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Organic chemistry in drug recovery

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					                      DRUG DISCOVERY

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                                            Organic Chemistry in Drug Discovery
                                                                                Malcolm MacCoss1* and Thomas A. Baillie2

                      The role played by organic chemistry in the pharmaceutical industry continues to be                                              In the recent past, the usual flow of informa-
                      one of the main drivers in the drug discovery process. However, the precise nature                                           tion that was generated regarding any new com-
                      of that role is undergoing a visible change, not only because of the new synthetic                                           pound prepared in the laboratory of a drug dis-
                      methods and technologies now available to the synthetic and medicinal chemist, but                                           covery company followed a paradigm similar to
                      also in several key areas, particularly in drug metabolism and chemical toxicology, as                                       that shown in Fig. 1. This scheme was driven by
                      chemists deal with the ever more rapid turnaround of testing data that influences                                             the need to get the initial information on a com-
                      their day-to-day decisions.                                                                                                  pound first, before deciding whether its proper-
                                                                                                                                                   ties met appropriate criteria before moving onto
                  Numerous changes are now occurring in the                         scientific advances in synthetic techniques                    the next evaluation step. Such a linear sequence
                  pharmaceutical industry, not just in the way                      and new technologies for rational drug de-                     of events, although sparing of the number of
                  that the industry is perceived, but also in the                   sign, combinatorial chemistry, automated                       compounds taken down the pathway, often
                  rapid expansion of biomedical and scientific                      synthesis, and compound purification and                       meant that a considerable amount of time passed
                  knowledge, which affects the way science is                       identification. In addition, with the advent of                (several weeks) before it was known whether a
                  practiced in the industry. The recent changes                     high-throughput screening (HTS), we are                        particular change in a molecule was in fact a use-
                  in the way that synthetic chemistry is prac-                      now faced with many targets being screened                     ful transformation, or whether it was a potency-
                  ticed in this environment center around new                       and many hits being evaluated. However,                        enhancing change in the primary in vitro assay
                                                                                    success in this arena still requires skilled                   but was perhaps a liability in a downstream
                                                                                    medicinal chemists making the correct choic-                   evaluation. Thus, the delay in getting appropriate
                   Department of Basic Chemistry, Merck Research Lab-               es, often with insight gleaned from interac-                   feedback to the synthetic chemist meant that
                  oratories, 126 East Lincoln Avenue, Rahway, NJ
                  07065, USA. 2Department of Drug Metabolism, Merck
                                                                                    tions with computational chemists and struc-                   decisions about which molecules to prepare in
                  Research Laboratories, Sumneytown Pike, West Point,               tural biologists, about which “hits” (1) are                   the next round of synthesis were not guided by
                  PA 19486, USA.                                                    likely to play out as true “lead” (1) structures               input from downstream data. With the advent of
                  *To whom correspondence should be addressed. E-                   that will meet the plethora of hurdles that any                faster synthetic technologies, including advances
                  mail:                                   drug candidate must surmount.                                  in nuclear magnetic resonance (NMR) methods,

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                                                                                                                                                                 SPECIAL SECTION
rapid separations, and automated syntheses, the    that exhibits genetic polymorphism (poten-            teristics are taken into account in arriving at this
cycle time for synthetic manipulation of analogs   tially leading to large individual variability in     key decision, which requires considerable ex-
has decreased dramatically. In addition, in the    drug pharmacokinetics and clinical response           perience and sound judgment on the part of
same time frame, advances have been made           where metabolism is the major route of clear-         the group of senior scientists collectively
in the ability to assay compounds, both in         ance). Moreover, if the therapeutic target re-        charged with this responsibility.
vitro and in vivo, at a much greater speed         sides within the central nervous system                   This new paradigm has led to a different
than was previously possible, and so the           (CNS), it becomes important to determine              type of decision-making by chemistry group
current paradigm has shifted toward that           whether the structural series of interest serve       leaders. As noted above, the results from a
shown in Fig. 2, where it is now feasible to       as substrates for the efflux transporter P-           preliminary evaluation of the pharmacologi-
generate a tremendous amount of relevant           glycoprotein and thereby are denied access to         cal, pharmacokinetic, metabolic, and toxico-
data on a newly synthesized compound               brain tissue in vivo. By obtaining such infor-        logical profile of a series of molecules usu-
within 1 week of its initial preparation. This     mation in the discovery phase, potentially            ally will expose any serious deficits that
process allows for a much better-informed          serious liabilities in a given structural se-         would hinder or even preclude successful
set of decisions, as one considers the next        ries become evident at the outset, and in-            development of a drug candidate. As a result,
round of molecules that need to be prepared.       formed decisions can be made accordingly              such “flawed” compounds, or sometimes en-
    It should be stressed that an awareness of     to redirect chemistry efforts.                        tire structural series, are dropped from further
the potential downstream obstacles to suc-             The chemist also needs to be conversant           consideration, and development resources are
cessful drug development is an important           with issues of toxicology, given                                       conserved as a result.
consideration in the chemist’s decision-           that the primary cause of failure                                          In the majority of cases, how-
making process. Based on a rationalization of      of drug candidates in early de-                                        ever, there is no single factor that
experimental and computational approaches,         velopment continues to be pre-                                         would lead to the exclusion of a
Lipinski et al. presented the “rule of five” in    clinical toxicity. Although the                                        molecule from further consider-
the mid 1990s, which is an excellent working       potential for genotoxicity can be                                      ation, and the decision to advance
hypothesis for predicting good druglike prop-      assessed directly through a num-                                       a given compound needs to be
erties in new compounds (2, 3). Thus, close        ber of in vitro assays, the same                                       based on a critical assessment of
attention needs to be paid to molecular            does not hold true for end-organ                                       the relative attributes and poten-
weights, as well as to the physicochemical         toxicities (such as drug-induced                                       tial liabilities of that molecule.
properties of lead molecules, such as lipo-        liver damage) or immune-                                               Admittedly, the availability of
philicity (logP) and aqueous solubility (which     mediated toxicities (idiosyncrat-                                      more, rather than less, informa-
will affect oral bioavailability and the feasi-    ic reactions) (4). However,                                            tion on each drug candidate can
bility of generating a parenteral formulation),    based on the premise that some                                         introduce an element of ambigu-
together with animal pharmacokinetics,             (but certainly not all) drug-                                          ity into the chemist’s decision-
which can be extrapolated with caution to          related adverse events appear to                                       making process. For instance, if a
predict corresponding behavior in humans.          be mediated by a chemically re-                                        structural change leads to in-
The latter is particularly important in provid-    active, electrophilic metabolite                                       creased potency in the lead bio-
ing some assurance that the candidate drug         or metabolites, as opposed to the                                      chemical assay, but the com-
molecule will exhibit linear pharmacokinetics      parent drug itself, it may be ar-                                      pound is less orally bioavailable
in humans, with appropriate dose size and          gued that the generation of such                                       in a rodent, has more activity on a
elimination characteristics for the intended       electrophiles is an undesirable                                        biochemical counterscreen, and is
route and frequency of drug administration.        feature of any drug candidate.                                         less potent in a toxicity assay,
    Preliminary absorption, distribution, me-      By means of appropriate in vitro                                       then the decision to continue ex-
tabolism, and excretion (ADME) studies of          “trapping” experiments and as-                                         ploring that avenue is less clear.
lead compounds in animal species also pro-         sessments of covalent binding of                                           Of course, all knowledge is
vide information on routes of clearance (such      lead drug candidates to protein,                                       useful and so the ongoing de-
as renal, biliary, or metabolic), which is help-   both in vitro and in vivo, it is                                       tailed compilation of structure-
ful in guiding the selection of compounds that     usually possible for the medici-                                       activity relationships (SARs)
exhibit a balance between elimination path-        nal chemist, working closely                                           across many assays is already
ways and thus would not be unduly depen-           with colleagues in drug metabo-                                        helping our understanding of
dent on a single organ for excretion. At the       lism, to identify routes of meta-                                      what types of functionality are
same time, in vitro data are provided on the       bolic activation and, through                                          responsible for binding to various
interaction of drug candidates with human          appropriate structural modifica-                                       CYPs, cardiac ion channels,
cytochrome P-450 (CYP) enzymes, so that            tion, to minimize this potential Fig. 1. Linear path to drug transporters, nuclear receptors re-
CYP inhibitors and inducers are identified at      liability (5). Moreover, before candidate, with numerous sponsible for CYP induction, etc.
an early stage, and due consideration is given     selection of a lead compound for feedback loops designed In fact, the medicinal chemist has
                                                                                         to provide information for
to the attendant risk that such candidates may     development, information also target selection in the always had to make judgments
cause drug-drug interactions in the clinic. In     will be available from in vivo next round of synthesis.                regarding such data, but in the
cases where oxidative metabolism by CYP            studies in animals aimed at as-                                        current environment the task is to
enzymes is likely to be an important mecha-        sessing selected off-target phar-                                      make such decisions rapidly and
nism of drug clearance in humans, it is pref-      macological activities of the compound of in-         to know how to weigh the data as they come in
erable to have contributions from multiple         terest, including effects on the CNS and cardio-      from different sources. These decisions can, of
isoforms, as opposed to a single CYP (again,       vascular systems. It is true that different phar-     course, also be influenced by the nature of the
to minimize the potential for drug-drug inter-     maceutical companies generate and weigh the           target itself, because a tolerance for a particu-
actions), whereas it is particularly undesir-      above types of information to different extents       lar toxicity might well be different for diseases
able for metabolism to be catalyzed solely by      in selecting lead candidates for progression into     with such different profiles as obesity versus a
an enzyme, such as CYP2D6 or CYP2C19,              development. At Merck, all of the above charac-       particular cancer.

                                 SCIENCE VOL 303 19 MARCH 2004                                                                   1811
                   DRUG DISCOVERY

                                                                                                                        methods (14). Such rapidly obtained information
                                                                                                                        on newly synthesized compounds is one of the
                                                                                                                        most important factors in the quest to shorten the
                                                                                                                        times from lead molecules to drug candidates.
                                                                                                                            One must constantly be aware that the rapid
                                                                                                                        synthesis of large numbers of molecules that are
                                                                                                                        laden with ADME, physical property, or toxico-
                                                                                                                        logical shortcomings may provide intriguing hits
                                                                                                                        or leads, but they may not shorten the time to the
                                                                                                                        elaboration of such a hit into a drug candidate. In
                                                                                                                        fact, as noted above, most experienced medicinal
                                                                                                                        chemists would prefer to start in a structural
                                                                                                                        series that has inherently good ADME proper-
                  Fig. 2. Nonlinear time-optimized path to drug candidate, with numerous feedback loops designed        ties, albeit with poor potency on the target
                  to provide optimal information on the next round of synthesis.                                        receptor, and then set about improving the po-
                                                                                                                        tency on the target, rather than working in the
                      At Merck, as at several other pharmaceuti-       institutional knowledge of medicinal chemistry,  other direction (starting with a potent molecule
                  cal companies, we have found that the most           but now guided by more information, as           that requires modification to optimize ADME
                  fruitful approach to the selection of new drug       depicted in Fig. 2. This approach has led to moreand toxicological properties, which requires op-
                  candidates is to identify the key issues of a lead   outsourcing of research medicinal chemistry      timization of several, often opposing, structural
                  compound, based on early screening data, and         than was common practice a few years             parameters within the predefined tight structure-
                  then to focus on minimizing these deficiencies       ago (11–13).                                     activity boundaries required for potency), al-
                  by informed chemical intervention, bearing in            It should be noted that pharmaceutical com-  though the history of drug discovery is replete
                  mind SAR data for the pharmacological target.        panies have sample collections filled with mol-  with examples of both. A good recent example
                  For example, potent CYP inhibition in a lead         ecules that were prepared many years ago for old of this situation from our laboratories has been
                  compound may be localized to a single func-          discovery programs. Even if those molecules did  the development of the orally active substance P
                  tional group, which may then be replaced by a        not advance the program for which they were      antagonist EMEND (aprepitant) (15) (Fig. 3).
                  noninhibitory substituent. Likewise, CYP in-         initially made, they were designed at the time by    Merck and many other companies have
                  duction (for example, through activation of          medicinal chemists in the hope of interacting    worked in this area for many years. The field
                  the nuclear transcription factor PXR), metab-        with some type of proteinaceous domain (such     was stimulated in 1991 by the discovery of CP-
                  olism to a reactive electrophile, or unwanted        as an enzyme, heterotrimeric G protein–coupled   96,345 by Pfizer scientists, which showed that a
                  cardiovascular activities (for example, ion          receptor, ion channel, etc). It is not unusual,  potent subnanomolar small molecule could se-
                  channel activity that may lead to adverse            therefore, for these molecules to be the startinglectively antagonize substance P at the NK-1
                  cardiac effects in vivo, such as that reflected      point of new medicinal chemistry programs        receptor (16). However, because of the difficulty
                  by prolongation of the QT interval on an             when they show up as hits in a new HTS screen.   in advancing structurally related molecules
                  electrocardiogram) (6) may be traced to spe-         Thus, because of the rapid synthetic cycle times,through the drug development process, presum-
                  cific structural motifs that can be successfully     a medium-sized group of medicinal chemists can   ably due largely to off-target activities, metabo-
                  engineered out of the lead structure. This           now advance several different lead classes at thelism issues, and the need to penetrate the CNS, it
                  multidisciplinary approach to drug discovery,        same time and thus potentially shorten the time- took more than a decade before a small molecule
                  with organic chemistry serving as the corner-                                                         was identified that had the appropriate properties
                                                                       lines for developing a hit or lead into a true drug
                  stone of the process, is far removed from the                                                         to be a drug, and EMEND was launched by
                                                                       candidate. Usually, it is not clear at the start of
                  linear paradigm of former years (Fig. 1).            a project what the downstream toxicological,     Merck in 2003 for the treatment of both acute
                      Thus, while many new technologies such as                                                         and delayed-phase chemotherapy-induced nau-
                                                                       metabolic, or off-target liabilities of a particular
                  combinatorial chemistry, rapid analog synthesis,                                                      sea and vomiting. Based on our experiences and
                                                                       lead class are likely to be, and so different structural
                  automated synthesis, open access liquid chroma-      classes can now be investigated simultaneously toknowing the large number of other companies
                  tography mass spectrometry, and high-speed au-       allow for data-driven decisions.                 working in this area, it is very likely that tens of
                  tomated high-performance liquid chromatogra-             When experienced medicinal chemists are      thousands of molecules have been prepared in
                  phy (to name but a few) are now affecting            asked to reflect on why various
                  medicinal chemistry, their main effect has been      programs were advanced more
                  to shorten the cycle time of synthetic operations.   quickly than others, they will
                  This, in turn, has led to a profound difference in   invariably agree that it was be-
                  the way in which a medicinal chemistry project       cause of the nature and quality
                  progresses through the system. Different compa-      of the starting hit or lead. One
                  nies have embraced these new technologies in         of the most difficult properties
                  different ways (7–10). For instance, some invest-    to build into a newly discov-
                  ed heavily in the mid-1990s in combinatorial         ered lead molecule is the de-
                  chemistry and made this technology a key driver      sired pharmacokinetic (PK)
                  of their efforts to discover new leads and to        profile, particularly in the case
                  expand their existing sample collections, partic-    of orally dosed compounds. In
                  ularly when traditional sources of compounds         recent years, the resources
                  failed to deliver new leads. Others have used        available for early PK evalua-
                  these technologies in appropriate projects and       tions in rodents have been in-
                  have forged alliances with smaller companies         creased, both for single com-
                  that specialize in such efforts, thus freeing up     pounds and, where appropriate,
                  their internal operations to use their historical    with the use of cassette dosing Fig. 3. Structures of CP-96,345 and EMEND (aprepitant).

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                                                                                                                                                                                           SPECIAL SECTION
the past decade as substance P antagonists, a       important issues facing discovery medicinal                              “lead” is defined as a structure that has been derived
                                                                                                                             from an early “hit” and, although still not fully opti-
large percentage of which likely exhibited sub-     chemistry today: the continuing need for excel-                          mized, has been shown to have some appropriate char-
nanomolar potency at the NK-1 receptor, but         lent synthetic chemists. In large pharmaceutical                         acteristics to be a precursor of a drug entity. Often a
only one has made it to market. This example        companies, the drug discovery process is driven                          good lead will have shown some proof-of-concept ac-
                                                                                                                             tivity in an in vivo pharmacological model, but will likely
highlights the difficulty of and resources needed   by multidisciplinary teams made up of the very                           not have been fully optimized for pharmacokinetic
to optimize the ancillary properties of potent      best experts in each discipline, and chemistry is                        properties or undesirable off-target activities.
inhibitors/antagonists so that they can become      one key element in this. These teams have ready                     2.   C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney,
safe, viable medicines.                             access to experts in other areas of biomedical                           Adv. Drug Delivery Rev. 23, 3 (1997).
                                                                                                                        3.   In the discovery setting, the rule of five (2) predicts
    In the drug discovery process, we must also     science, and although chemists often end up as                           that poor absorption or permeation of drugs is more
be cognizant of the interrelatedness of academic,   group leaders of discovery efforts, that usually                         likely when a drug molecule possesses either (i) more
government, and industrial research in the devel-   occurs after much experience has been gained in                          than 5 hydrogen bond donors, (ii) 10 hydrogen bond
                                                                                                                             acceptors, (iii) a molecular weight greater than 500,
opment of new drug entities. Despite large re-      the drug discovery process. The recent advances                          or (iv) a calculated logP greater than 5.
search budgets, the biomedical research carried     discussed above have put more tools in the chem-                    4.   J. Uetrecht, Drug Discov. Today 8, 832 (2003).
out by pharmaceutical companies still represents    ist’s toolkit, but in order to use these tools effec-               5.   D. C. Evans, A. P. Watt, D. A. Nicoll-Griffith, T. A.
only a small percentage of the overall worldwide    tively, it invariably comes down to the ability to                       Baillie, Chem. Res. Toxicol. 17, 3 (2004).
                                                                                                                        6.   See (17) for an excellent review of the cardiovascular
research effort on diseases and approaches to       make the absolutely “correct” molecule in a timely                       effects manifested by QT interval prolongation and
their treatment. Academic and government lab-       and cost-effective manner. This process requires                         the evaluation of drug candidates for this parameter.
oratories, funded with public monies, often pro-    the very best organic chemistry skills, and we must                 7.   See the cover story in Drug Discov. Dev. 6, 30 (2003).
vide much basic research and fundamental in-        continue to provide funding in the university sys-                  8.   T. Koppal, Drug Discov. Dev. 6, 59 (2003).
sight into diseases that can direct researchers     tem for training in these core skill sets to chemists               9.   A. DePalma, Drug Discov. Dev. 5, 50 (2002).
                                                                                                                       10.   A. DePalma, Drug Discov. Dev. 6, 51 (2003).
toward novel ways of attacking diseases. How-       in their graduate and postdoctoral studies if we are
                                                                                                                       11.   M. McCoy, J.-F. Tremblay, Chem. Eng. News 81, 15 (2003).
ever, they are rarely organized (nor is it their    to continue to provide the very best in medicines                  12.   A.M. Rouhi, Chem. Eng. News 81, 75 (2003).
mission) to embrace the drug discovery process      for what is becoming an aging population.                          13.   T. Koppal, Drug Discov. Dev. 6, 22 (2003).
in the multidisciplinary fashion outlined above                                                                        14.   W. A. Korfmacher et al., Rapid Commun. Mass Spec-
that is the modern paradigm by which new hits                                                                                trom. 15, 335 (2001).
                                                        References and Notes
                                                     1. In this discussion, a “hit” is defined as a nonoptimized        15.   J. J. Hale et al., J. Med. Chem. 41, 4607 (1998).
or leads are first identified and then get trans-
                                                        structure obtained from some screening process on a            16.   R. M. Snider et al., Science 251, 435 (1991).
formed into new viable medicines. All of the            target protein. It is often a very weak binder and is likely   17.   R. Netzer, A. Ebneth, U. Bischoff, O. Pongs, Drug
above discussion speaks to one of the most              to have a nonoptimized pharmacokinetic profile. A                     Discov. Today 6, 78 (2001).


                       The Many Roles of Computation in
                               Drug Discovery
                                                                 William L. Jorgensen

   An overview is given on the diverse uses of computational chemistry in drug discovery.                              tor or enzyme. Molecular libraries are
   Particular emphasis is placed on virtual screening, de novo design, evaluation of drug-                             screened, and the resulting leads are opti-
   likeness, and advanced methods for determining protein-ligand binding.                                              mized in a cycle that features design, syn-
                                                                                                                       thesis and assaying of numerous analogs,
“Is there really a case where a drug that’s         suggests misunderstanding and oversimpli-                          and animal studies. Crystal structure deter-
on the market was designed by a comput-             fication of the drug discovery process.                            mination for complexes of some analogs
er?” When asked this, I invoke the profes-          First, it is the rare case today when an                           with the biomolecular target is often possi-
sorial mantra (“All questions are good              unmodified natural product like taxol be-                          ble, which enables “structure-based drug
questions.”), while sensing that the desired        comes a drug. It is also inconceivable that a                      design” (SBDD) and the efficient optimi-
answer is “no”. Then, the inquisitor could          human with or without computational tools                          zation of leads. The success of SBDD is well
go back to the lab with the reassurance that        could propose a single chemical structure                          documented (1, 2); it has contributed to the
his or her choice to avoid learning about           that ends up as a drug; there are far too                          introduction of 50 compounds into clinical
computational chemistry remains wise. The           many hurdles and subtleties along the way.                         trials and to numerous drug approvals. Min-
reality is that the use of computers and            Most drugs now arise through discovery                             imally, the role of computation here is in the
computational methods permeates all as-             programs that begin with identification of                         structure refinement using simulated anneal-
pects of drug discovery today. Those who            a biomolecular target of potential thera-                          ing (3), development of the underlying molec-
are most proficient with the computational          peutic value through biological studies in-                        ular mechanics (MM) force fields, structure
tools have the advantage for delivering new         cluding, for example, analysis of mice                             display, and building and MM evaluation of
drug candidates more quickly and at lower           with gene knockouts. A multidisciplinary                           analogs. All top pharmaceutical companies
cost than their competitors.                        project team is then assembled with the                            have substantial structural biology and com-
   However, the phrasing of the question            goal of finding clinical candidates, i.e.,                         putational chemistry groups that are inter-
                                                    druglike compounds that are ready for hu-                          twined and participate on the project teams.
Department of Chemistry, Yale University, New
                                                    man clinical trials, which typically selec-                            There is usually much “tweaking” to-
Haven, CT 06520-8107, USA. E-mail: william.         tively bind to the molecular target and in-                        ward the end of the preclinical period of                                  terfere either with its activity as a recep-                       drug discovery when a series of compounds

                                  SCIENCE VOL 303 19 MARCH 2004                                                                                            1813