Indole fragments for the design of lead molecules against pancreatitis.

Communicated by Ramaswamy H. Sarma.

Rational design and interaction studies of combilexins towards duplex DNA.

DNA, which is the genetic material, plays a predominant role in all living organisms. Alterations in the structure and function of this genetic material correlate with complex diseases such as cancer. A number of anticancer drugs exert their action by binding to DNA. Although DNA binding compounds exert genotoxicity, there is a high demand for novel DNA binding molecules because they can be further developed into anticancer drugs. In the present study, the mode of interaction of two compounds, 2,4-D and tacrine, has been determined to be minor groove binding and intercalation, respectively. Subsequently, from their binding modes, novel combilexin molecules were designed using computational tools and their mode of binding and affinities towards DNA were determined through a series of molecular modeling experiments such as molecular docking, molecular dynamics and binding free energy calculations. The entire study focuses on the potential effects of combilexins compared to intercalators and minor groove binders. The combilexins deduced from the current study may be considered as lead compounds for the development of better anticancer drugs.

Comparative studies on the inhibitory activities of selected benzoic acid derivatives against secretory phospholipase A2, a key enzyme involved in the inflammatory pathway.

Inflammation is considered to be a key factor in major diseases like cancer, Alzheimer's disease, Parkinson's disease, etc. For the past few decades, pharmaceutical companies have explored new effective medications against inflammation. As a part of their detailed studies, many drug targets and drugs have been introduced against inflammation. In the present study, the inhibiting capacities of selected benzoic acid derivatives like gallic acid, vannilic acid, syringic acid and protocatechuic acid against secretory phospholipase A2 (sPLA2), a major enzyme involved in the inflammatory pathway, have been investigated. The detailed in vitro, biophysical and in silico studies carried out on these benzoic acid derivatives revealed that all the selected compounds have a uniform mode of binding in the active site of sPLA2 and are inhibitory in micromolar concentrations. The study also focuses on the non-selective inhibitory activity of an NSAID, aspirin, against sPLA2.

Interactions of selected indole derivatives with COX-2 and their in silico structure modifications towards the development of novel NSAIDs.

Cyclooxygenase-2 (COX-2) is an important enzyme responsible for the formation of potent inflammatory mediators like prostaglandins, prostacyclin and thromboxane. Hence, inhibition of COX-2 is one of the best ways to control the inflammation. Non-steroidal anti-inflammatory drugs can control inflammation by inhibiting Cyclooxygenase. Selective inhibition of COX-2 is preferable over the inhibition of COX-1 because of the fewer adverse effects produced. Molecular modeling and docking of 134 selected indole compounds were done against COX-2. The pharmacophore-based in silico structural modifications of the best scored compounds were carried out in order to enhance the binding affinity and selectivity. The modification resulted in derivatives with better binding energies than that of known COX-2 inhibitors. The four best derivatives in terms of the binding energies were selected and their binding stabilities were studied by molecular dynamics simulation methods.

Flavanone glycosides as acetylcholinesterase inhibitors: computational and experimental evidence.

Acetylcholinesterase hydrolyzes the neurotransmitter called acetylcholine and is crucially involved in the regulation of neurotransmission. One of the observable facts in the neurodegenerative disorders like Alzheimer's disease is the decrease in the level of acetylcholine. Available drugs that are used for the treatment of Alzheimer's disease are primarily acetylcholinesterase inhibitors with multiple activities. They maintain the level of acetylcholine in the brain by inhibiting the acetylcholinesterase function. Hence acetylcholinesterase inhibitors can be used as lead compounds for the development of drugs against AD. In the present study, the binding potential of four flavanone glycosides such as naringin, hesperidin, poncirin and sakuranin against acetylcholinesterase was analysed by using the method of molecular modeling and docking. The activity of the top scored compound, naringin was further investigated by enzyme inhibition studies and its inhibitory concentration (IC50) towards acetylcholinesterase was also determined.