Small-molecule binding sites to explore protein–protein interactions in the cancer proteome

Abstract

The Cancer Genome Atlas (TCGA) offers an unprecedented opportunity to identify small-molecule binding sites on proteins with overexpressed mRNA levels that correlate with poor survival. Here, we analyze RNA-seq and clinical data for 10 tumor types to identify genes that are both overexpressed and correlate with patient survival. Protein products of these genes were scanned for binding sites that possess shape and physicochemical properties that can accommodate small-molecule probes or therapeutic agents (druggable). These binding sites were classified as enzyme active sites (ENZ), protein-protein interaction sites (PPI), or other sites whose function is unknown (OTH). Interestingly, the overwhelming majority of binding sites were classified as OTH. We find that ENZ, PPI, and OTH binding sites often occurred on the same structure suggesting that many of these OTH cavities can be used for allosteric modulation of enzyme activity or protein-protein interactions with small molecules. We discovered several ENZ (PYCR1, QPRT, and HSPA6) and PPI (CASC5, ZBTB32, and CSAD) binding sites on proteins that have been seldom explored in cancer. We also found proteins that have been extensively studied in cancer that have not been previously explored with small molecules that harbor ENZ (PKMYT1, STEAP3, and NNMT) and PPI (HNF4A, MEF2B, and CBX2) binding sites. All binding sites were classified by the signaling pathways to which the protein that harbors them belongs using KEGG. In addition, binding sites were mapped onto structural protein-protein interaction networks to identify promising sites for drug discovery. Finally, we identify pockets that harbor missense mutations previously identified from analysis of the TCGA data. The occurrence of mutations in these binding sites provides new opportunities to develop small-molecule probes to explore their function in cancer.

Targeting Neph1 and ZO-1 protein-protein interaction in podocytes prevents podocyte injury and preserves glomerular filtration function

“…It was long believed that PPI interfaces are too large and not suitable for the binding of small molecules, which was one of the major reasons for slow progress in this field 2 , 3 . However, recent studies have shown that functional region in a PPI is small enough to be regulated by small molecules 1 , 3 , 4 . Almost all drug development using this approach has targeted “inhibiting” PPIs, where many of these drugs have entered various phases of clinical trials 2 , 5 , 6 .…”

“…Almost all drug development using this approach has targeted “inhibiting” PPIs, where many of these drugs have entered various phases of clinical trials 2 , 5 , 6 . Mechanistically, majority of these drugs bind one target protein and inhibit its ability to form a functional complex with its binding partner, thereby modulating its downstream signaling events 2 , 4 . Many small molecules have been developed that inhibit various PPIs including the Ras-SOS1 complex that produces anticancer effects by targeting Ras oncogene 4 , 7 ; small molecules LEDGINs were shown to inhibit LEDGF/p75-integrase binding 8 and inhibit HIV replication; Verteporfin was shown to inhibit YAO-TEAD complex with anticancer properties 8 , 9 .…”

Computational‐based discovery of FAK FERM domain chemical probes that inhibit HER2‐FAK cancer signaling

“…To calculate druggability of the FERM F1 lobe and the specific pockets to target for virtual‐based drug discovery, we first started with the program SiteMap (Schrödinger), which utilizes a grid‐based searching algorithm to search for drug‐binding protein cavities and calculates the physiochemical properties of found cavities. This program is a useful tool when it comes to druggability determination of a variety of protein–protein interactions, including, but not limited to, PPIs on the cancer genome that drive cancer function (Halgren, 2009; Xu, Jalal, Sledge, & Meroueh, 2016). For these reasons, we chose to use SiteMap to determine the key druggability of the FERM F1 lobe.…”

Small-molecule Ca V α 1 ⋅Ca V β antagonist suppresses neuronal voltage-gated calcium-channel trafficking

“…To identify small molecules that bind to Ca V β at the protein-protein interaction interface, we resorted to virtual screening, focusing on the large binding cavity on Ca V β 3 . SiteMap (44) scoring of the cavity leads to a SiteScore of 1.01, suggesting that the pocket is highly druggable (45). Therefore, small molecules that bind to this pocket have the potential to exhibit in vivo efficacy similar to those of Food and Drug Administrationapproved drugs.…”