Pharmaceutical Sciences and Natural Products - Research Publications

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Subject: search.filters.subject.3D-QSAR

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    Identification of 1,3,4-oxadiazoles as tubulin-targeted anticancer agents: a combined field-based 3D-QSAR, pharmacophore model-based virtual screening, molecular docking, molecular dynamics simulation, and density functional theory calculation approach
    (Taylor and Francis Ltd., 2023-09-11T00:00:00) Das, Agnidipta; Sarangi, Manaswini; Jangid, Kailash; Kumar, Vijay; Kumar, Amit; Singh, Praval Pratap; Kaur, Kamalpreet; Kumar, Vinod; Chakraborty, Sudip; Jaitak, Vikas
    Cancer is one of the most prominent causes of death worldwide and tubulin is a crucial protein of cytoskeleton that maintains essential cellular functions including cell division as well as cell signalling, that makes an attractive drug target for cancer drug development. 1,3,4-oxadiazoles disrupt microtubule causing G2-M phase cell cycle arrest and provide anti-proliferative effect. In this study, field-based 3D-QSAR models were developed using 62 bioactive anti-tubulin 1,3,4-oxadiazoles. The best model characterized by PLS factor 7 was rigorously validated using various statistical parameters. Generated 3D-QSAR model having high degree of confidence showed favourable and unfavourable contours around 1,3,4-oxadiazole core that assisted in defining proper spatial positioning of desired functional groups for better bioactivity. A five featured pharmacophore model (AAHHR_1) was developed using same ligand library and validated through enrichment analysis (BEDROC160.9 value = 0.59, Average EF 1% = 27.05, and AUC = 0.74). Total 30,212 derivatives of 1,3,4-oxadiazole obtained from PubChem database was prefiltered through validated pharmacophore model and docked in XP mode on binding cavity of tubulin protein (PDB code: 1SA0) which led into the identification of 11 HITs having docking scores between ?7.530 and ?9.719 kcal/mol while the reference compound Colchicine exerted docking score of ?7.046 kcal/mol. Following the analysis of MM-GBSA and ADME studies, HIT1 and HIT4 emerged as the two promising hits. To verify their thermodynamic stability at the target site, molecular dynamic simulations were carried out. Both HITs were further subjected to DFT analysis to determine their HOMO-LUMO energy gap for ensuring their biological feasibility. Finally, molecular docking based structural exploration for 1,3,4-oxadiazoles to set up a lead of Formula I for further advancements of tubulin polymerization inhibitors as anti-cancer agents. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.
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    Molecular docking, 3D-QSAR and simulation studies for identifying pharmacophoric features of indole derivatives as 17?-hydroxysteroid dehydrogenase type 5 (17?-HSD5) inhibitors
    (Taylor and Francis Ltd., 2023-02-06T00:00:00) Kulkarni, Swanand; Singh, Yogesh; Biharee, Avadh; Bhatia, Neha; Monga, Vikramdeep; Thareja, Suresh
    Excess of androgens leads to various diseases such as Poly-Cystic Ovarian Syndrome, Prostate Cancer, Hirsutism, Obesity and Acne. 17?-Hydroxysteroid Dehydrogenase type 5 (17?-HSD5) converts androstenedione into testosterone peripherally, thereby significantly contributing to the development of these diseases. Indole-bearing scaffolds are reported as potential 17?-HSD5 inhibitors for the manifestation of diseases arising due to androgen excess. In the present work, we have extensively performed a combination of molecular docking, Gaussian field-based 3D-QSAR, Pharmacophore mapping and MD-simulation studies (100 ns) to identify the pharmacophoric features of indole-based compounds as potent 17?-HSD5 inhibitors. Molecular simulation studies of the most potent compound in the binding pocket of enzyme revealed that the compound 11 was stable in the binding pocket and showed good binding affinity through interactions with various residues of active site pocket. The Molecular mechanics Generalized Born surface area continuum solvation (MM/GBSA) and Molecular mechanics Poisson�Boltzmann surface area (MM/PBSA) calculations revealed that the compound 11 possessed a free binding energy of ?36.36 kcal/mol and ?7.00 kcal/mol, respectively, which was better as compared to reference compound Desmethyl indomethacin (DES). The developed pharmacophore will be helpful to design novel indole-based molecules as potent 17?-HSD5 inhibitors for the treatment of various androgenic disorders. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.
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    Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine-sulfonamide hybrids as selective BRAFV600E inhibitors
    (Royal Society of Chemistry, 2022-10-21T00:00:00) Singh, Ankit Kumar; Novak, Jurica; Kumar, Adarsh; Singh, Harshwardhan; Thareja, Suresh; Pathak, Prateek; Grishina, Maria; Verma, Amita; Yadav, Jagat Pal; Khalilullah, Habibullah; Pathania, Vikas; Nandanwar, Hemraj; Jaremko, Mariusz; Emwas, Abdul-Hamid; Kumar, Pradeep
    The �RAS-RAF-MEK-ERK� pathway is an important signaling pathway in melanoma. BRAFV600E (70-90%) is the most common mutation in this pathway. BRAF inhibitors have four types of conformers: type I (?C-IN/DFG-IN), type II (?C-IN/DFG-OUT), type I1/2 (?C-OUT/DFG-IN), and type I/II (?C-OUT/DFG-OUT). First- and second-generation BRAF inhibitors show resistance to BRAFV600E and are ineffective against malignancies induced by dimer BRAF mutants causing �paradoxical� activation. In the present study, we performed molecular modeling of pyrimidine-sulfonamide hybrids inhibitors using 3D-QSAR, molecular docking, and molecular dynamics simulations. Previous reports reveal the importance of pyrimidine and sulfonamide moieties in the development of BRAFV600E inhibitors. Analysis of 3D-QSAR models provided novel pyrimidine sulfonamide hybrid BRAFV600E inhibitors. The designed compounds share similarities with several structural moieties present in first- and second-generation BRAF inhibitors. A total library of 88 designed compounds was generated and molecular docking studies were performed with them. Four molecules (T109, T183, T160, and T126) were identified as hits and selected for detailed studies. Molecular dynamics simulations were performed at 900 ns and binding was calculated. Based on molecular docking and simulation studies, it was found that the designed compounds have better interactions with the core active site [the nucleotide (ADP or ATP) binding site, DFG motif, and the phospho-acceptor site (activation segment) of BRAFV600E protein than previous inhibitors. Similar to the FDA-approved BRAFV600E inhibitors the developed compounds have [?C-OUT/DFG-IN] conformation. Compounds T126, T160 and T183 interacted with DIF (Leu505), making them potentially useful against BRAFV600E resistance and malignancies induced by dimer BRAF mutants. The synthesis and biological evaluation of the designed molecules is in progress, which may lead to some potent BRAFV600E selective inhibitors. � 2022 The Royal Society of Chemistry.
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    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, Suresh
    Aromatase, 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.
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    Molecular dynamics and 3D-QSAR studies on indazole derivatives as HIF-1? inhibitors
    (Taylor and Francis Ltd., 2022-03-23T00:00:00) Singh, Yogesh; Sanjay, Kulkarni Swanand; Kumar, Pradeep; Singh, Satwinder; Thareja, Suresh
    Hypoxia-inducible factor (HIF) is a transcriptional factor which plays a crucial role in tumour metastasis thereby responsible for development of various forms of cancers. Indazole derivatives have been reported in the literature as potent HIF-1? inhibitor via interaction with key residues of the HIF-1? active site. Taking into consideration the role HIF-1? in cancer and potency of indazole derivative against HIF-1?; it was considered of interest to correlate structural features of known indazole derivatives with specified HIF-1? inhibitory activity to map pharmacophoric features through Three-dimensional quantitative structural activity relationship (3D-QSAR) and pharmacophore mapping. Field and Gaussian based 3D-QSAR studies were performed to realize the variables influencing the inhibitory potency of HIF-1? inhibitors. Field and Gaussian- based 3D-QSAR models were validated through various statistical measures generated by partial least square (PLS). The steric and electrostatic maps generated for both 3D-QSAR provide a structural framework for designing new inhibitors. Further; 3D-maps were also helpful in understanding variability in the activity of the compounds. Pharmacophore mapping also generates a common five-point pharmacophore hypothesis (A1D2R3R4R5_4) which can be employed in combination with 3D-contour maps to design potent HIF-1? inhibitors. Molecular docking and molecular dynamics (MD) simulation of the most potent compound 39 showed good binding efficiency and was found to be quite stable in the active site of the HIF-1? protein. The developed 3D-QSAR models; pharmacophore modelling; molecular docking studies along with the MD simulation analysis may be employed to design lead molecule as selective HIF-1? inhibitors for the treatment of Cancer. � 2022 Informa UK Limited, trading as Taylor & Francis Group.