Pharmaceutical Sciences and Natural Products - Research Publications
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Item Multifaceted 3D-QSAR analysis for the identification of pharmacophoric features of biphenyl analogues as aromatase inhibitors(Taylor and Francis Ltd., 2021-12-29T00:00:00) Banjare, Laxmi; Singh, Yogesh; Verma, Sant Kumar; Singh, Atul Kumar; Kumar, Pradeep; Kumar, Shashank; Jain, Akhlesh Kumar; Thareja, SureshAromatase, a cytochrome P450 enzyme, is responsible for the conversion of androgens to estrogens, which fuel the multiplication of cancerous cells. Inhibition of estrogen biosynthesis by aromatase inhibitors (AIs) is one of the highly advanced therapeutic approach available for the treatment of estrogen-positive breast cancer. Biphenyl moiety aids lipophilicity to the conjugated scaffold and enhances the accessibility of the ligand to the target. The present study is focused on the investigation of, the mode of binding of biphenyl with aromatase, prediction of ligand-target binding affinities, and pharmacophoric features essential for favorable for aromatase inhibition. A multifaceted 3D-QSAR (SOMFA, Field and Gaussian) along with molecular docking, molecular dynamic simulations and pharmacophore mapping were performed on a series of biphenyl bearing molecules (1�33) with a wide range of aromatase inhibitory activity (0.15�920 nM). Among the generated 3D-QSAR models, the Force field-based 3D-QSAR model (R 2 = 0.9151) was best as compared to SOMFA and Gaussian Field (R 2=0.7706, 0.9074, respectively). However, all the generated 3D-QSAR models were statistically fit, robust enough, and reliable to explain the variation in biological activity in relation to pharmacophoric features of dataset molecules. A four-point pharmacophoric features with three acceptor sites (A), one aromatic ring (R) features, AAAR_1, were obtained with the site and survival score values 0.890 and 4.613, respectively. The generated 3D-QSAR plots in the study insight into the structure�activity relationship of dataset molecules, which may help in the designing of potent biphenyl derivatives as newer inhibitors of aromatase. Communicated by Ramaswamy H. Sarma. � 2021 Informa UK Limited, trading as Taylor & Francis Group.Item Dual Aromatase-Sulphatase Inhibitors (DASIs) for the Treatment of Hormone Dependent Breast Cancer(Bentham Science Publishers, 2021-01-19T00:00:00) Banjare, Laxmi; Jain, Akhlesh Kumar; Thareja, SureshBreast cancer is the most frequently diagnosed cancer in women and the second most common form of cancer, causing death after lung cancer, all across the globe at an alarming rate. The level of estrogens in breast cancer tissues of postmenopausal women is 10-40 folds higher than the non-carcinogenic breast tissues. As a result of this greater level of estrogen, breast tissue becomes more prone to develop breast cancer; mainly, estradiol plays a significant role in the initiation and development of hormone-dependent breast cancer. Androstenedione, Adrenal dehydroepiandrosterone sulfate, and estrone-sulfate also play an important role as precursors for estrogen biosynthesis. Estrogen deprivation exhibits an attractive phenomenon in the advancement of ideal therapeutics for the treatment of breast cancer. Inhibition of aromatase and sulphatase emerged as an attractive therapy for the treatment of hormone-dependent breast cancer via deprivation of estrogen by different pathways. The cocktail of aromatase and sulphatase inhibitors known as Dual Aromatase-sulphatase Inhibitors (DASIs) emerged as an attractive approach for effective estrogen deprivation. The present review arti-cle focused on the journey of dual aromatase-sulphatase inhibitors from the beginning to date (2020). Keeping in view the key observations, this review may be helpful for medicinal chemists to design and develop new and efficient dual aromatase-sulphatase inhibitors for the possible treatment of hor-mone-related breast cancer. � 2021 Bentham Science Publishers.Item De novo designing, assessment of target affinity and binding interactions against aromatase: Discovery of novel leads as anti-breast cancer agents(Springer, 2020-11-13T00:00:00) Verma, Sant Kumar; Ratre, Pooja; Jain, Akhlesh Kumar; Liang, Chengyuan; Gupta, Ghanshyam Das; Thareja, SureshAromatase inhibitors (AIs) have been emerged as promising anti-cancer agents for the treatment of hormone dependent breast cancer (HDBC) in women because of their excellent ability of inhibiting oestrogen synthesis. Here, we have implicated structure-based comprehensive approaches to discover novel drug/lead-like AIs. The molecular modelling and energy optimization were performed using Chem Office package. The e-LEA3D web server was used to design novel drug/lead-like AIs as well as generation of ADME/drug-likeness parameters. Target binding affinities and mode of binding interactions were mapped using Molegro Virtual Docker (MVD) to re-optimize the best de novo generated molecules. We have successfully designed novel AIs (compounds 1�7) using de novo technique performed on e-LEA3D. All the designed molecules were found optimum drug-like candidates based on various in silico screening parameters including �rule of five�. The energy optimized conformers of generated molecules (1�7) were docked in the active site, corresponding to co-crystallized androstenedione (ASD), of aromatase to predict ligand-target binding affinity and their binding interactions. The molecules (1�7) showed comparable to higher binding affinity towards aromatase with MolDock Score ranges from ? 134.881 to ? 152.453�Kcal/mol as compared with natural substrate ASD (? 128.639�Kcal/mol) and standard letrozole (? 136.784�Kcal/mol). The de novo designed molecules (1�7) can be developed as novel AIs, and their binding properties can be used for the further designing of newer AIs by medicinal chemists. � 2020, Springer Science+Business Media, LLC, part of Springer Nature.