Three-dimensional Quantitative Structure-activity Relationship Research Articles

Reduced estrogenic risks of a sunscreen additive: Theoretical design and evaluation of functionally improved salicylates

Salicylic esters (SEs), the widely used ultraviolet (UV) absorbers in sunscreen products, have been found to have health risks such as skin sensitization and estrogenic effects. This study aims to design SE substitutes that maintain high UV absorbance while reducing estrogenicity. Using molecular docking and Gaussian09 software for initial assessments and further application of a combination of two-dimensional and three-dimensional quantitative structure–activity relationships (2D-QSAR and 3D-QSAR, respectively) models, we designed 73 substitutes. The best-performing molecules, ethylhexyl salicylate (EHS)−5 and EHS-15, significantly reduced estrogenicity (44.54 % and 17.60 %, respectively) and enhanced UV absorbance (249.56 % and 46.94 %, respectively). Through screening for human health risks, we found that EHS-5 and EHS-15 were free from skin sensitivity and eye irritation and exhibited reduced skin permeability compared with EHS. Furthermore, the photolysis and synthetic pathways of EHS-5 and EHS-15 were deduced, demonstrating their good photodegradability and potential synthesizability. In addition, we analyzed the mechanisms underlying the changes in estrogenic effects and UV absorption properties. We identified covalent hydrogen bond basicity and acidity Propgen value for atomic molecular properties and the highest occupied molecular orbital eigenvalue as the main factors affecting the estrogenic effect and UV absorbance of SEs, respectively. This study focuses on the design and screening of SEs, exhibiting enhanced functionality, reduced health risks, and synthetic feasibility.

Three-Dimensional Quantitative Structure-Activity Relationship Study of Transient Receptor Potential Vanilloid 1 Channel Antagonists Reveals Potential for Drug Design Purposes.

Transient receptor potential vanilloid 1 (TRPV1) was reported to be a putative target for recovery from chronic pain, producing analgesic effects after its inhibition. A series of drug candidates were previously developed, without the ability to ameliorate the therapeutic outcome. Starting from previously designed compounds, derived from the hybridization of antagonist SB-705498 and partial agonist MDR-652, we performed a virtual screening on a pharmacophore model built by exploiting the Cryo-EM 3D structure of a nanomolar antagonist in complex with the human TRPV1 channel. The pharmacophore model was described by three pharmacophoric features, taking advantage of both the bioactive pose of the antagonist and the receptor exclusion spheres. The results of the screening were implemented inside a 3D-QSAR model, correlating with the negative decadic logarithm of the inhibition rate of the ligands. After the validation of the obtained 3D-QSAR model, we designed a new series of compounds by introducing key modifications on the original scaffold. Again, we determined the compounds' binding poses after alignment to the pharmacophoric model, and we predicted their inhibition rates with the validated 3D-QSAR model. The obtained values resulted in being even more promising than parent compounds, demonstrating that ongoing research still leaves much room for improvement.

Novel mandelic acid derivatives containing piperazinyls as potential candidate fungicides against Monilinia fructicola: Design, synthesis and mechanism study

Brown rot of stone fruit, a disease caused by the ascomycete fungus Monilinia fructicola, has caused significant losses to the agricultural industry. In order to explore and discover potential fungicides against M. fructicola, thirty-one novel mandelic acid derivatives containing piperazine moieties were designed and synthesized based on the amide skeleton. Among them, target compound Z31 exhibited obvious in vitro antifungal activity with the EC50 value of 11.8 mg/L, and significant effects for the postharvest pears (79.4 % protective activity and 70.5 % curative activity) at a concentration of 200 mg/L. Antifungal activity for the target compounds was found to be significantly improved by the large steric hindrance of the R1 groups and the electronegative of the piperazines in the molecular structure, according to a three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis. Further mechanism studies have demonstrated that the compound Z31 can disrupt cell membrane integrity, resulting in increased membrane permeability, release of intracellular electrolytes, and affect the normal growth of hyphae. Additional, morphological study also indicated that Z31 may disrupt the integrity of the membrane by inducing generate excess endogenous reactive oxygen species (ROS) and resulting in the peroxidation of cellular lipids, which was further verified by the detection of malondialdehyde (MDA) content. These studies have provided the basis for the creation of novel fungicides to prevent brown rot in stone fruits.

AI-based 3D-QSAR model of FDA-approved repurposed drugs for inhibiting sclerostin

BACKGROUND: Wnt activation promotes bone formation and prevents bone loss. The Wnt pathway antagonist sclerostin and additional anti-sclerostin antibodies were discovered as a result of the development of the monoclonal antibody romosozumab. These monoclonal antibodies greatly increase the risk of cardiac arrest. Three-dimensional quantitative structure-activity relationships (3D-QSAR) predicts biological activities of ligands based on their three-dimensional features by employing powerful chemometric investigations such as artificial neural networks (ANNs) and partial least squares (PLS). OBJECTIVE: In this study, ligand-receptor interactions were investigated using 3D-QSAR Comparative molecular field analysis (CoMFA). Estimates of steric and electrostatic characteristics in CoMFA are made using Lennard-Jones and Coulomb potentials. METHODS: To identify the conditions necessary for the activity of these molecules, fifty Food and Drug Administration (FDA)-approved medications were chosen for 3D-QSAR investigations and done by CoMFA. For QSAR analysis, there are numerous tools available. This study employed Open 3D-QSAR for analysis due to its simplicity of use and capacity to produce trustworthy results. Four tools were used for the analysis on this platform: Py-MolEdit, Py-ConfSearch, and Py-CoMFA. RESULTS: Maps that were generated were used to determine the screen’s r2 (Coefficient of Multiple Determinations) value and q2 (correlation coefficient). These numbers must be fewer than 1, suggesting a good, trustworthy model. Cross-validated (q2) 0.532 and conventional (r2) correlation values of 0.969 made the CoMFA model statistically significant. The model showed that hydroxamic acid inhibitors are significantly more sensitive to the steric field than the electrostatic field (70%) (30%). This hypothesis states that steric (43.1%), electrostatic (26.4%), and hydrophobic (20.3%) qualities were important in the design of sclerostin inhibitors. CONCLUSION: With 3D-QSAR and CoMFA, statistically meaningful models were constructed to predict ligand inhibitory effects. The test set demonstrated the model’s robustness. This research may aid in the development of more effective sclerostin inhibitors that are synthesised using FDA-approved medications.

Quantification- and structural-taste intensity of umami peptides from Agrocybe aegerita through quantitative structure-activity relationship

Agrocybe aegerita, one of the edible mushroom varieties, is popular among consumers for its umami taste. Umami peptides, including EV, EG, EY, ENG, ECG, DEL, DDL, PEG, PEEL, DGPL, and EDCS are the main umami compounds in A. aegerita. In this study, when the concentration of these 11 umami peptides was 5 mg/mL, the corresponding relative umami intensity (measured by MSG concentration) ranged from 4.457 to 5.240 mg/mL, with DDL being the highest. All umami peptides exhibited better umami taste under neutral and weakly acidic conditions (pH 6-7). EY and ENG, with a higher umami intensity at 70 °C, were more suitable for a wide application in thermally processed foods. Additionally, the relationship between the structure and strength of umami peptides was explored using a three-dimensional quantitative structure-activity relationship model with an R2 of 0.987. Overall, umami peptides in A. aegerita possess strong potential for application in food processing.

Homologous Design and Three-Dimensional Quantitative Structure-Activity Relationship Study of Acaricidal 2,4-Diphenyloxazolines Containing Different Heteroatoms and Alkyl Chains.

In order to speculate the three-dimensional structure of the potential binding pocket of the chitin synthase inhibitor, a series of 2,4-diphenyloxazoline derivatives with different lengths of alkyl chains and heteroatoms were designed and synthesized by a homologous strategy. The bioassay results indicate that both the length of the alkyl chains and the type of substituents can affect the acaricidal activity against mite eggs. Compounds containing chloropropyl, alkoxyalkyl, and para-substituted phenoxyalkyl or phenylthioalkyl groups exhibit good activity, while those containing steric hindrance substituents or carbonyl substituents on the benzene ring exhibit reduced activity. Three-dimensional quantitative structure-activity relationship (3D-QSAR) study showed that there may be a narrow hydrophobic region deep in the pocket, and the steric effect plays a more important role than the electrostatic effect. The current work will provide assistance for future molecular design and target binding research.

Design, synthesis and bactericidal activity of novel coumarin derivatives containing pyridinium salts

Coumarin is a natural product known for its diverse biological activities. While its antifungal properties in agricultural chemistry have been extensively studied, there is limited research on its antibacterial potential. In this study, we developed several novel coumarin derivatives by combining coumarin with pyridinium salt through molecular hybridization and chemical synthesis. Our findings reveal that most of these derivatives exhibit promising antibacterial activity. Among them, derivative A25 has been identified as the most effective compound based on three-dimensional quantitative structure-activity relationships. It demonstrates significant in vitro and in vivo activity against Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas oryzae pv. oryzicola (Xoc), and Xanthomonas campestris pv. citri (Xac), outperforming the commercially available thiediazole copper. Initial investigations into its mechanism of action suggest that A25 disrupts the cell membranes of Xoc and Xoo, thereby inhibiting bacterial growth. Additionally, A25 enhances the activity of defense enzymes in rice and modulates the expression of proteins related to the pyruvate metabolism pathway. This dual action contributes to rice's resistance against bacterial infestation. We anticipate that this study will serve as a foundation for the development of coumarin-based bactericides.

Design, Synthesis, and 3D-QASR of 2-Ar-1,2,3-triazole Derivatives Containing Hydrazide as Potential Fungicides.

A series of novel 2-Ar-1,2,3-triazole derivatives were designed and synthesized based on our previously discovered active compound 6d against Rhizoctonia solani. Most of these compounds exhibited good antifungal activity against R. solani at a concentration of 25 μg/mL. Based on the results of biological activity, we established a three-dimensional quantitative structure-activity relationship (3D-QSAR) model that guided the synthesis of compound 7y. Compound 7y exhibited superior activity against R. solani (EC50 = 0.47 μg/mL) compared to the positive controls hymexazol (EC50 = 12.80 μg/mL) and tebuconazole (EC50 = 0.87 μg/mL). Furthermore, compound 7y demonstrated better protective activity than the aforementioned two commercial fungicides in both detached leaf assays and greenhouse experiments, achieving 56.21% and 65.75% protective efficacy, respectively, at a concentration of 100 μg/mL. The ergosterol content was determined and molecular docking was performed to explore the mechanism of these active molecules. DFT calculation and MEP analysis were performed to illustrate the results of this study. These results suggest that compound 7y could serve as a novel 2-Ar-1,2,3-triazole lead compound for controlling R. solani.

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods.

Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to the regulation of various biological processes. Thus, HDACs play pivotal roles in various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews the structure and function of the four classes of human HDACs. While four HDAC inhibitors are currently available for treating hematological malignancies, numerous others are undergoing clinical trials. However, their non-selective toxicity necessitates ongoing research into safer and more efficient class-selective or isoform-selective inhibitors. Computational methods have aided the discovery of HDAC inhibitors with the desired potency and/or selectivity. These methods include ligand-based approaches, such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure-activity relationships, and structure-based virtual screening (molecular docking). Moreover, recent developments in the field of molecular dynamics simulations, combined with Poisson-Boltzmann/molecular mechanics generalized Born surface area techniques, have improved the prediction of ligand binding affinity. In this review, we delve into the ways in which these methods have contributed to designing and identifying HDAC inhibitors.

Design, Synthesis, and Biological Activity of Novel Triketone-Containing Phenoxy Nicotinyl Inhibitors of HPPD.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a crucial target enzyme in albino herbicides. The inhibition of HPPD activity interferes with the synthesis of carotenoids, blocking photosynthesis and resulting in bleaching and necrosis. To develop herbicides with excellent activity, a series of 3-hydroxy-2-(6-substituted phenoxynicotinoyl)-2-cyclohexen-1-one derivatives were designed via active substructure combination. The title compounds were characterized via infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopies, and high-resolution mass spectrometry. The structure of compound III-17 was confirmed via single-crystal X-ray diffraction. Preliminary tests demonstrated that some compounds had good herbicidal activity. Crop safety tests revealed that compound III-29 was safer than the commercial herbicide mesotrione in wheat and peanuts. Moreover, the compound exhibited the highest inhibitory activity against Arabidopsis thaliana HPPD (AtHPPD), with a half-maximal inhibitory concentration of 0.19 μM, demonstrating superior activity compared with mesotrione (0.28 μM) in vitro. A three-dimensional quantitative structure-activity relationship study revealed that the introduction of smaller groups to the 5-position of cyclohexanedione and negative charges to the 3-position of the benzene ring enhanced the herbicidal activity. A molecular structure comparison demonstrated that compound III-29 was beneficial to plant absorption and conduction. Molecular docking and molecular dynamics simulations further verified the stability of the complex formed by compound III-29 and AtHPPD. Thus, this study may provide insights into the development of green and efficient herbicides.

Study on β-glucosidase activators by 3D-QSAR, molecular docking and molecular dynamics simulation

To investigate the conformational relationship and mechanism of action of β-glucosidase (BGL) activators, a theoretical study of three-dimensional quantitative structure activity relationship, molecular docking, molecular dynamics (MD) simulations, and binding free energy analysis were performed. The results indicate that comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models had good stability and predictive ability, with r2cv/ r2pred values of 0.540/0.998 and 0.654/0.993, respectively. The derived contour maps of steric, electrostatic, and hydrogen bond donor field further displayed the modified information of these activators. Molecular docking and MD were performed on calcium diascorbate (CaAS) and L-Ascorbyl 2,6-Dipalmitate (L-ADP), which have good activating ability. The study indicates a positive interaction between the activators and the enzyme, and this interaction does not cause irreversible negative effects on the conformation of BGL. The MD results show that the total binding free energies of CaAS and L-ADP with BGL were −19.837 kJ/mol and −37.798 kJ/mol, respectively, and the binding force of the activators with BGL was mainly derived from hydrophobic interaction and hydrogen bonding. This study offers important guidance for the efficient use of BGL and for the research and development of effective activators.

Concurrent Optimizations of Efficacy and Blood-Brain Barrier Permeability in New Macrocyclic LRRK2 Inhibitors for Potential Parkinson's Disease Therapeutics.

The elevated activity of leucine-rich repeat kinase 2 (LRRK2) is implicated in the pathogenesis of Parkinson's disease (PD). The quest for effective LRRK2 inhibitors has been impeded by the formidable challenge of crossing the blood-brain barrier (BBB). We leveraged structure-based de novo design and developed robust three-dimensional quantitative structure-activity relationship (3D-QSAR) models to predict BBB permeability, enhancing the likelihood of the inhibitor's brain accessibility. Our strategy involved the synthesis of macrocyclic molecules by linking the two terminal nitrogen atoms of HG-10-102-01 with an alkyl chain ranging from 2 to 4 units, laying the groundwork for innovative LRRK2 inhibitor designs. Through meticulous computational and synthetic optimization of both biochemical efficacy and BBB permeability, 9 out of 14 synthesized candidates demonstrated potent low-nanomolar inhibition and significant BBB penetration. Further assessments of in vitro and in vivo effectiveness, coupled with pharmacological profiling, highlighted 8 as the promising new lead compound for PD therapeutics.

Discovery of Trisubstituted N-Phenylpyrazole Containing Diamides with Improved Insecticidal Activity.

To increase the structural diversity of insecticides and meet the needs of effective integrated insect management, the structure of chlorantraniliprole was modified based on a previously established three-dimensional quantitative structure-activity relationship (3D-QSAR) model. The pyridinyl moiety in the structure of chlorantraniliprole was replaced with a 4-fluorophenyl group. Further modifications of this 4-fluorophenyl group by introducing a halogen atom at position 2 and an electron-withdrawing group (e.g., iodine, cyano, and trifluoromethyl) at position 5 led to 34 compounds with good insecticidal efficacy against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Among them, compound IV f against M. separata showed potency comparable to that of chlorantraniliprole. IV p against P. xylostella displayed a 4.5 times higher potency than chlorantraniliprole. In addition, IV d and chlorantraniliprole exhibited comparable potencies against S. frugiperda. Transcriptome analysis showed that the molecular target of compound IV f is the ryanodine receptor. Molecular docking was further performed to verify the mode of action and insecticidal activity against resistant P. xylostella.

Novel 5-Sulfonyl-1,3,4-thiadiazole-Substituted Flavonoids as Potential Bactericides and Fungicides: Design, Synthesis, Three-Dimensional Quantitative Structure-Activity Relationship Studies.

Flavonoids, ubiquitous natural products, provide sources for drug discovery owing to their structural diversity, broad-spectrum pharmacological activity, and excellent environmental compatibility. To develop antibacterial and antifungal agents with novel mechanisms of action and innovative structures, a series of novel 5-sulfonyl-1,3,4-thiadiazole-substituted flavonoids were designed and synthesized, and their biological activities against seven agriculturally common phytopathogenic microorganisms were evaluated. The results of the antimicrobial bioassay showed that most of the target compounds displayed excellent inhibitory effects against Xanthomonas oryzae, Rhizoctonia solani, and Colletotrichum orbiculare. Compounds 1, 3, 7, 9, 13, and 14 exhibited remarkable antibacterial activity against X. oryzae pv. oryzae with EC50 values below 10 μg/mL, which were superior to bismerthiazol (70.89 μg/mL). Compound 2 (EC50 = 0.41 μg/mL) displayed the most effective inhibitory potency against R. solani in vivo, comparable protective effects with the positive control carbendizam. Preliminary mechanistic studies indicated that compound 2 induced disordered entanglement of hyphae, shrinkage of hyphal surfaces, extravasation of cellular contents, and vacuole swelling and rupture, which disrupted normal hyphal growth. Subsequently, compounds 35-53 with good antifungal activity were designed and synthesized based on reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) models. Compound 49 showed high efficacy and superior antifungal activity against R. solani, with an EC50 value of 0.28 μg/mL and a half-maximal effective concentration of 0.46 μg/mL.

Strategic development and validation of Isoquinoline-Derived inhibitors targeting ROCK1 kinase

Rho-associated coiled-coil containing kinases (ROCKs) have emerged as pivotal downstream effectors of small guanosine triphosphatases. In recent years, isoquinoline derivatives have garnered substantial attention as potent inhibitors of ROCK1 (RKIs). To delve deeper into their pharmacological properties and to identify potential inhibitors, we conducted an in-depth exploration of a series of RKIs derived from isoquinoline derivatives. This exploration encompassed a multifaceted approach, combining three-dimensional quantitative structure–activity relationship modeling, induced fit docking, and virtual screening. Our comparative molecular field analysis model (q2 = 0.609, R2 = 0.991, ONC = 6, and r2pred = 0.973) and the most robust comparative molecular similarity indices analysis model (q2 = 0.712, R2 = 0.998, ONC = 7, and r2pred = 0.89) exhibited commendable predictive accuracy, bolstered by robust validation parameters. To gain deeper insights into the mechanism of action of isoquinoline-based RKIs, we harnessed precise docking techniques, including induced fit docking, structural interaction fingerprints, and binding pose metadynamics simulations. Employing the PRRR_2 pharmacophore, we meticulously screened Enamine's HLL-460 compound library, unearthing thousands of isoquinoline compounds that aligned with the desired profile. Subsequently, we identified three promising compounds (DS01, DS02, and DS03) through Glide docking, each assessed at varying precision levels. These compounds underwent comprehensive evaluation for their drug-like properties, leveraging QikProp and SwissADME, ultimately unveiling their potential as novel and efficacious RKIs. Furthermore, bolstered by molecular dynamics simulations and validated through activity assays, the bioactivity of the screened molecules DS02, and DS03 was corroborated. DS02 and DS03, previously unreported for their activity against ROCK1, delivered exceptionally promising results. This comprehensive study not only elucidates validated strategies for drug development but also imparts invaluable insights into the design of potent RKIs.

Design, Synthesis, Antifungal Activity, and 3D-QASR of Novel Oxime Ether-Containing Coumarin Derivatives as Potential Fungicides.

Structural modification of natural products is an effective approach for improving antifungal activity and has, therefore, been used extensively in the development of new agrochemical products. In this work, a series of novel coumarin derivatives containing oxime ether structures were designed, synthesized, and evaluated for antifungal activity. Some of the designed compounds exhibited promising antifungal activities against tested fungi, and compounds 4a, 4c, 5a, and 6b had EC50 values equivalent to those of commercial fungicides. Compound 6b was the most promising candidate fungicide against Rhizoctonia solani (EC50 = 0.46 μg/mL). In vivo antifungal bioassays suggested that compounds 5a and 6b could serve as novel agricultural antifungals. Furthermore, microscopy demonstrated that compound 6b induced the sprawling growth of hyphae, distorted the outline of cell walls, and reduced mitochondrial numbers. Additionally, the effects of the substituent steric, electrostatic, hydrophobic, and hydrogen-bond fields were elucidated using an accurate and reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) model. The results presented here will guide the discovery of potential novel fungicides for plant disease control in agriculture.

Risk mitigation strategy and mechanism analysis of neonicotinoid pesticides on earthworms

Neonicotinoid insecticides (NNIs) are a new class of widely used insecticides with certain risks to non-target organisms, like earthworms. The gray correlation method was used to calculate the comprehensive risk effect value of acute toxicity (LC50) and bioaccumulation (logKow) of NNIs on earthworms. A comprehensive effects three-dimensional quantitative structure–activity relationship (3D-QSAR) model was constructed, using NNIs molecular structures and the comprehensive effect value as the independent and dependent variables, respectively. One of the representatives guadipyr (GUA) was selected as the template molecule for the molecular design and modification. A total of 63 NNIs alternatives were designed with a reduced comprehensive value higher than 10%, and as high as 42%. After screening, 15 NNIs alternatives were screened with decreased acute toxicity to earthworms, bioaccumulation effects and improved functional property. The calculated primary acute risk quotient of earthworms shows that the designed NNIs alternatives have lower earthworm risks (reduction of 70.48–99.99%). Results also found that the electronic, geometric and topological parameters of NNIs are the key descriptors that affect NNIs alternatives' toxicity. The number of hydrophobic interaction amino acid residues in NNIs molecules also contributes to the acute toxicity and the bioaccumulation of NNIs alternatives on earthworms. This study aims to design and screen functionally improved and environmentally friendly NNIs alternatives that have low risk to earthworms and provide theoretical methods and new ideas for the risk control and development of pesticides represented by NNIs.

A Potential Fungicide against Pseudoperonospora Cubensis: Design, Synthesis and 3D-QSAR of New Pyrazole-5-Carboxamide Derivatives.

Downy mildew is one of the major fungi causing significant economic losses to crops. The resistance of this fungus to current fungicides is increasing and new fungicides with a unique mode of action are needed. To find a novel pyrazole amide derivative as a potential fungicide. A series of pyrazole-5-carboxamide derivatives containing a diaryl ether were designed and synthesized by the Intermediate derivatization method (IDM). Their fungicidal activities against Pseudoperonospora cubensis (P. cubensis, cucumber downy mildew) were evaluated in the greenhouse. Bioassays indicated that several compounds exhibited excellent fungicidal activity against P. cubensis in vivo. In particular, T24 (EC50 = 0.88 mg L-1) had the highest activity compared with Dimethomorph and Fluazinam and other analogues. The relationship between the activity and the structure of these derivatives was analyzed, and an accurate and reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established to determine that electrostatic and steric fields had important effects on the improvement of fungicidal activity. The novel pyrazole-5-carboxamide derivative T24 can be considered a potential fungicide for P. cubensis control.

Scaffold hopping for designing of potent and selective CYP1B1 inhibitors to overcome docetaxel resistance: synthesis and evaluation

Cytochrome P450 1B1, a tumor-specific overexpressed enzyme, significantly impairs the pharmacokinetics of several commonly used anticancer drugs including docetaxel, paclitaxel and cisplatin, leading to the problem of resistance to these drugs. Currently, there is no CYP1B1 inhibition-based adjuvant therapy available to treat this resistance problem. Hence, in the current study, exhaustive in-silico studies including scaffold hopping followed by molecular docking, three-dimensional quantitative structure-activity relationships (3D-QSAR), molecular dynamics and free energy perturbation studies were carried out to identify potent and selective CYP1B1 inhibitors. Initially, scaffold hopping analysis was performed against a well-reported potent and selective CYP1B1 inhibitor (i.e. compound 3n). A total of 200 scaffolds were identified along with their shape and field similarity scores. The top three scaffolds were further selected on the basis of these scores and their synthesis feasibility to design some potent and selective CYP1B1 inhibitors using the aforementioned in-silico techniques. Designed molecules were further synthesized to evaluate their CYP1B1 inhibitory activity and docetaxel resistance reversal potential against CYP1B1 overexpressed drug resistance MCF-7 cell line. In-vitro results indicated that compounds 2a, 2c and 2d manifested IC50 values for CYP1B1 ranging from 0.075, 0.092 to 0.088 μM with at least 10-fold selectivity. At low micromolar concentrations, compounds 1e, 1f, 2a and 2d exhibited promising cytotoxic effects in the docetaxel-resistant CYP1B1 overexpressed MCF-7 cell line. In particular, compound 2a is most effective in reversing the resistance with IC50 of 29.0 ± 3.6 μM. All of these discoveries could pave the way for the development of adjuvant therapy capable of overcoming CYP1B1-mediated resistance. Communicated by Ramaswamy H. Sarma

A virtual insight into mushroom secondary metabolites: 3D-QSAR, docking, pharmacophore-based analysis and molecular modeling to analyze their anti-breast cancer potential

Breast cancer is a major issue of investigation in drug discovery due to its rising frequency and global dominance. Plants are significant natural sources for the development of novel medications and therapies. Medicinal mushrooms have many biological response modifiers and are used for the treatment of many physical illnesses. In this research, a database of 89 macro-molecules with anti-breast cancer activity, which were previously isolated from the mushrooms in literature, has been selected for the three-dimensional quantitative structure–activity relationships (3D-QSAR) studies. The 3D-QSAR model was necessarily used in Pharmacopoeia virtual evaluation of the database to develop novel MCF-7 inhibitors. With the known potential targets of breast cancer, the docking studies were achieved. Using molecular dynamics simulations, the targets’ stability with the best-chosen natural product molecule was found. Furthermore, the absorption, distribution, metabolism, excretion, and toxicity of three compounds, resulting after the docking study, were predicted. The compound C1 (Pseudonocardian A) showed the features of effective compounds because it has bioavailability from different coral species and is toxicity-free for the prevention of many dermatological illnesses. C1 is chemically active and possesses charge transfer inside the monomer, as seen by the band gaps of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) electrons. The reactivity descriptors ionization potential, electron affinity, chemical potential (μ), hardness (η), softness (S), electronegativity (χ), and electrophilicity index (ω) have been estimated using the energies of frontier molecular orbitals (HOMO–LUMO). Additionally, molecular electrostatic potential maps were created to show that the C1 is reactive. Communicated by Ramaswamy H. Sarma