Download Medicinal Chemistry for Drug Discovery

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
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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
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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
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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.
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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
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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
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