Figure 1. The degree of pharmacophore overlap varies significantly among ‘designed multiple’ ligands. There is a continuum from conjugates where the pharmacophores are well separated by a linker group to ligands where the pharmacophores are highly intermingled. Abbreviation: P, pharmacophore.

Figure 2. Cleavable conjugates and ‘designed multiple’ ligands for GPCR and enzyme targets. Abbreviations: APN, aminopeptidase-N; AT, angiotensin receptor; CAT-L, cathepsin L; COX, cyclooxygenase; DM, designed multiple; ET, endothelin receptor; GPCR, G-protein-coupled receptor; MMP, matrix metalloproteases; NEP, neutral endopeptidase; NO, nitric oxide.

Figure 3. A high molecular weight conjugate in which a direct thrombin inhibitor is linked to a pentasaccharide fragment via a polyethylene glycol linker. Dual inhibition of thrombin and ATIII-mediated factor Xa produces potent antithrombotic activity. Abbreviation: AT, antithrombin.

Figure 4. Designed multiple ligands can span target superfamilies. Enzyme and transporter activity was observed for (18) and enzyme and GPCR activity for (21) and (24). Abbreviations: AChE, acetylcholinesterase; PAF, platelet-activating factor; SERT, serotonin transporter; TxR, thromboxane-A₂ receptor; TxS, thromboxane-A₂ synthase.

Figure 5. ‘Designed multiple’ ligands can be identified from the screening of random libraries [e.g. (26)], focussed libraries [e.g. (27)] or known drugs [e.g. (29)]. Abbreviations: 5-HT₃, 5-hydroxytryptamine-3 receptor; α7-nAChR, α7-nicotinic acetylcholine receptor; NK₁, neurokinin-1 receptor; PPAR, peroxisome proliferator-activated receptor; SERT, serotonin transporter.

Table 1. Target combinations for 92 designed multiple ligands

The numbers in parentheses refer to the total number of examples of each particular combination of activities identified from the literature. Abbreviations: A, adenosine receptor; α₂, α₂-adrenoceptor; α₄β₁, α₄β₇, α₄β₁, α₄β₇ integrins; ACE, angiotensin-converting enzyme; AChE, acetylcholinesterase; α7-nAChR, α7-nicotinic acetylcholine receptor; APN, aminopeptidase-N; AT, angiotensin receptor; ATIII, antithrombin III; β₂, β₂-adrenoceptor; COX, cyclooxygenase; δ, δ-opioid receptor; D, dopamine receptor; DAT, dopamine transporter; DHFR, dihydrofolate reductase; ECE, endothelin-converting enzyme; EGFR, epidermal growth factor receptor; ET_A, endothelin-A receptor; FPT, farnesyl protein transferase; GPT, geranyl protein transferase; GR, glucocorticoid receptor; GSK3, glycogen synthase kinase-3; H, histamine receptor; HNMT, histamine N-methyltransferase; 5-HT, 5-hydroxytryptamine receptor; κ, κ-opioid receptor; 5-LOX, 5-lipoxygenase; LTD₄, leukotriene D₄ receptor; μ, μ-opioid receptor; MAO, monoamine oxidase; MMP, matrix metalloprotease; MRP₁, multidrug resistance protein-1; NEP, neutral endopeptidase; NET, norepinephrine transporter; NK, neurokinin receptor; NO, nitric oxide; NOS, nitric oxide synthase; PAF, platelet-activating factor receptor; Pgp, P-glycoprotein; PKC, protein kinase-C; PPAR, peroxisome proliferator-activated receptor; SERT, serotonin transporter; STS, steroid sulfatase; TACE, tumour necrosis factor-α-converting enzyme; TS, thymidylate synthase; TxR, thromboxane-A₂ receptor; TxS, thromboxane-A₂ synthase.

Table 2. Average physicochemical properties for oral drugs and designed multiple ligands

Abbreviations: cLogP, calculated LogP; CNS, central nervous system; DM, designed multiple; GPCR, G-protein-coupled receptor; H-Accs, hydrogen bond acceptors, H-Dons, hydrogen bond donors; MW, molecular weight; PSA, polar surface area.