Multiple non-specific protein surfaces

Multiple non-specific protein surfaces refers to the collective array of protein regions that engage in low-affinity, non-selective interactions with small molecules or biologics. These interactions are typically driven by general physicochemical properties such as lipophilicity and charge rather than the specific structural complementarity found in traditional drug-target binding sites (Baell & Walters, 2014). In drug discovery, high affinity for these non-specific surfaces is viewed as a significant liability, as it often correlates with high plasma protein binding and an increased risk of off-target toxicity (Di & Kerns, 2016). Compounds that interact broadly with these surfaces are frequently classified as Pan-Assay Interference Compounds (PAINS) or promiscuous binders, which can confound experimental results by inhibiting enzymes through non-specific mechanisms like aggregation (McGovern et al., 2002). Furthermore, extensive non-specific binding can sequester a drug, reducing the free concentration available to interact with its intended therapeutic target. Consequently, characterizing and minimizing these interactions is a critical component of lead optimization to ensure a favorable therapeutic index and predictable pharmacokinetics (Sasseville, 2004).

Other names

Non-specific protein binding sitesPromiscuous binding surfacesOff-target protein surfacesNon-selective protein surfaces

Non-specific adsorption via hydrophobic effects, van der Waals forces, and electrostatic interactions