Cdd_december_inner.pdf

CDD3-10_Hardy feature.qxd 28/11/2003 15:03 Page 15 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 oseltamivir
zanamivir
lopinavir
captopril
amprenavir
dorzolamide
nelfinavir
Figure 1. Approved and marketed drugs whose discovery has been aided by structure-guided design methods.
CDD3-10_Hardy feature.qxd 28/11/2003 15:03 Page 16 (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.
CDD3-10_Hardy feature.qxd 02/12/2003 11:43 Page 17 Table 1. Drugs and drug candidates developed using SGDD methods.
CDD3-10_Hardy feature.qxd 01/12/2003 16:03 Page 18 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 rmal
o
n
r (
alue per year (normalized)
V
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

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