Cancer is a serious and life-eliminating disease. Majority of anticancer agents are non-selective. Along with the cancerous cells they also target the normal ones. An important aspect is to hit the developing mechanism of the tumor, which is highlighted by in silico drug designing. On the basis of novel molecular targets, in silico (computational approach) drug discovery has emerged as today's need. Histone deacetylases are an important therapeutic target for many human cancers. The first and only approved (in 2006) histone deacetylase inhibitors (HDACIs) is Zolinza. Depending on the types of the histone deacetylase (HDAC) enzymes, discovery of type-specific inhibitors is important. With continued research and development, in near future HDACIs are likely to figure prominently in cancer treatment plans. This review presents the overview of HDACs, their role in cancer, their structural classes, activity, catalytic domain and the inhibitors of HDACs for cancer therapy. Also it helps in understanding the open directions in this area of research and highlights the importance of computational approaches in discovering specific drugs for cancer therapy.

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BackgroundAlzheimer's disease, known to be associated with the gradual loss of memory, is characterized by low concentration of acetylcholine in the hippocampus and cortex part of the brain. Inhibition of acetylcholinesterase has successfully been used as a drug target to treat Alzheimer's disease but drug resistance shown by butyrylcholinesterase remains a matter of concern in treating Alzheimer's disease. Apart from the many other reasons for Alzheimer's disease, its association with the genesis of fibrils by β-amyloid plaques is closely related to the increased activity of butyrylcholinesterase. Although few data are available on the inhibition of butyrylcholinesterase, studies have shown that that butyrylcholinesterase is a genetically validated drug target and its selective inhibition reduces the formation of β-amyloid plaques.RationaleWe previously reported the inhibition of cholinesterases by 2,3-dihydro-1, 5-benzothiazepines, and considered this class of compounds as promising inhibitors for the cure of Alzheimer's disease. One compound from the same series, when substituted with a hydroxy group at C-3 in ring A and 2-thienyl moiety as ring B, showed greater activity against butyrylcholinesterase than to acetylcholinesterase. To provide insight into the binding mode of this compound (Compound A), molecular docking in combination with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases.ConclusionMolecular docking studies revealed that the potential of Compound A to inhibit cholinesterases was attributable to the cumulative effects of strong hydrogen bonds, cationic-π, π-π interactions and hydrophobic interactions. A comparison of the docking results of Compound A against both cholinesterases showed that amino acid residues in different sub-sites were engaged to stabilize the docked complex. The relatively high affinity of Compound A for butyrylcholinesterase was due to the additional hydrophobic interaction between the 2-thiophene moiety of Compound A and Ile69. The involvement of one catalytic triad residue (His438) of butyrylcholinesterase with the 3'-hydroxy group on ring A increases the selectivity of Compound A. C-C bond rotation around ring A also stabilizes and enhances the interaction of Compound A with butyrylcholinesterase. Furthermore, the classical network of hydrogen bonding interactions as formed by the catalytic triad of butyrylcholinesterase is disturbed by Compound A. This study may open a new avenue for structure-based drug design for Alzheimer's disease by considering the 3D-pharmacophoric features of the complex responsible for discriminating these two closely-related cholinesterases.

The current investigation employed rosuvastatin for evaluation as an antiarthritic agent by in vitro and in vivo studies. In vitro studies comprised egg albumin and bovine serum albumin protein denaturation assays along with membrane stabilization assays, while in vivo studies comprised formaldehyde and complete Freund’s adjuvant (CFA)-provoked arthritis. The antioxidant potential was estimated via DPPH free radical scavenging and ferric reducing assays. Rosuvastatin significantly inhibited heat-provoked protein denaturation of egg albumin and bovine serum in a concentration-dependent way with the highest inhibition of 1225 ± 9.83 and 82.80 ± 4.03 at 6400 μg/mL. The percentage protection of the RBC membrane from hypotonicity-prompted lysis was found to be 80.67 ± 2.7. Rosuvastatin promisingly subdued formaldehyde-provoked arthritis, with maximum reduction (65.47%) of the paw volume being observed at a dose of 40 mg/kg. Rosuvastatin also significantly (p < 0.001) attenuated arthritis induced by CFA injection by reducing the paw volume and arthritic index. The reduction in the body weight due to CFA injection was also preserved by rosuvastatin treatment. Hematological and biochemical changes due to arthritis induction by CFA injection were also maintained near normal values by rosuvastatin. The histopathological and radiographic investigation also revealed the protective effect of rosuvastatin on preventing structural changes. Gene expression of IL-1β, TNF-α, and IL-6 was reduced, while IL-4 and IL-10 levels were elevated by rosuvastatin in comparison to those for the disease control group. Concentration-dependent antioxidant potential was shown by rosuvastatin. Thus, rosuvastatin possesses a notable antiarthritic potential as evidenced via in vitro and in vivo studies.

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