Fig. 6.

Multiple possible binding forces involved the stabilization of a “Zn²⁺ sandwich” between various biguanide derivatives and the active site regions of cysteinyl cathepsins. Left side: Zn²⁺ has 6 ligand-binding sites. Biguanide forms bidentate Zn²⁺ complexes through the two imino nitrogens (Figs. 2, 4). Catalytic partners consisting of Cys(thiolate)-His(imidazole) also have bidentate affinity for Zn²⁺. The thiolate-imidazole catalytic partners, and the imino biguanide nitrogens can reversibly form a mixed complex with a centrally coordinated Zn²⁺ i.e. a “drug-Zn²⁺-protease sandwich”. Access of water to the 2 unoccupied sites of Zn²⁺ in the recessed active site is uncertain. Right side: Diverse papain-like proteases have various arrays of substrate-binding sites on the protease surface surrounding the catalytic partners (schematized collectively by the bottom square plane; see the text). Appropriate biguanide substituent moieties (top square plane) can register with the array of substrate-binding sub-sites surrounding the metal sandwich. However, drug interactions with the protease surface surrounding the catalytic pair need not involve defined binding pockets. Many different substituents of biguanide at the 1 or 1 and 5 positions are possible (Fig. 1). The selectivity of the inhibitory interaction depends upon the extent of 3D structural and chemical complementarity between substituents and protease surface. The potency of inhibition is a different property, which depends upon attractive vs. repulsive forces stabilizing the metal sandwich. (Color figure online)