The significance of chirality in drug design and development

Abstract

Proteins are often enantioselective towards their binding partners. When designing small molecules to interact with these targets, one should consider stereoselectivity. As considerations for exploring structure space evolve, chirality is increasingly important. Binding affinity for a chiral drug can differ for diastereomers and between enantiomers. For the virtual screening and computational design stage of drug development, this problem can be compounded by incomplete stereochemical information in structure libraries leading to a "coin toss" as to whether or not the "ideal" chiral structure is present. Creating every stereoisomer for each chiral compound in a structure library leads to an exponential increase in the number of structures resulting in potentially unmanageable file sizes and screening times. Therefore, only key chiral structures, enantiomeric pairs based on relative stereochemistry need be included, and lead to a compromise between exploration of chemical space and maintaining manageable libraries. In clinical environments, enantiomers of chiral drugs can have reduced, no, or even deleterious effects. This underscores the need to avoid mixtures of compounds and focus on chiral synthesis. Governmental regulations emphasizing the need to monitor chirality in drug development have increased. The United States Food and Drug Administration issued guidelines and policies in 1992 concerning the development of chiral compounds. These guidelines require that absolute stereochemistry be known for compounds with chiral centers and that this information should be established early in drug development in order that the analysis can be considered valid. From exploration of structure space to governmental regulations it is clear that the question of chirality in drug design is of vital importance.

Fig. (1)

a) Basic chirality. These two molecules have the same atoms and the same atom-atom connections but they cannot be fully superimposed. They are therefore referred to as enantiomers and appear as mirror images in three-dimensional depictions. The central atom (*) is therefore considered to be a chiral center. (Note that bond lengths and atomic diameters have been simplified in order to focus on the basic concepts in these depictions.) (b) R / S conformations. In order to differentiate enantiomer pairs, R (rectus) and S (sinister) are used. To determine the R or S notation for the chiral molecules of Figure 1, the substituent atoms attached to the chiral atom are prioritized based on their atomic number with the higher number being the higher priority (therefore, F>N>C>H). The molecule is rotated until the lowest priority substituent, in this case H, is behind the chiral center. The chiral center is R if the three remaining substituents go clockwise from highest (F) to lowest priority (C). The chiral center is S if the three remaining stituents go counter-clockwise from highest to lowest priority.

Fig. (2)

(a) Sample of the SDF for the NCI Diversity Set II. Compound 479 is a chiral compound. The SDFile for this compound contains no chiral information. The (*) denotes the chiral site. (b). 2D SDfile for Nutlin 2 from PubChem lacking Z coordinate information. Relative stereochemistry information is present in the atomic parameters block, (c). 3D sdf for Nutlin 2 from PubChem possessesing Z coordinate information. Relative stereochemistry information is present in the atomic parameters block.

Fig. (3)

a) Comparison of the docking pose of the R,S Nutlin (from crystal structure; grey carbons) to the enantiomer (S,R; blue). When seeded into the NCI Diversity Set II for docking, the original form of nutlin (R,S) ranks 51 and the enantiomer ranks 3,482 (out of 3,718 docked structures). GScores are -6.70 kcal/mol (R,S) vs -3.95 (S,R). RMSD = 7.07. (b) Line structure of R,S Nutlin. (c) Line structure of S,R Nutlin. (d) Comparison of the docking pose of the R,R Atorvastatin (from crystal structure; grey carbons) to the enantiomer (R,R; blue). When seeded into the NCI Diversity Set II for docking, the S,S Atorvastatin ranks 1 and the enantiomer ranks 2 (out of 3,718 docked structures). GScores are -8.80 kcal/mol (S,S) vs -8.25 (R,R). RMSD = 0.70. (e) Line structure of R,R Atorvastatin. (f) Line structure of S,S Atorvastatin. (g) Comparison of the docking pose of the R,S Sertraline (from crystal structure; grey carbons) to the enantiomer (S,R: blue). Wlien seeded into the NCI Diversity Set II for docking, the R,S Sertraline ranks 67 and the enantiomer ranks 407 (out of 3,879 docked structures). GScores are -7.05 kcal/mol (R,S) vs -6.29 (S,R). RMSD = 2.64. (h) Line structure of R,S Sertraline, (i) Line structure of S, R Sertraline.

Fig. (4)

Generating a stereo enantiomer. If the coordinates for one chiral molecule are available, the other stereo enantiomer can be created by simply multiplying the Z coordinate by -1. When three of the four substituent first-level atoms of a chiral center are superimposed, it simplifies the relationship between the enantiomers such that you only need to multiple the Z coordinate of every atom by -1 to generate the missing stereo enantiomer. The relation is then Z_S = |-Z_R| for each atom.