaffold hopping? In general, Informatics Chemist: That is not unreasonable. That’s fine. Once you have some hits to guide you, especially in a fragment-based approach where you have small things, you look to the structurebased methods to guide how you can build this thing and what the avenues for growth are that the target is offering you. So that’s fine, and that’s what I think pretty much all large pharma is doing with fragments. You get your fragment hit out of whatever screening methodology you’re using. Then you get some structural information and look for growth opportunities. So if you see that there is a void in the protein and you’ve got a nice synthetic site, you might ask whether you should grow a hydrogen bond donor into that region, or something. So I think that’s pretty much standard practice in terms of fragment-based drug design, and also large-molecule drug design. molecular targets can be said to view ligands as 3D surfaces with localized areas of charge, polarity, and other bonding interactions. 3.2. Diversity-Oriented Synthesis in Drug Design Ideally, large screening libraries contain compounds representing both diverse molecular architectures and sufficient skeletal redundancy to provide preliminary SAR. The redundancy part is reasonably straightforward to implement, but the diversity aspect is still undergoing conceptual evolution. Indeed, as far as we know, there is no generally accepted set of criteria for diversity, which of course must also be considered in the context of the molecular target and medical indication in question. In general, however, molecular targets can be said to view ligands as 3D surfaces with localized areas of charge, polarity, and other bonding interactions. Diversity-oriented synthesis (DOS), then, represents an attempt to replicate this variety with groups of skeletally diverse small molecules. DOS is still in its early days, and the utility of its application in lead generation has yet to be fully tested. However, evidence does exist to show that the chemical space a compound collection occupies correlates with its functional, biological diversity.12 32 • www.InsightPharmaReports.com • Reproduction prohibited Applications of Organic and Medicinal Chemistry in Drug Discovery Virtual screening, offered by 19 of the 32 vendors considered, constitutes a third common modality. Explicit inclusion of natural products or natural products-based design in drug discovery relates to only five of the 32 companies considered, and diversity-oriented synthesis is explicitly offered by only four. Viewing the data in Table 4.1 by rows, we see that only one company offers the full range of modalities under consideration. Interestingly, this company, Aurigene, the outsourcing subsidiary of Dr. Reddy’s Laboratories, is located in India. Three companies feature four of the five modalities; nine companies offer three modalities; 11 companies offer two; and eight companies specialize with only a single modality. 4.2. Overview of Service Offerings by Drug Discovery Outsourcing Vendors Table 4.2 tabulates outsourcing vendors according to five service categories plus whether they also do their own drug discovery. The services categories are: hit discovery, lead discovery (aka hit-tolead), lead optimization, library provision, and computer-based drug design. Table 4.2 lists 36 companies compared to 32 for Table 4.1. The additional four companies appear to feature none of the technological modalities considered in Table 4.1. Notably, 13 of the 36 companies are either located entirely in countries with emerging economies or have a large percentage of their chemists stationed there. Table 4.2. Product/Service Offerings of Selected Drug Discovery Outsourcing Vendors Company 1 2 3 4 5 Accelrys In silico-based + Analyticon Discovery + + Argenta Discovery + + + + + Array BioPharma + + + + + Aurigene BioBlocks + + + + + + + + + + + + + + Astex Therapeutics + Other Albany Molecular Research ASINEX + 6 + + + + + Computational chemistry Chemists in Russia Chemists in India Hungary/San Diego teams Continued 50 • www.InsightPharmaReports.com • Reproduction prohibited Market Dynamics Delving further into respondents’ work function (Table 5.4), we find that 29 of 47 are either group leaders or managers in medicinal chemistry. Another eight manage multiple functions, one of which is medicinal chemistry. Another five are involved as leaders or members of project teams, and three respondents work at the lab bench. The greatest diversity in function is found in precommercial biopharmas, where more than one-quarter of respondents manage multiple functions. Table 5.4. Involvement in Drug Discovery Chemistry I am involved in organic/medicinal chemistry for drug discovery as a: Organization Bench Scientist Group Leader/ Manager Multi-Group Manager Project Team Leader/Member Other Big Pharma 1 18 3 1 1 Small pharma/Biopharma 2 5 1 1 0 Precommercial Biopharma 0 6 4 3 1 Totals 3 29 8 5 2 Source: Insight Pharma Reports’ Organic & Medicinal Chemistry Survey—November 2008 Further respondent characterization deals with stages of medicinal chemistry operations (Table 5.5). Given that many individuals operate at more than one stage, this question garnered 111 responses. The largest numbers deal with hit-to-lead synthesis (n = 38) and lead optimization (n = 39). Hit discovery is the third-most prevalent activity (n = 25). Most respondents participate in all three activities, particularly the first two mentioned. The fact that fewer individuals are involved at the earliest stage, hit discovery, is consistent with the observation that many companies tap existing compound libraries or go outside to buy compounds for HTS. Not surprisingly, the greatest difference in this regard is found in the big pharma sector. 70 • www.InsightPharmaReports.com • Reproduction prohibited Conclusions and Future Trends technology advances, which as I said just 20 years ago were not available. We didn’t invest in doing certain types of experiments until we had a reason to believe we had a good compound that was worth doing those extra experiments with. Now these highthroughput methods and the ability to do things on a micro-scale have allowed us to examine more things at once and do more things in parallel. Former Abbott researcher, Celerino Abad-Zapatero, PhD, offered the following comments on this issue: “In my opinion, the major missing elements are in the biology. In many cases, people will tell you that a project failed not because of the chemistry but because of the biology. Often the chemistry and the chemists are excellent, but the biological knowledge is incomplete…from not knowing how good the target is, from not knowing whether the target is validated properly, from not knowing whether there’s a competitive (or compensatory) biological pathway that will prevent that therapy from being effective. So biology has to play a critical role in regard to your question. As proteomics and related technologies mature more, you’ll have a much better biology set to address these questions.” 6.2. Effects of the “Industrialization” of Drug Discovery Given pharma’s current deficit in R&D productivity, one might suspect that big pharma lost something during the rapid growth of companies by acquisition and merger and the industrialization of drug discovery. The anonymous big pharma medicinal chemistry executive we interviewed for this report had the following perspective to offer. Insight Pharma Reports: In a certain way, it seems to me that this whole trend toward industrialization of drug discovery has also interfered with what you’ve called institutional memory. Is that a fair statement? Medicinal Chemistry Executive: Yes, I think it is. I think the term you have used, the “industrialization” of medicinal chemistry (and I have also heard the term “commoditization” of medicinal chemistry) are completely incorrect concepts. These are terms I had not heard until very recently, and I find them totally out of line with what we actually do in medicinal chemistry and 100 • www.InsightPharmaReports.com • Reproduction prohibited Expert Interviews this. Some of the metabolic pathway proteins have receptor sites that have borrowed structural features from receptor sites in other target families. You can literally overlay these features from different target families. Again, it’s this notion that nature has borrowed from itself. We should try to leverage that and learn from it and try to do it ourselves. An example is the PXR site, the pregnane X receptor. Apparently PXR binds 50% or more of all drugs. Using receptor site similarity searching within our TIP knowledge base identified a number of proteins with similar receptor sites, including bile acid receptor FXR, PPAR-gamma, H2 thyroid, caspase 3, even HMG CoA reductase (the statin target), etc. They have receptor site features very, very similar to the PXR site, which is consistent with the observation that PXR is a protein that binds the majority of drugs (Figure 7.1). So the point I’m making is that nature has leveraged these structures and there is a lot of receptor site conservation across families, which is used as a mechanism to help clear drugs from the body. Figure 7.1. PXR – Promiscuous Ligand-Binding Site Source: Eidogen-Sertanty 148 • www.InsightPharmaReports.com • Reproduction prohibited