Small‐molecule protein–protein interaction inhibitors: Therapeutic potential in light of molecular size, chemical space, and ligand binding efficiency considerations

Abstract

SummaryAs the ultimate function of proteins depends to a great extent on their binding partners, protein-protein interactions (PPIs) represent a treasure trove of possible new therapeutic targets. Unfortunately, interfaces involved in PPIs are not wellsuited for effective small molecule binding. Nevertheless, successful examples of small-molecule PPI inhibitors (PPIIs) are beginning to accumulate, and the sheer number of PPIs that form the human interactome implies that, despite the relative unsuitability of PPIs to serve as ''druggable'' targets, small-molecule PPIIs can still provide novel pharmacological tools and new innovative drugs in at least some areas. Here, after some illustrative examples, accumulating information on the binding efficiency, molecular size, and chemical space requirements will be briefly reviewed. Therapeutic success can only be achieved if these considerations are incorporated into the search process and if careful medicinal chemistry approaches are used to address the absorption, distribution, metabolism, and excretion requirements of larger molecules that are often needed for this target class due to the lower efficiency of binding. IUBMBIUBMB Life, 62(10): 724-731, 2010

Interface Peptide Mimetics-Rationale and Application as Therapeutic Agents

“…Collectively the convergent evolution and the minimal binding consensus suggest that the PPI interfaces are excellent targets for drug design and discovery [8][9][10].…”

“…The efficacy of small molecule inhibitors are largely limited to a subset of PPI that present tight hydrophobic binding pockets within a relatively smaller area ranging between 300-1000 A 2 [2,9,11]. However, most PPI interface present non-contiguous distribution of hot spot residues and large surface area with little or no binding pockets.…”

“…Efficacious competitive PPI antagonists should be large enough to simultaneously interact with multiple hot spot patches to gain considerable part of the distributed free energy and achieve significant affinity. It is suggested that medium sized molecules with large contact surfaces could achieve nanomolar potency at PPI interfaces and function as better inhibitors [1,9].…”

Targeting Cas Family Proteins as a Novel Treatment for Breast Cancer

“…For instance, humanized therapeutic antibodies, intrabodies, peptide inhibitors, peptidomimetics, or small-molecule inhibitors have been employed in cancer therapies and are undergoing clinical trials (Buchwald 2010;Leader et al 2008;Lo et al 2008). Although therapeutic antibodies usually show a high specificity, they are in general not cellpermeable, thus excluding them as potential drug for targeting the intracellular Cas proteins.…”

“…In the context of the Cas proteins that mediate their function as adapters by providing docking sites for multiple PPI, progress particularly in developing small-molecule inhibitors to block PPI is of major importance. Peptide inhibitors represent potent therapeutic agents and over the past decade more than 50 peptides have been approved for the treatment of various diseases and several hundred are in preclinical development and clinical testing (Buchwald 2010). Advantages of peptide inhibitors are the high specificity, low toxicity, and low accumulation in tissues.…”