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The impact of structure-guided drug design onclinical agents
Aurigene Discovery Technologies, USA & India
Structure-based or structure-guided drug design methods have had a
significant impact on the creation of high-value compounds entering
the market as drugs, or at least entering clinical trials. This report
provides an update on the utility of structure-guided methods for
creating compounds that have reached human testing. Seven such
compounds are now approved and marketed drugs.
structures of proteins, derived mostly from
methods, that have entered clinical trials.
covery relied upon the explicit use of X-
ray structural information as a guide for
ligands. In some cases, a targeted protein
directed against two-dozen different mol-
small molecule design. This occurred over
structure is used directly. In other cases,
ecular targets, in a wide range of thera-
the template is a ‘homology model,’ based
upon an experimental study of a structural
homolog of the actual target. Here we look
the recognition of the ‘heuristic’ value of
Figure 1. Approved and marketed drugs whose discovery has been aided by structure-guided design methods.
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(based on the experimental X-ray structure
potential interactions that may be explored
candidates listed in Table 1, the applica-
structures to be determined via NMR.
generic products. The largest fraction of
affinity for the target protein. Completely
A rule-of-thumb in medicinal chemistry is
guided methods is the set of HIV protease
de novo design of a lead molecule that pro-
that the more potent an inhibitor or agonist
inhibitors, which were pivotal during the
duced a clinical candidate is clearly docu-
is, the greater its selectivity. This rule is
its greatest impact in optimization, rather
more perfectly a ligand fits one target, the
less well it will fit any other. This rule may
racy of computational methods increases.
a therapeutic target belongs to a protein
family whose members all contain a highly
Almost all of the structural information for
conserved active site (eg, protein kinases).
target protein to design the perfect ligand
inhibitors that bind near the ATP binding
“The power of SGDD lies in its ability to rapidly generate
robust hypotheses that can be tested in iterative cycles,
with experimentally determined co-crystal structures
and physiologically relevant bioassays, using
which oseltamivir is a prodrug exemplifies
used in drug discovery in the past several
unpredictable flexibility; in this example,
possible, so that the desired selectivity can
target. Accurate calculation of interaction
candidates. An exception to this general-
be designed ‘in’ by designing ‘out’ affinity
ization is provided by the fibrinogen recep-
for counter-targets. The plasticity of protein
electronic structures of both proteins and
active sites and the difficulty in making
small molecules, and from their difficult-
lead molecules that led to elarofiban were
to-model solvation in aqueous solutions.
not necessary to have the X-ray structures
information cannot explicitly guide which
Ingelheim led to early recognition that a
atoms in the molecular scaffold should not
a novel mode of binding to an inactive con-
(receptor). This distinction between crys-
novel structure. The fact that binding of
crystal structures also empower medicinal
now directly probe target protein - small
conformational change suggested that this
chemists with direct visualization of new
molecule interactions in favorable cases.
binding mode might be target-specific.
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Table 1. Drugs and drug candidates developed using SGDD methods.
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Entry Target Compound Therapeutic utility Status1 Company
References (reference numbers refer to table entries).
Baldwin JJ et al (1989) Thienothiopyran-2-sulfonamides: Novel topically active carbonic anhydrase inhibitors for the treatment of glaucoma. Journal ofMedicinal Chemistry 32:2510-2513.
Kim KS et al (2002) Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2: Synthesis, X-ray crystallographic analysis, and biological activities.
Journal of Medicinal Chemistry 45:3905-3927.
Smaill JB et al (2000) Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-
(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. Journal of Medicinal Chemistry 43:1380-1397.
Hoekstra WJ et al (1999) Potent, orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit. Structure-activity studies leading to the discovery ofRWJ-53308. Journal of Medicinal Chemistry 42:5254-5265.
12. Ludovici DW et al (2001) Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues. Bioorganic and Medicinal Chemistry Letters 11:2235.
15. Sham HL et al (1998) ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrobrial Agents and Chemotherapy 42:3218-
16. Turner SR et al (1998) Tipranavir (PNU-140690): A potent, orally bioavailable nonpeptidic HIV Protease Inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone
sulfonamide class. Journal of Medicinal Chemistry 41:3467-3476.
19. Jain J et al (2002) Characterization of pharmacological efficacy of VX-148, a new, potent immunosuppressive inosine 5’-monophosphate dehydrogenase
inhibitor. Journal of Pharmacology and Experimental Therapeutics 302:1272-1277.
27. Oliver WR et al (2001) A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proceedings of the National
Academy of Science USA 98:5306-5311.
33. Bantia S et al (2003) Mechanism of inhibition of T-acute lymphoblastic leukemia cells by PNP inhibitor – BCX-1777. International Immunopharmacology 3:879-
34. Laird AD et al (2000) SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Research 60:4152-4160.
35. Wood JM et al (2003) Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochemistry and Biophysics Research Communications 308:698-
38. Burgey CS et al (2003) Pharmacokinetic optimization of 3-amino-6-chloropyrazinone acetamide thrombin inhibitors. Implementation of P3 pyridine N-oxides
to deliver an orally bioavailable series containing P1 N-benzylamides. Bioorganic and Medicinal Chemistry Letters 13:1353-1357.
39. Burgey CS et al (2003) Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series
containing P1 and P3 pyridines. Journal of Medicinal Chemistry 46:461-473.
1 Most advanced stage attained and current status, if available. 2 For entries that have no publication cited, see the first paper listed in the futher reading box for references to the relevant primaryliterature. The chemical structures of all the compounds listed are available in a PDF file at www.aurigene.com/newsroompress.asp. 3 In 2002, the US FDA did not approve the ViroPharma new drugapplication for oral dosing of Picovir for treatment of the ‘common cold’. ViroPharma is pursuing the utility of the compound for more narrow indications.
CDD3-10_Hardy feature.qxd 01/12/2003 16:03 Page 19
alue per year (normalized)
Figure 2. The plots show the number of publications within the Pu
bMed database that used the term ‘structure-based design’ (in red) or ‘therapeutic’
(in green), and the number of X-ray structures (deposited within the indicated year) in the Protein Data Bank (in blue). The values were normalizedby dividing the number of citations (structures) in each year by the mean annual value over the 12 years analyzed.
This idea was confirmed when that hit was
guided the manipulation of ligand stereo-
converted by iterative SGDD into one of the
An early example of this process in action
target potency, and ultimately yielding the
carbonic anhydrase inhibitors were admin-
“Cleverly applied, SGDD can be used to address a
variety of DMPK issues, as well as attacking the
problem of drug resistance. The utilization and
impact of SGDD will surely continue to increase.”
the lead molecule structure can be altered
to improve solubility, metabolic stability, or
sirable systemic side effects. Development
other ADME-relevant properties. This struc-
of a more amphiphilic inhibitor, which was
tural knowledge, used in parallel with direct
oseltamivir at Gilead and of peramavir at
potency and water solubility, was aided by
against influenza. Crystal structures were
directed optimization of several thrombin
possible at random. Again, the structures
brane penetration enough to allow topical
CDD3-10_Hardy feature.qxd 01/12/2003 16:03 Page 20
structures of therapeutic target proteins by
attacking the problem of drug resistance.
candidates in the development pipeline in
affinities of the drugs for their targets by
upon interaction with target residues that
Figure 2) is the frequency of publications
transcriptase inhibitor in phase II trials.
strains of HIV that are resistant to previous
structures of drug target proteins is a well-
drugs. Lopinavir is dosed with another HIV
proven method to speed drug discovery.
protease inhibitor, ritonavir, to slow its
discovery process has allowed the creation
is marketed as Kaletra. Extensive clinical
than structure determinations. To be most
effective, it must be used within a broad
Hardy LW, Abraham DJ, Safo MK (2003) Structure-based drug design. Chapter 10
in Burger’s Medicinal Chemistry and Drug Discovery Sixth edition, (Abraham DJ,
ed), New York: Wiley Interscience, 1:417-469.
Kubinyi H (1998) Structure-based design of enzyme inhibitors and receptor
ligands. Current Opinion in Drug Discovery and Development 1:4-15.
Davis AM, Teague SJ, Kleywegt GJ (2003) Application and limitations of X-ray
crystallographic data in structure-based ligand and drug design. Angewandte
Chemie International Edition 42:2718-2736.
Borman S (2003) Promising drugs. Chemical and Engineering News 81(21):29-31.
biology capabilities internally. Most of the
For excellent presentations on SGDD home.t-online.de/home/kubinyi/lectures.html
Information on drugs in clinical trials www.clinicaltrials.gov/ct/gui
revenues for 2001) have structural biology
La lettura come terapia Si può cambiare con un libro? Se l'ormai celebre motto di Lou Marinoff, il più famoso consulentefilosofico americano e autore del testo Platone è meglio del Prozac , propone di esercitare la praticafilosofica, per affrontare problemi esistenziali e di relazione, altrettanto valido potrebbe essere ilricorso alla biblioterapia. Il termine indica il valore del
What you need to know about Smart Release Q. How is control achieved with Smart Release Technology? A . Smart Release chemistry is a diffusion-based chemistry developed on the premise of osmotic pressure. The osmotic pressure forces the chemistry out of the polymer coating (or membrane) at a consistent rate over a defined time period and applies the chemistry similarly to