Structure-based optimization

Krier M, de Araujo-Junior JX, Schmitt M, Duranton J, Justiano-Basaran H, Lugnier C, Bourguignon JJ, Rognan D. Design of small-sized libraries by combinatorial assembly of linkers and functional groups to a given scaffold application to the structure-based optimization of a phosphodiesterase 4 inhibitor. J Med Chem 2005 48 3816-22. 

Direct InhA inhibitors have also been sought to avoid isoniazid resistance mediated by catalase-peroxidase mutation. Lipophilic analogs of triclosan such as 36 show a nanomolar K on the enzyme with an MIC of 1-2 pg/mL on isoniazid-resistant strains [56]. Structure-based optimization of two separate HTS leads afforded 37 and 38, both submicromolar inhibitors of InhA but devoid of any significant antibacterial activity [57,58],... 

Lu, Q., Wang, D.S., Chen, C.S., Hu, Y.D. and Chen, C.S. (2005) Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors. Journal of Medicinal Chemistry, 48, 5530-5535. 

It is noteworthy that the offrate of category IV and V inhibitors can be slow relative to the time involved in crystallization and X-ray data collection. As a result of this, the nature of the interactions of the inhibitor with the enzyme seen in the X-ray structure may not bear any relationship to the interactions that occur in driving the rate of inhibition. Thus, the structure-based optimization of inhibitors may be flawed when using structures of complexes involving these types of inhibitors. 

Fig. 10.6 Structure-based lead optimization. Structure-based optimization of the initial fragment hit (AT381) allows affinity to be rapidly and efficiently built-up using focused chemical synthesis. The resulting compound (AT3851) is a potent inhibitor of CDK2 and has good physicochemical properties and shows cell-based activity against a variety of cancer cell lines.

The SHAPES force field" has been implemented in CHARMM and used to examine the structures of several square planar rhodium complexes. This force field is based on angular overlap considerations and treats angular distortions for a variety of geometries. Spherical internal coordinates and Fourier potential functions form the basis for the description of these molecular shapes. The parameters for this force field were derived from normal coordinate analysis, ab initio calculations, and structure-based optimizations. The average rms deviation for bond lengths was 0.026 A, and the average rms deviation for bond angles was 3.2°. 

Then, close analogs of the first series of hits were assayed, resulting in a total screen of 3000 compounds. This provided 150 hits, clustered into 14 chemical classes. Seven of these classes could be demonstrated as novel DNA gyrase inhibitors competingfor the ATP binding site. Subsequent structure-based optimization resulted in inhibitors with potencies equal to or up to 10 times better than those of known antibiotics. 

Human elastase Good orai bioavaiiabiiity was achieved by minimizing compound size through iterative structure-based optimization of a peptide iead. 185... 

Maccari R, Ottana R, Ciurleo R et al (2009) Structure-based optimization of benzoic acids as inhibitors of protein tyrosine phosphatase IB and low molecular weight protein tyrosine phosphatase. ChemMedChem 4 957-962... 

Caflisch, A., and Nevado, C. (2009) Structure-based optimization of potent and selective inhibitors of the tyrosine... 

Figure 8.26 Activity and half-life in mouse plasma at 37°C for some PKB inhibitors (data from Breitenlechner, C.B., et al. Structure-based optimization of novel azepane derivatives as PKB inhibitors.

Figure 11 An inhibitor of DNA gyrase B, discovered at Roche by means of virtual screening and subsequent structure-based optimization.

J. Jacobs, V. Grum-Tokars, Y. Zhou, M. Turlington, S. A. Saldanha, R Chase, A. Eggler, E. S. Dawson, Y. M. Baez-Santos, S. Tomar, A. M. Mielech, S. C. Baker, C. W. Lindsley, P. Hodder, A. Mesecar, S. R. Stauffer, J. Med. Chem. 2013,56, 534—546. Discovery, synthesis, and structure-based optimization of a series of V-(fert-butyl)-2-(V-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavi-rus (SARS-CoV) 3CL protease. 

Structure-based optimization of a novel class of arylamide FMS inhibitors... 

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