Aravinda Pai

Novel flavonol analogues as potential inhibitors of JMJD3 histone demethylase—A study based on molecular modelling

Epigenetic modulation of gene expression has drawn enormous attention among researchers globally in the present scenario. Since their discovery, Jmj-C histone demethylases were identified as useful markers in understanding the role of epigenetics in inflammatory conditions and in cancer as well. This has created arousal of interest in search of suitable candidates. Potential inhibitors from various other scaffolds such as hydroxyquinolines, hydroxamic acids and triazolopyridines have already been identified and reported. In this direction, our present study attempts to target one of the important members of the family- namely JMJD3 (also known as KDM6B), that plays a pivotal role in inflammatory and immune reactions. Using molecular modeling approaches, myricetin analogues were identified as promising inhibitors of JMJD3. Extensive literature review showed myricetin as the most promising flavonol inhibitor for this enzyme. It served as a prototype for our study and modification of its scaffold led to generation of analogues. The ZINC database was used as a repository for natural compounds and their analogues. Using similarity search options, 65 analogues of myricetin were identified and screened against JMJD3 (PDB ID: 4ASK), using the high throughput virtual screening and ligand docking tools in Maestro Molecular Modeling platform (version 10.5) from Schrödinger, LLC. 8 analogues out of 65 were identified as the most appropriate candidates which gave the best pose in ligand docking. Their binding mode and energy calculations were analysed using induced fit docking (IFD) and prime-MMGBSA tool, respectively. Thus, our findings highlight the most promising analogues of myricetin with comparable binding affinity as well as binding energy than their counterparts that could be taken for further optimisation as inhibitors of JMJD3 in both in vitro and in vivo screening studies.

Application of two-dimensional binary fingerprinting methods for the design of selective Tankyrase I inhibitors

In the present study, five important binary fingerprinting techniques were used to model novel flavones for the selective inhibition of Tankyrase I. From the fingerprints used: the fingerprint atom pairs resulted in a statistically significant 2D QSAR model using a kernel-based partial least square regression method. This model indicates that the presence of electron-donating groups positively contributes to activity, whereas the presence of electron withdrawing groups negatively contributes to activity. This model could be used to develop more potent as well as selective analogues for the inhibition of Tankyrase I.Graphical AbstractSchematic representation of 2D QSAR work flow

Application of Molecular Descriptors in Modern Computational Drug Design –An Overview

The last decade witnessed several scientific experiments with the aim to correlate the structure of chemical entities to their biological activities, toxicities and other molecular properties. Chemical species are mathematically represented based on specified algorithms in molecular descriptors. They play extremely important role in the field of chemistry, pharmacy, environmental toxicology and health research. Till today, more than 5000 molecular descriptors being reported and are calculated mainly using dedicated softwares, which are run on advanced machines. Molecular descriptors play important roles in the fields of quantitative structure–activity relationship studies (QSAR) as well as quantitative structure– property relationship studies (QSPRs).The path breaking progress in the field of chemoinformatics has showed us new paths for identifying key links between the molecular structure and their biological properties. In the present review, some of the pharmaceutically important molecular descriptors and their applications are presented.

Computational Approach for the Design of Novel Tankyrase Inhibitors: A Rational Study based on Pharmacophore and Atom based 3D QSAR

Pharmacophore based screening was undertaken for a set of 30 flavones exhibiting Tankyrase I inhibitory activity. The two isoenzymes Tankyrase I and Tankyrase II share 80% sequence homology. This gives rise to the fine tuning required in the designing of small molecules wchich can selectively inhibit one or the other. In a recent study it was reported that, small molecule inhibitors of Tankyrases will be benificial in certain types of cancers like colorectal cancers. In future it may be a slective target for cancers like colorectal cancer.Four feature pharmacophores with one H bond acceptor and three aromatic rings were developped.The hypothesis ARRR2 was considered as best hypothesis ,which gave a statistically significant three dimensional QSAR model with corresponding statistical parameters (0.9028 as r2 value and 0.8548 as q2 value). The generated model was applied sucessfully on a set of both training and test set molecules. The squared corelation coefficient of 0.85 was observed between actual and predicted values in test set. The squared corelation coefficient of 0.96 was observed between actual and predicted value in training set. The built model will be useful in predicting the structural requirements needed for the selective inhibition of Tankyrase I.

In-Silico and In-Vitro correlation studies of natural β-secretase inhibitor: An approach towards Alzheimer’s Disease

Alzheimer’s disease (AD) is one among the common type of dementia in elder people above the age group of 65 years. This was once considered a rare disorder but in recently was considered as a great threat and risk factor to the elderly community above 60 years. AD is also considered a highly prevalent neurodegenerative disease. AD is characterized by loss of neuron and disturbed signal between cells in the brain. The neurotransmitter deficit is discovered in AD include acetylcholine (ACh). The major pathophysiological character of AD are the accumulation of extracellular neuritic plaques and neurofibrillary tangles in brain specially located in the memory related areas. The neuritic plaques are composed of β-amyloid peptide with 40 to 42 residues, on hydrolysis of amyloid precursor protein (APP) by the β-secretase 1 (BACE-1). Inhibition of β-secretase is one of the most promising treatment for AD. Ayurveda is one of the oldest system of medicine which is practiced till today and is gaining importance due to its unique principles and usage of many crude drugs for memory related disorders. Ashwagandha and pepper widely used in Ayurveda, in the present work molecular modelling techniques such as extra precision docking of natural BACE inhibition and in-vitro β-secretase inhibition assay was done on withanolide and piperine. Both the natural marker compounds showed promising inhibitory activity and proved the potential in treating memory related disorders.

Cognitive Enhancement and Neuroprotective Effects of Ancient Ayurvedic Medicinal Plant Celastrus Paniculatus: An Overview

Celastrus paniculatus, commonly known as Malkangani and Jyothishmati. Which is a traditional medicinal plant used in Ayurveda used for various purposes as a memory enhancer, analgesic, antiepileptic agent, antiinflammatory and sedative. The seed extracts are extensively investigated for various neuropharmacological actions and other reports are available confirming that the plant and their extract have nontropic action. It is also evaluated for the analgesic, anti-inflammatory, and anticonvulsantaction. The drug is also included in many formulations as one of the content which is available in market used for memory related problems. Alzheimer’s disease is a most common type of dementia characterized by progressive neuronal degeneration. Enhancement of the duration of life in human beings especially in developing as well as developed countries have resulted in increment in the patients number with dementia proportionally. Alzheimer’s disease (AD) is considered to be one of the main death cause in aged and elderly people. Therefore, the present paper is a complete review of the various pharmacological effects especially Alzhiemers disease of Celastrus paniculatus.