Studies on two types of PTP1B inhibitors for the treatment of type 2 diabetes: Hologram QSAR for OBA and BBB analogues.
ABSTRACT Hologram quantitative structure-activity relationships (HQSAR) analysis were conducted on two series of PTP1B inhibitors, 39 2-(oxalylamino) benzoic acid (OBA) analogues and 60 benzofuran and benzothiophene biphenyls (BBB) analogues. The optimal HQSAR model of the OBA analogue has q(2)=0.592 and r(2)=0.940, while the optimal HQSAR model for the BBB analogues shows q(2)=0.667 and r(2)=0.863. Two models were employed to predict the biological activities of two test sets. For OBA analogues, the optimal model was validated by an external test set of six compounds with satisfactory predictive r(2) value of 0.786. For BBB analogues, the optimal model shows satisfactory predictive r(2) value of 0.866 for an external test set of 10 compounds. The contribution maps derived from the optimal HQSAR models are consistent with the biological activities of the studied compounds. Two virtual combinatorial libraries were designed and screened by the optimal HQSAR models and potential candidates with high predictive biological activities were discovered. This work may provide valuable information for future design of more promising inhibitors for PTP1B.
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ABSTRACT: The liver is one of the richest organs in terms of number and density of mitochondria. Most chronic liver diseases are associated with the accumulation of damaged mitochondria. Hepatic mitochondria have unique features compared to other organs' mitochondria, since they are the hub that integrates hepatic metabolism of carbohydrates, lipids and proteins. Mitochondria are also essential in hepatocyte survival as mediator of apoptosis and necrosis. Hepatocytes have developed different mechanisms to keep mitochondrial integrity or to prevent the effects of mitochondrial lesions, in particular regulating organelle biogenesis and degradation. In this paper, we will focus on the role of mitochondria in liver physiology, such as hepatic metabolism, reactive oxygen species homeostasis and cell survival. We will also focus on chronic liver pathologies, especially those linked to alcohol, virus, drugs or metabolic syndrome and we will discuss how mitochondria could provide a promising therapeutic target in these contexts.Biochemistry research international. 01/2012; 2012:387626.
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ABSTRACT: Computer-aided drug designwas performed on a diverse set of 103 biphenyl derivatives that demonstrated antidiabetic activity by restraining the protein tyrosine phosphatase 1B (PTP 1B) receptor. A four-point pharmacophore hypothesis using the PHASE module of Schrödinger suite with one hydrogen bond acceptor (A) and three aromatic rings (R) as pharmacophoric features was generated. The hypothesis, ARRR.2, considered the best hypothesis in the present study is characterized by survival score (3.553), cross-validated r2 (Q2) (0.722), regression coefficient (0.949), Pearson R (0.867), and F value (492.6). The developed pharmacophore model was externally validated by predicting the activity of test setmolecules. Docking algorithmcombined with the drug–receptor binding free energetic and pharmacokinetic drug profile envisaged a novel concept, which may provide structural insights for the development of potential PTP 1B inhibitors. The study also provided a valid rapport between pharmacophore drug mapping, atom-based three-dimensional quantitative structure–activity relationship,molecular docking, sitemap, molecular simulations, and pharmacokinetic prediction approaches demonstrating the trends in activity. The results of these ligand–receptor relationship studies may account to design a legitimate template for the development and optimization of highly selective and potent PTP 1B inhibitors.Journal of Chemometrics 11/2012; · 1.80 Impact Factor
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ABSTRACT: Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin and leptin signaling, which suggests that it is an attractive therapeutic target in type II diabetes and obesity. The aim of this research is to explore residues which interact with phosphotyrosine substrate can be affected by D181 point mutations and lead to increased substrate binding. To achieve this goal, molecular dynamics simulations were performed on wild type (WT) and two mutated PTP1B/substrate complexes. The cross-correlation and principal component analyses show that point mutations can affect the motions of some residues in the active site of PTP1B. Moreover, the hydrogen bond and energy decomposition analyses indicate that apart from residue 181, point mutations have influence on the interactions of substrate with several residues in the active site of PTP1B.Scientific reports. 01/2014; 4:5095.