Histone deacetylases (HDACs) play an important role in gene transcription. Inhibitors of HDACs induce cell differentiation and suppress cell proliferation in tumor cells. Although many HDAC inhibitors have been designed and synthesized, selective inhibition for class I HDAC isoforms is a goal that has yet to be achieved. To understand the difference between class I HDAC isoforms that could be exploited for the design of isoform-specific HDAC inhibitors, we have built three-dimensional models of four class I histone deacetylases, HDAC1, HDAC2, HDAC3, and HDAC8. Comparison of the homology model of HDAC8 with the recently published X-ray structure shows excellent agreement and validates the approach. A series of HDAC inhibitors were docked to the homology models to understand the similarities and differences between the binding modes. Molecular dynamic simulations of these HDAC-inhibitor complexes indicate that the interaction between the protein surface and inhibitor is playing an important role; also some active site residues show some flexibility, which is usually not included in routine docking protocols. The implications of these results for the design of isoform-selective HDAC inhibitors are discussed.

Histone deacetylases (HDACs) play an important role in gene transcription. Inhibitors of HDACs induce cell differentiation and suppress cell proliferation in tumor cells. AutoDock calculations of known and novel HDAC inhibitors as well as of several probe molecules to histone deacetylase-like protein (HDLP), using a modified scoring function for metalloproteins, demonstrate excellent agreement (R = 0.92) between experimental and computed binding constants. Analysis of the docked structures allows a determination of the different binding motifs in known inhibitors. Such calculations are a useful tool for the prediction of binding constants for new HDAC inhibitors. Exploration of the 14 A long internal cavity adjacent to the active site by docking of small molecular probes suggest that it plays a crucial role by accepting the cleaved acetate and releasing it at the far side of the cavity. The importance of the findings for the design of new inhibitors is discussed.

The conformational preference of calix[4]pyrrole and its fluoride and chloride anion-binding properties have been investigated by density functional theory calculations. Geometries were optimized by the BLYP/3-21G and BLYP/6-31G methods, and energies were evaluated with the BLYP/6-31+G method. To model the effect of medium, the SCIPCM solvent model was also employed. Four typical conformations of the parent substituent-free calix[4]pyrrole were studied. Both in the gas phase and in CH(2)Cl(2) solution, the stability sequence is predicted to be 1,3-alternate > partial cone > 1,2-alternate > cone. The cone conformation is predicted to be about 16.0 and 11.4 kcal/mol less stable in the gas phase and CH(2)Cl(2) solution, respectively. This is mainly due to electrostatic repulsions arising from the all-syn pyrrole/pyrrole/pyrrole/pyrrole arrangement present in this conformer. The existence of possible 1:1 and 1:2 anion-binding modes were explored in the case of fluoride anion, and the factors favoring the 1:1 binding mode are discussed. The calculated binding energy for fluoride anion is about 15 kcal/mol larger than that for chloride anion. The calculated binding energy for chloride anion agrees with the experimental value very well. The presence of meso-alkyl substituents destabilizes the cone conformer with respect to the 1,3-alternate conformer and, therefore, reduces the anion-binding affinity by 3-4 kcal/mol. The strength of N-H- - -anion hydrogen bonds in the various structures subject to study were estimated on the basis of the calculated anion-binding energies and the predicted structural deformation energies of substituent-free calix[4]pyrrole.

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BACKGROUNDBactrocera dorsalis (Hendel) is a notorious agricultural pest worldwide, and its resistance to insecticides is a major obstacle in successful control. Cytochrome P450s (P450s) are major metabolic enzymes associated with insecticide resistance. The genome of B. dorsalis was sequenced recently, allowing an integrated genome‐wide analysis of P450 genes (P450s) and the analysis of correlations between these genes and insecticide resistance in this pest.RESULTSTotally, 101 P450s were identified in the B. dorsalis genome and classified into four clans, 25 families and 57 subfamilies. Quantitative reverse transcription polymerase chain reaction results showed that most of these genes were highly expressed in adults (46) and in metabolic tissues, including the fatbody (63), midgut (61) and Malphagian tubules (66). In a malathion‐resistant strain, 13 and 9 genes were significantly upregulated and downregulated, respectively, compared with a susceptible strain, and these genes were screened as candidate genes associated with malathion resistance.CONCLUSIONThis study provides useful information for understanding the evolution and potential functions of P450s in B. dorsalis, and the results lay the foundation for further studies on the correlations between P450s and malathion resistance in B. dorsalis. © 2020 Society of Chemical Industry

A Toll-like receptor 9-mediated pathway stimulates perilipin 3 (TIP47) expression and induces lipid accumulation in macrophages.

Abstract. The bones are the most common location for metastases, which may cause severe pain and damage, including osteolytic destruction and fractures. Pathological fractures of the spine are extremely painful and cause significant disability and morbidity in patients. Traditional open surgery has numerous complications, and radiation therapy may take weeks to become effective. To avoid the trauma and complication of open surgery, percutaneous kyphoplasty (PKP) is a minimally invasive procedure that has played a great role in the treatment of spinal metastases over the past several years. To evaluate the efficacy and safety of the treatment of spinal metastasis using PKP, the present study evaluated 282 patients who had received PKP between April 2009 and June 2014. The efficacy of PKP was evaluated using the visual analog scale for pain (VAS), Karnofsky performance score (KPS) and quality of life (QOL) score (short form with 36 questions). The KPS and QOL were measured pre-operatively and 3 months post-operatively. In addition, radiographical data, including the degree of restoration of the kyphotic angle and the anterior vertebral height, and leakage of bone cement, were measured. The safety of the surgery was assessed by complications and side effects reported during or subsequent to surgery. The present study measured the parameters prior to the surgery and at 24 h, 3 months, 6 months and 1 year post-surgery, as well as at the last follow-up date. The range of the follow-up time was between 105 days and 15 months (mean, 401 days). The 282 patients underwent successful operations and the pain felt by the patients prior to the surgery was significantly alleviated. In addition, the analgesic intake of patients greatly decreased following PKP. KPS improved prior to and 3 months after the surgery. QOL also improved prior to and 3 months after the surgery. Radiographical data demonstrated that the kyphotic angle decreased following PKP, and the anterior vertebral height increased. Paravertebral leakage of bone cement occurred in 10 patients through a cortical defect, but without spinal cord compression or pulmonary embolism. Therefore, as a minimally invasive procedure, PKP may not only rapidly relieve the pain and disability experienced by patients, but it may also restore the kyphotic angle observed at the 1-year follow-up. Notably, PKP may safely improve the QOL of patients. IntroductionThe most frequent site of bone metastasis is the spine, and 39% of patients with bone metastases exhibit axial bone lesions (1,2). The most common location for spinal metastases is the thoracic spine (40-50%); however, all spinal column levels may be affected and >70% of spinal metastases may involve more than one vertebral level at presentation (3). The predominant symptom in spinal metastases is pain, including constant localized, radicular and axial pain (4). In addition to pain, spinal metastases may lead to pathological fractures of the vertebrae and paraplegia caused by spinal cord compression (5). Advances in diagnosing ...

Although there are tremendous studies about the conformational feature of calix[4]arenes and its analogies, no theoretical study has been done systematically about why some structural modifications could completely lead to a change of conformational preference. For example, calix[4]arene 1 adopts a cone conformation while its analogue calix[4]pyrrole 7 only adopts a 1,3-alternate conformation. So if this is only because of the effect of OH—OH hydrogen bonds, then why does O-methyl substituted calix[4]arene 2 still has cone conformation? In this paper, the conformational features of a series of seven calix[4]aromatics, calix[4]arene and calix[4]pyrrole related structures, have been investigated at BLYP/6–31G* level both in the gas phase and in CH 2 Cl 2 solution. The calculations demonstrated that three main factors influence the conformational preference of these calix[4]aromatics, i.e. the intramolecular hydrogen bond, the adjacent ring-ring electrostatic interaction and the intrinsic flexibility of the [14] metacyclophane framework. Calix[4]benzene 3 and calix[4]pyridine 4 have little conformational preferences due to their flexible [14] metacyclophane framework, the lack of hydrogen-bonding interactions and weak ring-ring electrostatic interactions. In contrast, calix[4]aromatics 1 and 5–7 have either intramolecular hydrogen bonds (1) or ring-ring electrostatic interactions (5–7). Consequently, calix[4]arene 1 has the cone preference and calix[4]pyrrole, calix[4]furan, and calixthiophene (5–7) have the 1,3-alternate preference. Methoxy calix[4]arene prefers a cone or partial cone conformation, because the 1,3-alternate and 1,2-alternate conformations are destabilized by electrostatic repulsions involving the methoxy group and the adjacent phenyl ring.