Session Presenter

Multi-Target Drug Design for New Cognition-Enhancers In Series Of Glutamate-Receptors Ligands
Bachurin S.O., Grigoriev V.V., Proshin A.N., Palyulin V.A., Zefirov N.S

According to World Health Organisation’s statistics, more than 220 million people and at least 400 million people worldwide suffer from diabetes and obesity, respectively. Diabetes has very serious consequences such as cardiovascular diseases, strokes, neuropathy, retinopathy and kidney failure. Also, obesity is a major risk factor for diabetes again andcardiovascular diseases. Despite the fact that many antidiabetic agents
present in the market show an effective increase in insulin secretion, they are associated with many undesirable side effects for instance hypoglycemia, abnormalities in cardiovascular responses and β-cell apoptosis. Therefore, the development of efficient drugs for both diseases with less serious adverse effects is extremely necessary.

PTP1B knock-out mouse experiment launched PTP1B as a novel druggable target for type II diabetes mellitus and diet-induced obesity. It was observed that treating such diabetic obese mice with PTP1B antisense oligonucleotides was able to normalise blood glucose level and reduces body weight. However, the highly charged environment of PTP1B catalytic site hinders the development of inhibitors with a good oral bioavailibility. Moreover, PTP1B share with all protein tyrosine phosphatases (PTP) a common motif in its active pocket which brings about a selectivity issue. Hence, we need to develop lead molecules that are able to inhibit PTP1B with good potency and oral
activity. Our approach here is to target the allosteric site of PTP1B as this pocket has a less polar environment and it is not shared with many other phosphatases.

In this project, a novel virtual screening method in combination with biochemical enzyme assay was used to discover leadlike PTP1B inhibitors (Figure 1). The screening started with filtering a library of more than 300000 ligands based on Oprea’s leadlike rules. The leadlike library was screened according to their shape and color similarity of four known PTP1B allosteric ligands. The top 5,000 ligands were docked into PTP1B allosteric
site in order to filter out ligands that clashed with the surrounding residues. After ranking, 59 compounds were selected from different structural clusters, based on the goodness of fit of their binding modes.
Finally, they were tested for their inhibitory activity against PTP1B enzyme.

Thirteen compounds show inhibitory activity in the range of 20% to 99% at 250 μM inhibitor concentration; half of these show more than 50% inhibition. The inhibitors carry novel and varied structural scaffolds with no net charge on most of them.