Molecular modelling studies in explaining the higher GPVI antagonistic activity of the racemic 2-(4-methoxyphenylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide than its enantiomers.

The GPVI receptor on the platelets plays a major role in inhibiting arterial thrombosis with limited risk of bleeding and is considered a potential anti-thrombotic target for arterial thrombosis. In the reported anti-thrombotics, tetrahydropyridoindoles, the title compound was the best inhibitor of the collagen mediated platelet aggregation by antagonizing the platelet receptor GPVI. Interestingly, the racemic title compound showed better antagonism (IC50 racemate = 6.7 µM) than either of its enantiomers (IC50 S enantiomer = 25.3 µM; IC50 R enantiomer = 126.3 µM). In order to explain this, the molecular modelling approaches viz. site map analysis, protein-protein docking and molecular dynamics simulation were carried out, which led to the identification of a second binding site located near the primary antagonist binding site known to bind losartan. The induced fit docking studies for both the enantiomers at the primary and secondary binding sites showed that the S-enantiomer has better interactions at the primary binding site than the R-enantiomer, while the R-enantiomer has better interactions at the secondary site than the S-enantiomer. Hence, the overall interactions of the racemic compound containing equimolar mixture may be higher than any one of the enantiomers and may explain the higher activity than its enantiomers of the racemic compound.

Modelling inhibition of avian aromatase by azole pesticides.

The potential effects of pesticides and their metabolites on the endocrine system are of major concern to wildlife and human health. In this context, the azole pesticides have earned special attention due to their cytochrome P450 aromatase inhibition potential. Cytochrome P450 aromatase (CYP19) catalyses the conversion of androstenedione and testosterone into oestrone and oestradiol, respectively. Thus, aromatase modulates the oestrogenic balance essential not only for females, but also for male physiology, including gonadal function. Its inhibition affects reproductive organs, fertility and sexual behaviour in humans and wildlife species. Several studies have shown that azole pesticides are able to inhibit human and fish aromatases but the information on birds is lacking. Consequently, it appeared to be of interest to estimate the aromatase inhibition of azoles in three different avian species, namely Gallus gallus, Coturnix coturnix japonica and Taeniopygia guttata. In the absence of the crystal structure of the aromatase enzyme in these bird species, homology models for the individual avian species were constructed using the crystal structure of human aromatase (hAr) (pdb: 3EQM) that showed high sequence similarity for G. gallus (82.0%), T. guttata (81.9%) and C. japonica (81.2%). A homology model with Oncorhynchus mykiss (81.9%) was also designed for comparison purpose. The homology-modelled aromatase for each avian and fish species and crystal structure of human aromatase were selected for docking 46 structurally diverse azoles and related compounds. We showed that the docking behaviour of the chemicals on the different aromatases was broadly the same. We also demonstrated that there was an acceptable level of correlation between the binding score values and the available aromatase inhibition data. This means that the homology models derived on bird and fish species can be used to approximate the potential inhibitory effects of azoles on their aromatase.

Molecular modelling studies on 2-substituted octahydropyrazinopyridoindoles for histamine H2 receptor antagonism.

The human histamine H2 receptor (hH2HR) is a G-protein coupled receptor protein with seven transmembrane (TM)-spanning helices primarily involved in regulation of gastric acid secretion. Antagonists targeting hH2HR are useful in the treatment of hyperacidic conditions such as peptic ulcers, gastresophageal reflux disease and gastrointestinal bleeding. We have previously reported the antagonism of 2-substituted pyrazinopyridoindoles at the human histamine H1 receptor and mode of binding of these compounds at the hH1HR using in silico methods. Interestingly, some of the compounds in the series also showed promising activity towards hH2HR that prompted us to investigate the mode of binding of these compounds at hH2HR. In the absence of the crystal structure of hH2HR a homology model has been constructed using multiple sequence alignment, using the X-ray crystal structures of Turkey ß1-adrenergic receptor (tß1AR), Human histamine H1 receptor (hH1HR), Human ß2-adrenergic receptor (hß2AR) and Human D3 dopamine receptor (hD3R). The important residues for binding were depicted in TMIII, TMV, TMVI and TMVII by the homology modelled hH2HR for 2-substituted pyrazinopyridoindoles. A comparative study for deducing the selectivity regarding the binding towards hH1HR and hH2HR has been carried out, which may be useful in designing of selective hH1HR/hH2HR antagonists in these classes of compounds.

Docking studies of novel pyrazinopyridoindoles class of antihistamines with the homology modelled H(1)-receptor.

Histamine is an important neurotransmitter as it controls a multitude of physiological functions by activating specific receptors on target cells. It exerts its effects by binding to four different histamine receptors (H(1)-H(4)), which all belong to the large family of G protein-coupled receptors (GPCRs). Research and development of H(1) ligand has largely focused on antagonists which are used for their anti-allergy effects in the periphery. Recent understanding of the clinical importance of H(1) receptors in brain, however, suggests the pharmacotherapeutic potential of H(1) agonists in neurodegenerative and neuropsychiatric disorders. Despite the therapeutic importance of the H(1) receptor, for many years the molecular features of the H(1) receptor protein had been unknown. In view of the recently reported crystal structure of human H(1) receptor and in continuation of our work on 3D-pharmacophore on antihistamine H(1) and homology model of histamine H(1) receptor, docking studies have been carried out on some promising pyrazinopyridoindole class of antihistamine H(1), including two outliers, to validate our earlier reported models/hypotheses on H(1)-receptor, where a good explanation between estimated and observed activities has been obtained. In addition, the docking study also provided insights about the optimal activity of the outliers, for which no explanation was reported previously.

Pharmacophore modelling, molecular docking and virtual screening for EGFR (HER 1) tyrosine kinase inhibitors.

A pharmacophore model has been developed using diverse classes of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors useful in the treatment of human tumours. Among the top 10 generated hypotheses, the second hypothesis, with one hydrogen bond acceptor, one ring aromatic and three hydrophobic features, was found to be the best on the basis of Cat Scramble validation as well as test set prediction (r(training) = 0.89, r(test) = 0.82). The model also maps well to the external test set molecules as well as clinically active molecules and corroborates the docking studies. Finally, 10 hits were identified as potential leads after virtual screening of ZINC database for EGFR TK inhibition. The study may facilitate the designing and discovery of novel EGFR TK inhibitors.