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1.
Article in English | MEDLINE | ID: mdl-37921212

ABSTRACT

BACKGROUND: In the current scenario, breast cancer is measured as one of the most dangerous health issues. An effective therapeutic class of drugs known as aromatase inhibitors is dominant against estrogen receptor-positive breast cancer. However, there is an urgent need to create target-specific AIs with better anti-breast cancer profiles due to the increased toxicity and adverse effects related to currently existing anti-breast cancer drugs. OBJECTIVES: In the present study, we have designed 100 novel tiazole analogues as aromatase inhibitors and their pharmacophoric features are explored. METHOD: Molecular docking is applied in a series of 4-substituted-1, 2, 3-triazoles containing letrozole for their aromatase inhibitory effects. The aromatase inhibitory activity of the compound in a series varies from the range of (IC50 = 0.008-31.26 µM). A hydrogen atom positioned at R1 of triazole ring in compound (01) is responsible for the most potent compound (IC50 = 0.008µM) in the series of 28 compounds as compared to letrozole. The self-organizing molecular field study was used to assess the molecular characteristics and biological activities of substances in succession. The four models were developed from PLS and MLR methods. The PLS method was good for statistical analysis. The letrozole scaffold based 100 compounds were designed by selecting an effective pharmacophore responsible for aromatase inhibitory activity. The designed compound was placed on the previous SOMFA model as test set and their IC50 values were calculated. RESULT: Hydrogen bonds were established between the powerful molecule (01) and the essential residues Met 374 and Arg 115, which were responsible for the aromatase-inhibiting action. Cross-validated q2 (0.6349) & noncross-validated r2 (0.7163) were discovered in the statistical findings as having reliable predictive power. Among 100 designed compounds, seven compounds showed good aromatase inhibitory activities. CONCLUSION: The additional final SOMFA model created for the interactions between the enzyme & the letrozole blocker may be helpful for future modification and enhancement of the inhibitors of this crucial enzyme.

2.
J Biomol Struct Dyn ; 41(4): 1322-1341, 2023 03.
Article in English | MEDLINE | ID: mdl-34963408

ABSTRACT

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 (R2 = 0.9151) was best as compared to SOMFA and Gaussian Field (R2=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.


Subject(s)
Aromatase Inhibitors , Aromatase , Humans , Aromatase Inhibitors/pharmacology , Aromatase Inhibitors/chemistry , Molecular Docking Simulation , Quantitative Structure-Activity Relationship , Ligands , Estrogens
3.
Eur J Med Chem ; 219: 113442, 2021 Jul 05.
Article in English | MEDLINE | ID: mdl-33878562

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) is becoming dangerous to human beings due to easy transmission mode and leading to the difficult-to-treat situation. The rapid resistance development of MRSA to many approved antibiotics is of major concern. There is a lot of scope to develop novel, efficient, specific, and nontoxic drug candidates to fight against MRSA isolates. The interesting molecular structure and adaptable feature of oxadiazole moiety which are bioisosteres of esters and amides, and these functional groups show improved resistance to esterases mediated hydrolytic cleavage, attracting researchers to develop required novel antibiotics based on oxadiazole core. This review summarizes the developments of oxadiazole-containing derivatives as potent antibacterial agents against multidrug-resistant MRSA strains and discussing the structure-activity relationship (SAR) in various directions. The current survey is the highlight of the present scenario of oxadiazole hybrids on MRSA studies, covering articles published from 2011 to 2020. This collective information may become a good platform to plan and develop new oxadiazole-based small molecule growth inhibitors of MRSA with minimal side effects.


Subject(s)
Anti-Bacterial Agents/pharmacology , Oxadiazoles/chemistry , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Binding Sites , Drug Design , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Molecular Docking Simulation , Oxadiazoles/metabolism , Oxadiazoles/pharmacology , Structure-Activity Relationship
4.
Mini Rev Med Chem ; 21(20): 3144-3165, 2021.
Article in English | MEDLINE | ID: mdl-33463462

ABSTRACT

Breast 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 article 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 hormone- related breast cancer.


Subject(s)
Aromatase Inhibitors , Breast Neoplasms , Aromatase/metabolism , Aromatase Inhibitors/pharmacology , Aromatase Inhibitors/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Estrogens , Female , Humans , Sulfatases/metabolism
5.
Med Chem ; 17(6): 611-622, 2021.
Article in English | MEDLINE | ID: mdl-31951171

ABSTRACT

BACKGROUND: Owing to its potential to interfere in microtubule dynamics in the mitotic phase of cell cycle and selectively induce apoptosis in cancer cells without affecting normal cells, noscapine and its synthetic analogues have been investigated by other research groups in different cell lines for their capability to be used as anti-cancer agents. OBJECTIVE: The present study is focused on the investigation of the mode of binding of noscapinoids with tubulin, prediction of target binding affinities and mapping of their spatial fingerprints (shape and electrostatic). METHODS: Molecular docking assisted alignment based 3D-QSAR was used on a dataset (43 molecules) having an inhibitory activity (IC50 = 1.2-250 µM) against human lymphoblast (CEM) cell line. RESULTS AND CONCLUSION: Key amino acid residues of target tubulin were mapped for the binding of most potent noscapine analogue (Compound 11) and were compared with noscapine. Spatial fingerprints of noscapinoids for favorable tubulin inhibitory activity were generated and are proposed herewith for further pharmacophoric amendments of noscapine analogues to design and develop novel potent noscapine based anti-cancer agents that may enter into drug development pipeline.


Subject(s)
Noscapine/chemistry , Noscapine/pharmacology , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Tubulin/metabolism , Cell Line , Drug Evaluation, Preclinical , Humans , Molecular Docking Simulation , Noscapine/metabolism , Protein Conformation , Quantitative Structure-Activity Relationship , Tubulin/chemistry , Tubulin Modulators/metabolism
6.
Anticancer Agents Med Chem ; 21(9): 1191-1199, 2021.
Article in English | MEDLINE | ID: mdl-32842946

ABSTRACT

BACKGROUND: It takes a lot more studies to evaluate the molecular interaction of nanoparticles with the drug, their drug delivery potential and release kinetics. Thus, we have taken in silico and in vitro approaches into account for the evaluation of the drug delivery ability of the chitosan nanoparticles. OBJECTIVE: The present work was aimed to study the interaction of chitosan nanoparticles with appropriate aromatase inhibitors using in silico tools. Further, synthesis and characterization of chitosan nanoparticles having optimal binding energy and affinity between drug and polymer in terms of size, encapsulation efficiency were carried out. METHODS: In the current study, molecular docking was used to map the molecular interactions and estimation of binding energy involved between the nanoparticles and the drug molecules in silico. Letrozole is used as a model cytotoxic agent currently being used clinically; hence Letrozole loaded chitosan nanoparticles were formulated and characterized using photomicroscope, particle size analyzer, scanning electron microscope and fourier transform infra-red spectroscopy. RESULTS: Letrozole had the second-highest binding affinity within the core of chitosan with MolDock (-102.470) and Re-rank (-81.084) scores. Further, it was investigated that formulated nanoparticles were having superior drug loading capacity and high encapsulation efficiency. In vitro drug release study exhibited prolonged release of the drug from chitosan nanoparticles. CONCLUSION: Results obtained from the in silico and in vitro studies suggest that Letrozole loaded nanoparticles are ideal for breast cancer treatment.


Subject(s)
Antineoplastic Agents/pharmacology , Aromatase Inhibitors/pharmacology , Breast Neoplasms/drug therapy , Letrozole/pharmacology , Molecular Docking Simulation , Nanoparticles/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Chitosan/chemistry , Chitosan/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Letrozole/chemical synthesis , Letrozole/chemistry , Molecular Structure , Polymers/chemistry , Polymers/pharmacology , Structure-Activity Relationship
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