Structure Based Drug Design for Nuclear Receptors

Natural ligands of NRs are chemically very diverse, including steroids, retinoids, amino acid derivatives (thyroid hormones), fatty acids and fatty acid derivatives (prostaglandins, leukotrienes), bile acids, and phospholipids (Table 1). Even heme was shown very recently to be the ligand of Drosophila E75.28 Initially ligands were not known for NRs that were either cloned by homology or found in the human genome, hence these newly identified receptors were called orphans. For many of them, ligands were subsequently found, most of the time by high-throughput screening. Orphan NRs for which ligands could be identified are called 'adopted,' for instance the LXRs (oxysterols) and FXR (bile acids).

Although NRs represent only ~2% of all current drug targets (Figure 3 in 29), eight among the 100 top prescription drugs targeted NRs and their worldwide sales amounted to over US$9 billion in 2002.1 Examples of currently marketed drugs targeting various NRs are given in Table 2.

Intense efforts are being undertaken by both academic and industrial groups on classical receptors (validated targets) and adopted receptors (promising targets). For classical receptors, the aim is to design drugs with reduced side effects. For adopted receptors, the first goal is to validate them as therapeutic targets (for instance, LXRs for

Structure Based Drug Discovery

Figure 5 Nuclear receptor ligand-binding pocket (LBP). (a) LBP in the complex of all-trans retinoic acid with human RARg (2LBD). (b) LBP in the complex of 9-c/s retinoic acid with human RXRa (1FBY). (c) LBP in the complex of 1,25 (OH)2 vitamin D3 with human VDR (1DB1). The key residues contacting the ligands are shown for each ligand. The molecular surface is shown around the ligand. Thin lines represent hydrogen bonds between polar groups.

Figure 5 Nuclear receptor ligand-binding pocket (LBP). (a) LBP in the complex of all-trans retinoic acid with human RARg (2LBD). (b) LBP in the complex of 9-c/s retinoic acid with human RXRa (1FBY). (c) LBP in the complex of 1,25 (OH)2 vitamin D3 with human VDR (1DB1). The key residues contacting the ligands are shown for each ligand. The molecular surface is shown around the ligand. Thin lines represent hydrogen bonds between polar groups.

cardiovascular diseases, inflammation, diabetes, and neurodegenerative diseases, FXR for bile acid- and lipid-related diseases, and RORa for metabolic diseases).

Unwanted side effects of drugs targeting NRs arise from the receptor pleiotropic effects. Quite often an optimized drug will be a selective NR modulator, which is a partial agonist/antagonist that either recruits selectively a given cofactor or recruits other cofactors too weakly to activate other pathways. The term was coined first in the case of estrogen receptor (selective estrogen receptor modulators or SERMs).30

4.28.3.1 Retinoic Acid Receptors and Retinoid X Receptors

Retinoids are used in the treatment of various skin diseases, including psoriasis and acne, and in the treatment or chemoprevention of cancer, such as acute promyelocytic leukemia and skin, cervical, and breast cancer.31 RARb gene is frequently deleted or its expression is epigenetically silenced during cancer progression and RARb re-expression can restore retinoic acid-mediated growth control, suggesting that the anticancer action of retinoids is mediated by RARb. RARb has been viewed as a tumor suppressor.

Numerous synthetic agonist and antagonist retinoids differentiate RXR from RAR or are selective for the RARa, b, or g isotypes. A sequence alignment of RARa, b, and g shows that all but three residues in the LBP are conserved. These divergent residues are the most important discriminatory elements for synthetic retinoid selectivity (Figure 6).4'32

Existing isotype-selective ligands dissociate mostly RARa from RARb/g by exploiting the presence of RARaS232, which can establish hydrogen bonds with suitable ligands; this was predicted for ligands harboring an amide group, such as Am80 and Am580.24 The crystal structures of a RARb LBD complexed to b-selective ligands33 clarify the selectivity potential of the I263-M272 replacement in RARg. The main consequence of methionine is to allow specific H bonds as, for example, in the case of BMS270394 (see below). The side-chain orientation of I263 opens a cavity that is closed in RARg. Ligands with a bulky substituent require such a cavity to accommodate acquire b-selectivity.

The different activity of RARg-specific enantiomers has been described for two retinoids: BMS270394 and the inactive BMS270395.25,34,35 Synthesis and characterization of the individual enantiomers showed that the biological

Table 2 Examples of marketed nuclear receptor-targeting drugs

Target receptor

Class of drug

Example

Therapeutic indications

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