Multitarget nociceptor sensitization by a promiscuous peptide from the venom of the King Baboon spider.

The King Baboon spider, Pelinobius muticus, is a burrowing African tarantula. Its impressive size and appealing coloration are tempered by reports describing severe localized pain, swelling, itchiness, and muscle cramping after accidental envenomation. Hyperalgesia is the most prominent symptom after bites from P. muticus, but the molecular basis by which the venom induces pain is unknown. Proteotranscriptomic analysis of P. muticus venom uncovered a cysteine-rich peptide, δ/κ-theraphotoxin-Pm1a (δ/κ-TRTX-Pm1a), that elicited nocifensive behavior when injected into mice. In small dorsal root ganglion neurons, synthetic δ/κ-TRTX-Pm1a (sPm1a) induced hyperexcitability by enhancing tetrodotoxin-resistant sodium currents, impairing repolarization and lowering the threshold of action potential firing, consistent with the severe pain associated with envenomation. The molecular mechanism of nociceptor sensitization by sPm1a involves multimodal actions over several ion channel targets, including NaV1.8, KV2.1, and tetrodotoxin-sensitive NaV channels. The promiscuous targeting of peptides like δ/κ-TRTX-Pm1a may be an evolutionary adaptation in pain-inducing defensive venoms.

In Silico Target Druggability Assessment: From Structural to Systemic Approaches.

This chapter will focus on today's in silico direct and indirect approaches to assess therapeutic target druggability. The direct approach tries to infer from the 3D structure the capacity of the target protein to bind small molecule in order to modulate its biological function. Algorithms to recognize and characterize the quality of the ligand interaction sites whether within buried protein cavities or within large protein-protein interface will be reviewed in the first part of the paper. In the case a ligand-binding site is already identified, indirect aspects of target druggability can be assessed. These indirect approaches focus first on target promiscuity and the potential difficulties in developing specific drugs. It is based on large-scale comparison of protein-binding sites. The second aspect concerns the capacity of the target to induce resistant pathway once it is inhibited or activated by a drug. The emergence of drug-resistant pathways can be assessed through systemic analysis of biological networks implementing metabolism and/or cell regulation signaling.

Mapping of inhibitors and activity data to the human kinome and exploring promiscuity from a ligand and target perspective.

An up-to-date collection of publicly available kinase inhibitors and activity data was mapped to the human kinome to comprehensively analyze current small molecule-kinase interactions. Compound distributions across the kinome were explored, structural relationships between inhibitors determined, and the tendency to form activity cliffs assessed. Furthermore, promiscuity was analyzed at the level of inhibitors and kinases, and a number of kinase targets with distinct preferences for single- or multitarget inhibitors were identified. Taken together, the results of current analysis provide a detailed view of kinase-inhibitor interaction characteristics across the human kinome.