The placebo phenomenon and the underlying mechanisms.

The clinical role of the placebo effect is a topic of increasing interest for the scientific community. Focus is shifting from the inert role of placebos in randomized controlled trials (RCTs) to potential effects in clinical applications, since the phenomenon is thought to be inherent in routine clinical practice, affecting therapy success rates. Mediation of the mind-brain-body relationship involves both psychosocial and neurobiological factors, the interaction of which comprises the placebo mechanisms. Psychosocial factors include environmentally induced expectations, reward expectations, and even conditioned responses to certain stimuli. Expectations also depend on previous experience of the patient with a similar procedure and can affect future responses. Moreover, the supportive bedside behavior of the clinician and the positive framing of information provided to the patient have proven to be of great importance, setting the foundations for reconsideration of standardized practices. Neurobiological mechanisms mediate these effects through neurotransmitter and neuromodulator pathways. The best understood mechanisms are those regulating non-opioid- and opioid-mediated analgesic responses that implicate specific brain regions of pain control and activation of endogenous opioids. Other responses concern, among others, hormonal control, motor performance, and antidepressant responses. Although mechanisms underlying placebo responses are not as yet completely elucidated, there is substantial evidence suggesting that placebo effects are indicative of healthy functioning of intact brain structures and occur through actual functional changes, and are not simply subjective symptom reports. These effects can be utilized in treatment optimization while maintaining an ethical and respectful manner toward the patient and the standardized disclosure procedures.

Docking analysis targeted to the whole enzyme: an application to the prediction of inhibition of PTP1B by thiomorpholine and thiazolyl derivatives.

PTP1b is a protein tyrosine phosphatase involved in the inactivation of insulin receptor. Since inhibition of PTP1b may prolong the action of the receptor, PTP1b has become a drug target for the treatment of type II diabetes. In the present study, prediction of inhibition using docking analysis targeted specifically to the active or allosteric site was performed on 87 compounds structurally belonging to 10 different groups. Two groups, consisting of 15 thiomorpholine and 10 thiazolyl derivatives exhibiting the best prediction results, were selected for in vitro evaluation. All thiomorpholines showed inhibitory action (with IC50 = 4-45 µΜ, Ki = 2-23 µM), while only three thiazolyl derivatives showed low inhibition (best IC50 = 18 µΜ, Ki = 9 µΜ). However, free binding energy (E) was in accordance with the IC50 values only for some compounds. Docking analysis targeted to the whole enzyme revealed that the compounds exhibiting IC50 values higher than expected could bind to other peripheral sites with lower free energy, Eo, than when bound to the active/allosteric site. A prediction factor, E- (ΣEo × 0.16), which takes into account lower energy binding to peripheral sites, was proposed and was found to correlate well with the IC50 values following an asymmetrical sigmoidal equation with r2 = 0.9692.