Characterizing Protein Domain Associations by Small-Molecule Ligand Binding.

Characterizing protein domain associations by Small-molecule ligand binding.

J Proteome Sci Comput Biol. 2012 Dec 3; 1:
Li Q, Cheng T, Wang Y, Bryant SH

Protein domains are evolutionarily conserved building blocks for protein structure and function, which are conventionally identified based on protein sequence or structure similarity. Small molecule binding domains are of great importance for the recognition of small molecules in biological systems and drug development. Many small molecules, including drugs, have been increasingly identified to bind to multiple targets, leading to promiscuous interactions with protein domains. Thus, a large scale characterization of the protein domains and their associations with respect to small-molecule binding is of particular interest to system biology research, drug target identification, as well as drug repurposing.We compiled a collection of 13,822 physical interactions of small molecules and protein domains derived from the Protein Data Bank (PDB) structures. Based on the chemical similarity of these small molecules, we characterized pairwise associations of the protein domains and further investigated their global associations from a network point of view.We found that protein domains, despite lack of similarity in sequence and structure, were comprehensively associated through binding the same or similar small-molecule ligands. Moreover, we identified modules in the domain network that consisted of closely related protein domains by sharing similar biochemical mechanisms, being involved in relevant biological pathways, or being regulated by the same cognate cofactors.A novel protein domain relationship was identified in the context of small-molecule binding, which is complementary to those identified by traditional sequence-based or structure-based approaches. The protein domain network constructed in the present study provides a novel perspective for chemogenomic study and network pharmacology, as well as target identification for drug repurposing. HubMed – drug


Alternate dosing of cetuximab for patients with metastatic colorectal cancer.

Gastrointest Cancer Res. 2013 Mar; 6(2): 47-55
Hubbard JM, Alberts SR

Many chemotherapeutic regimens used to treat colorectal cancer (CRC), including 5-fluorouracil plus leucovorin in combination with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX), are administered on an every-other-week (q2w) dosing schedule. Chemotherapy in combination with a monoclonal antibody (mAb) directed toward the epidermal growth factor receptor (EGFR) has emerged as an effective treatment option. There are currently 2 anti-EGFR mAbs approved by the United States Food and Drug Administration: cetuximab and panitumumab. Mutations of KRAS, a downstream protein in the EGFR pathway, predict resistance to EGFR mAbs. Thus, cetuximab and panitumumab are indicated for patients without a KRAS mutation (KRAS wild-type). Whereas panitumumab is approved on a q2w dosing schedule, cetuximab is approved as a weekly dose. However, only cetuximab is approved with FOLFIRI for frontline metastatic CRC, whereas panitumumab is approved for third-line. Because concomitant therapies are often administered q2w, the weekly dosing of cetuximab results in additional medical office visits.Several studies have assessed the safety and efficacy of cetuximab q2w. For this review, a comprehensive literature search of studies evaluating cetuximab q2w dosing was conducted. Safety and efficacy results of these trials and retrospective analyses were summarized and reviewed.In general, results with cetuximab q2w were comparable to those obtained with the weekly regimen.These data suggest that for patients for whom weekly treatment with cetuximab presents a substantial burden to their quality of life, q2w dosing of cetuximab is a viable treatment option with a benefit:risk profile similar to that of the weekly regimen. HubMed – drug


First steps in experimental cancer evolution.

Evol Appl. 2013 Apr; 6(3): 535-48
Taylor TB, Johnson LJ, Jackson RW, Brockhurst MA, Dash PR

Evolutionary processes play a central role in the development, progression and response to treatment of cancers. The current challenge facing researchers is to harness evolutionary theory to further our understanding of the clinical progression of cancers. Central to this endeavour will be the development of experimental systems and approaches by which theories of cancer evolution can be effectively tested. We argue here that the experimental evolution approach – whereby evolution is observed in real time and which has typically employed microorganisms – can be usefully applied to cancer. This approach allows us to disentangle the ecological causes of natural selection, identify the genetic basis of evolutionary changes and determine their repeatability. Cell cultures used in cancer research share many of the desirable traits that make microorganisms ideal for studying evolution. As such, experimental cancer evolution is feasible and likely to give great insight into the selective pressures driving the evolution of clinically destructive cancer traits. We highlight three areas of evolutionary theory with importance to cancer biology that are amenable to experimental evolution: drug resistance, social evolution and resource competition. Understanding the diversity, persistence and evolution of cancers is vital for treatment and drug development, and an experimental evolution approach could provide strategic directions and focus for future research. HubMed – drug


Optogenetic inhibition of D1R containing nucleus accumbens neurons alters cocaine-mediated regulation of Tiam1.

Front Mol Neurosci. 2013; 6: 13
Chandra R, Lenz JD, Gancarz AM, Chaudhury D, Schroeder GL, Han MH, Cheer JF, Dietz DM, Lobo MK

Exposure to psychostimulants results in structural and synaptic plasticity in striatal medium spiny neurons (MSNs). These cellular adaptations arise from alterations in genes that are highly implicated in the rearrangement of the actin-cytoskeleton, such as T-lymphoma invasion and metastasis 1 (Tiam1). Previous studies have demonstrated a crucial role for dopamine receptor 1 (D1)-containing striatal MSNs in mediating psychostimulant induced plasticity changes. These D1-MSNs in the nucleus accumbens (NAc) positively regulate drug seeking, reward, and locomotor behavioral effects as well as the morphological adaptations of psychostimulant drugs. Here, we demonstrate that rats that actively self-administer cocaine display reduced levels of Tiam1 in the NAc. To further examine the cell type-specific contribution to these changes in Tiam1 we used optogenetics to selectively manipulate NAc D1-MSNs or dopamine receptor 2 (D2) expressing MSNs. We find that repeated channelrhodopsin-2 activation of D1-MSNs but not D2-MSNs caused a down-regulation of Tiam1 levels similar to the effects of cocaine. Further, activation of D2-MSNs, which caused a late blunted cocaine-mediated locomotor behavioral response, did not alter Tiam1 levels. We then examined the contribution of D1-MSNs to the cocaine-mediated decrease of Tiam1. Using the light activated chloride pump, eNpHR3.0 (enhanced Natronomonas pharaonis halorhodopsin 3.0), we selectively inhibited D1-MSNs during cocaine exposure, which resulted in a behavioral blockade of cocaine-induced locomotor sensitization. Moreover, inhibiting these NAc D1-MSNs during cocaine exposure reversed the down-regulation of Tiam1 gene expression and protein levels. These data demonstrate that altering activity in specific neural circuits with optogenetics can impact the underlying molecular substrates of psychostimulant-mediated behavior and function. HubMed – drug