Boston De Novo Design
Regine Bohacek, PhD
 
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  Examples:
Design with X-ray structures
Design with Pharmacophores
Design with "pseudo receptor"
   
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Drug design, docking using x-ray structure of target

Software: QXP/FLO+ Molecular Modeling Software

McMartin, C., Bohacek, R. J. (1997) QXP: Powerful, rapid computer algorithms for structure-based drug design. Computer-Aided Mol. Design 11: 333-344.

Examples

Goal: discovery of potent inhibitors of neutro endopeptidase (NEP)

for treatment of hypertension

Company: Novartis

Protein: thermolysin (model for NEP)

Ksander, G. M.; de Jesus, R.; Yuan, A.; Ghai, R. D.; Trapani, A.; McMartin C.; Bohacek, R. (1997) Ortho-substituted benzofused macrocyclic lactams as zinc metalloprotease inhibitors. J.Med.Chem. 40(4): 495-505.

Bohacek, R., De Lombaert, S., McMartin, C., Priestle, J., Grutter, M. (1996) Three-dimensional models of ACE and NEP Inhibitors and their use in the design of potent dual ACE/NEP inhibitors. JACS: 118(35): 8231-8249. (add picture)

MacPherson (add picture)

Design and synthesis of an orally active macrocyclic neutral endopeptidase 24.11 inhibitor
Lawrence J. MacPherson, Erol K. Bayburt, Michael P. Capparelli, Regine S. Bohacek, Frank H. Clarke, Rajendra D. Ghai, Yumi Sakane, Carol J. Berry, Jane V. Peppard, Angelo J. Trapani
J. Med. Chem.; 1993; 36(24); 3821-3828.

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goal: discovery of potent inhibitors of cathepsin B

for treatment of arthritis

company: Novartis

protein:cathepsin B

predicted predicted (purple), subsequently determined by X-ray (green)

Identification of Dipeptidyl Nitriles as Potent and Selective Inhibitors of Cathepsin B through Structure-Based Drug Design
Greenspan, P. D. et al, J. Med. Chem.; 2001 ; 44 (26); 4524-4534.

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goal: discovery of potent inhibitors of SRC-SH2

for treatment of osteoporosis

company: Ariad Pharmaceuticals

protein:SH2 domain of SRC kinase

 
predicted
predicted (white), subsequently determined by X-ray (green)

Structure-based design and synthesis of a novel class of Src SH2 inhibitors.
Bioorg Med Chem Lett. 1999 Aug 16;9(16):2353-8.

Buchanan, J.L.; Bohacek,R.S.;Luke, G.P.;Hatada,M.;Lu, X.;Dalgarno, D.C.;Narula, S.S.;Yuan,R.;Holt,D.A.;

 
   

 

X-ray Structure of Citrate Bound to Src SH2 Leads to a High-Affinity, Bone-Targeted Src SH2 Inhibitor

Bohacek, R. S.; Dalgarno, D. C.; Hatada, M.; Jacobsen, V. A.; Lynch, B. A.; Macek, K. J.; Merry, T.; Metcalf, C. A., III; Narula, S. S.; Sawyer, T. K.; Shakespeare, W. C.; Violette, S. M.; Weigele, M.
J. Med. Chem.; (Letter); 2001 ; 44 (5); 660-663.

 
   

 

Structure-based design of an osteoclast-selective, nonpeptide Src homology 2 inhibitor with in vivo antiresorptive activity
William Shakespeare, et al.(check)
PNAS 2000; 97: 9373-9378. (add picture)


Structure-Based Design of Novel Bicyclic Nonpeptide Inhibitors for the Src SH2 Domain
Shakespeare, W. C.; Bohacek, R. S.; Azimioara, M. D.; Macek, K. J.; Luke, G. P.; Dalgarno, D. C.; Hatada, M. H.; Lu, X.; Violette, S. M.; Bartlett, C.; Sawyer, T. K.
J. Med. Chem.; (Letter); 2000 ; 43 (21); 3815-3819. (add picture)

Structure-Based Design and Solid-Phase Parallel Synthesis of Phosphorylated Nonpeptides to Explore Hydrophobic Binding at the Src SH2 Domain
Metcalf, C. A., III; Eyermann, C. J.; Bohacek, R. S.; Haraldson, C. A.; Varkhedkar, V. M.; Lynch, B. A.; Bartlett, C.; Violette, S. M.; Sawyer, T. K.
J. Comb. Chem.; (Article); 2000 ; 2 (4); 305-313.

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goal: discovery of potent inhibitors of SRC kinase

for treatment of osteoporosis

company: Ariad Pharmaceuticals

protein:SRC kinase (homology model)

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goal: discovery of novel, potent inhibitor using de novo design program, GrowMol

university: University of Wisconsin

protein: pepstatin

GrowMol generated compound predicted, X-ray

Aspartic Protease Inhibitors Designed from Computer-Generated Templates Bind As Predicted
Ripka, A. S; Satyshur, K. A.; Bohacek, R. S.; Rich, D. H.
Org. Lett.; (Letter); 2001 ; 3 (15); 2309-2312.

Idea from GrowMol generated stucture protein/ligand complex; model

Peter Glunz and Daniel H. Rich, University of Wisconsin, unpublished data.

 

Design and Synthesis of Unsymmetrical Peptidyl Urea Inhibitors of Aspartic Peptidases
Dales, N. A.; Bohacek, R. S.; Satyshur, K. A.; Rich, D. H.
Org. Lett.; (Letter); 2001; 3(15); 2313-2316.  DOI: 10.1021/ol0160912