Association of Small Hydrophobic Solute in Presence of the Osmolytes Urea and Trimethylamine-N-oxide

2012 ◽  
Vol 116 (9) ◽  
pp. 2831-2841 ◽  
Author(s):  
Rahul Sarma ◽  
Sandip Paul
Keyword(s):  
Hydrophobic Solute ◽  
Small Hydrophobic

Targeting p53-MDM2 Interaction Using Small Molecule Inhibitors and the Challenges Needed to be Addressed

2019 ◽  
Vol 20 (11) ◽  
pp. 1091-1111 ◽  
Author(s):  
Maryam Zanjirband ◽  
Soheila Rahgozar
Keyword(s):  
Clinical Trials ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Tp53 Gene ◽  
Therapeutic Agents ◽  
Negative Regulator ◽  
Mdm2 Protein ◽  
Independent Effects ◽  
Small Hydrophobic ◽  
Targeted Therapeutic

MDM2 protein is the core negative regulator of p53 that maintains the cellular levels of p53 at a low level in normal cells. Mutation of the TP53 gene accounts for 50% of all human cancers. In the remaining malignancies with wild-type TP53, p53 function is inhibited through other mechanisms. Recently, synthetic small molecule inhibitors have been developed which target a small hydrophobic pocket on MDM2 to which p53 normally binds. Given that MDM2-p53 antagonists have been undergoing clinical trials for different types of cancer, this review illustrates different aspects of these new cancer targeted therapeutic agents with the focus on the major advances in the field. It emphasizes on the p53 function, regulation of p53, targeting of the p53-MDM2 interaction for cancer therapy, and p53-dependent and -independent effects of inhibition of p53-MDM2 interaction. Then, representatives of small molecule MDM2-p53 binding antagonists are introduced with a focus on those entered into clinical trials. Furthermore, the review discusses the gene signatures in order to predict sensitivity to MDM2 antagonists, potential side effects and the reasons for the observed hematotoxicity, mechanisms of resistance to these drugs, their evaluation as monotherapy or in combination with conventional chemotherapy or with other targeted therapeutic agents. Finally, it highlights the certainly intriguing questions and challenges which would be addressed in future studies.

scholarly journals An Effective and Safe Enkephalin Analog for Antinociception

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 927
Author(s):  
KK DurgaRao Viswanadham ◽  
Roland Böttger ◽  
Lukas Hohenwarter ◽  
Anne Nguyen ◽  
Elham Rouhollahi ◽  
...  
Keyword(s):  
Physical Dependence ◽  
Opioid Peptide ◽  
Vehicle Group ◽  
Endogenous Opioid ◽  
Endogenous Opioid Peptide ◽  
Extended Plasma ◽  
The Central Nervous System ◽  
Overdose Deaths ◽  
Plasma Half Life ◽  
Small Hydrophobic

Opioids account for 69,000 overdose deaths per annum worldwide and cause serious side effects. Safer analgesics are urgently needed. The endogenous opioid peptide Leu-Enkephalin (Leu-ENK) is ineffective when introduced peripherally due to poor stability and limited membrane permeability. We developed a focused library of Leu-ENK analogs containing small hydrophobic modifications. N-pivaloyl analog KK-103 showed the highest binding affinity to the delta opioid receptor (68% relative to Leu-ENK) and an extended plasma half-life of 37 h. In the murine hot-plate model, subcutaneous KK-103 showed 10-fold improved anticonception (142%MPE·h) compared to Leu-ENK (14%MPE·h). In the formalin model, KK-103 reduced the licking and biting time to ~50% relative to the vehicle group. KK-103 was shown to act through the opioid receptors in the central nervous system. In contrast to morphine, KK-103 was longer-lasting and did not induce breathing depression, physical dependence, and tolerance, showing potential as a safe and effective analgesic.

scholarly journals Size dependence of hydrophobic hydration at electrified gold/water interfaces

2021 ◽  
Vol 118 (15) ◽  
pp. e2023867118
Author(s):  
Alessandra Serva ◽  
Mathieu Salanne ◽  
Martina Havenith ◽  
Simone Pezzotti
Keyword(s):  
Free Energy ◽  
Energy Cost ◽  
Correction Term ◽  
Hydrophobic Hydration ◽  
Outer Sphere ◽  
Gold Surface ◽  
Electrochemical Reactions ◽  
Water Interface ◽  
Hydrophobic Solutes ◽  
Small Hydrophobic

Hydrophobic hydration at metal/water interfaces actively contributes to the energetics of electrochemical reactions, e.g. CO2 and N2 reduction, where small hydrophobic molecules are involved. In this work, constant applied potential molecular dynamics is employed to study hydrophobic hydration at a gold/water interface. We propose an adaptation of the Lum–Chandler–Weeks (LCW) theory to describe the free energy of hydrophobic hydration at the interface as a function of solute size and applied voltage. Based on this model we are able to predict the free energy cost of cavity formation at the interface directly from the free energy cost in the bulk plus an interface-dependent correction term. The interfacial water network contributes significantly to the free energy, yielding a preference for outer-sphere adsorption at the gold surface for ideal hydrophobes. We predict an accumulation of small hydrophobic solutes of sizes comparable to CO or N2, while the free energy cost to hydrate larger hydrophobes, above 2.5-Å radius, is shown to be greater at the interface than in the bulk. Interestingly, the transition from the volume dominated to the surface dominated regimes predicted by the LCW theory in the bulk is also found to take place for hydrophobes at the Au/water interface but occurs at smaller cavity radii. By applying the adapted LCW theory to a simple model addition reaction, we illustrate some implications of our findings for electrochemical reactions.

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