Bioactivity Score Research Articles

Molecular hybrid of 1,2,3-triazole and schiff base as potential antibacterial agents: DFT, molecular docking and ADME studies

Hybrid drugs help combat antibacterial drug resistance, which is an increasing problem globally. In addition to saving time and money, hybrid drugs offer multiple benefits. Using the triazole precursor compound 5 in conjunction with primary amines, a series of novel 1,2,3-triazole and Schiff base compounds were synthesized (6–16). Their chemical structures were characterized using 1H NMR, 13C NMR, FTIR, CHN-elemental, high-resolution mass spectrometry and SC-XRD analyses. All the compounds showed good antibacterial activities against twelve bacterial strains at different concentrations. From the minimum inhibitory concentration and cytotoxicity studies, compounds 7, 9, 10, 11, 12 and 15 were selected as the most potent potential drug candidates against Mycobacterium smegmatis, Proteus mirabilis, Escherichia coli and Klebsiella pneumonia. Molecular docking studies of the most active compounds were done against their specific bacteria targets. Experimentally observed structure-activity relationships (SARs) for the most active compounds are consistent with molecular docking studies, indicating that benzylic (7 and 9), heterocyclic (10, 11, and 12) and electron-withdrawing (15) subunits enhance antibacterial activity. The absorption, distribution, metabolism, and excretion (ADME) parameter, Molinspiration bioactivity score, and the PreADMET properties revealed that most of the synthesized compounds possess desirable physicochemical properties for druglikeness and may be considered as orally active potential drugs.

Design, synthesis, characterization, molecular docking studies, molecular properties, toxicity, and bioactivity score prediction evaluation of novel chalcone-sulfonate hybrid derivatives

Novel chalcone-sulfonate hybrid derivatives were synthesized by a triethylamine-based method and characterized 13C NMR, 1H NMR, and HRMS. The potential inhibitory effects of the synthesized compounds on acetylcholinesterase, butyrylcholinesterase, pancreatic lipase, glutathione s-transferase, tyrosinase, and alpha-amylase enzymes were evaluated by in silico method. The chalcone-sulfonate hybrid derivatives were found to exhibit more effective binding affinity than the glutathione s-transferase, tyrosinase, pancreatic lipase, and alpha-amylase enzyme standards. In addition, six compounds showed more potent affinity values than the acetylcholinesterase standard. Also, seven compounds showed more effective affinity values than the butyrylcholinesterase standard. Furthermore, the absorption distribution, metabolism, and excretion properties (ADME), molecular properties, estimation of toxicity, and bioactivity scores of chalcone-sulfonate hybrid derivatives were evaluated.

Design and synthesis of 2-amino-4,6-diarylpyrimidine derivatives as potent α-glucosidase and α-amylase inhibitors: structure–activity relationship, in vitro, QSAR, molecular docking, MD simulations and drug-likeness studies

In the present study, a series of 2-amino-4,6-diarylpyrimidine derivatives was designed, synthesized, characterized and evaluated for their in vitro α-glucosidase and α-amylase enzyme inhibition assays. The outcomes proved that this class of compounds exhibit considerable inhibitory activity against both enzymes. Among the target compounds, compounds 4p and 6p demonstrated the most potent dual inhibition with IC50 = 0.087 ± 0.01 μM for α-glucosidase; 0.189 ± 0.02 μM for α-amylase and IC50 = 0.095 ± 0.03 μM for α-glucosidase; 0.214 ± 0.03 μM for α-amylase, respectively as compared to the standard rutin (IC50 = 0.192 ± 0.02 μM for α-glucosidase and 0.224 ± 0.02 μM for α-amylase). Remarkably, the enzyme inhibition results indicate that test compounds have stronger inhibitory effect on the target enzymes than the positive control, with a significantly lower IC50 value. Moreover, these series of compounds were found to inhibit α-glucosidase activity in a reversible mixed-type manner with IC50 between 0.087 ± 0.01 μM to 1.952 ± 0.26 μM. Furthermore, molecular docking studies were performed to affirm the binding interactions of this scaffold to the active sites of α-glucosidase and α-amylase enzymes. The quantitative structure–activity relationship (QSAR) investigations showed a strong association between 1p–15p structures and their inhibitory actions (IC50) with a correlation value (R 2) of 0.999916. Finally, molecular dynamic (MD) simulations were carried out to assess the dynamic behavior, stability of the protein–ligand complex, and binding affinity of the most active inhibitor 4p. The experimental and theoretical results therefore exposed a very good compatibility. Additionally, the drug-likeness assay revealed that some compounds exhibit a linear association with Lipinski’s rule of five, indicating good drug-likeness and bioactivity scores for pharmacological targets. Communicated by Ramaswamy H. Sarma

A combined spectroscopic and quantum chemical approach to study the molecular interaction between anti-inflammatory drug Hydrocortisone and amino acid l-Phenylalanine

The work presented in the manuscript addresses the molecular interaction of Hydrocortisone with l-Phenylalanine accomplished by density functional theory (B3LYP/6–311 G(d,p)), and spectroscopic approaches such as Raman, SERS, FTIR, and Powder X-ray diffraction (PXRD) methods. Raman and FTIR spectra are collected and compared with the theoretically obtained data and they support each other. Insight into the delocalization scheme of the Hydrocortisone + l-Phenylalanine complex reveals the formation of C=O∙∙∙H intermolecular hydrogen bond. The characterization of the intermolecular interaction by AIM and RGD-NCI analysis demonstrates the presence of both electrostatic and covalent nature. Molecular electrostatic potential mapped and low FMO's gap (-4.99 eV) unveil the reactive nature of the interacting complex. The aqueous solubility assessment of the synthesized complex exhibits almost 2.95 times better solubility as compared to Hydrocortisone. Mulliken atomic charges and thermodynamic parameters are enumerated with B3LYP/6–311 G(d,p) level. The calculated bioactivity score and drug-likeness parameters show good oral bioavailability of the complex. In addition, molecular docking study performed with the target proteins JAK1 (PDB ID: 6DBN) shows binding affinity of −9.43 kcal/mol.

Spectral, quantum chemical, biological activity, and molecular docking analysis of 1,8-dihydroxyanthraquinone: A target drug exploration

In this current effort, the 1H and 13C NMR spectra as well as quantum chemical computational effort of 1,8 DHAQ molecule analyzed based on density functional theory (DFT) with the help of Gauss-View 6.0.6 and Gaussian 09W program package. The molecular structure of 1,8 DHAQ optimized first through DFT/B3LYP hybrid functional/6-311++G (d,p) basis-set. The NMR (1H and 13C) isotropic chemical shift values of the titled molecule (TMS as reference) was examined through gauge-invariant-atomic orbital (GIAO) process in DMSO‑d6 polar solvent using above similar basis set, then was correlated with the experimental outcomes. All the findings of DHAQ molecule correlated very well with each other. Reduced Density Gradients (RDG Scatter plot) give an evidence of various non-covalent intramolecular interactions inside molecule. ELF and LOL analysis proof a chemical association of molecules. It also reveals the main localization & delocalization of boding and non-bonding electrons within molecule. An in-silico ADMET profiles (absorption, distribution, metabolism, excretion, and toxicity), bioactivity score, and drug-likeness (based on the Lipinski rules of five) of 1,8 DHAQ molecule was executed via various computational online server tools. This study predicts that titled molecule have noble physicochemical and pharmacokinetic properties. Furthermore, the inhibitory nature of the DHAQ molecule has estimated by means of molecular docking analysis using various selected target proteins. The molecular docking is an effective computational analysis in estimating the binding affinity and binding sites of ligand together with the target proteins, which is much effective for future structure-based drug designing. Thus, the formation of numerous hydrogen bonds and docked binding affinities depicts that hydroxy-substituted Anthraquinone might serve as main structure for the development of upcoming drugs. As a result, this effort provide a summary of the chemistry, biology, and toxicology of 1,8 DHAQ molecule, focusing on innovative drugs discovery for treatment of various cancer diseases in pharmaceutical industries.

Vibrational and computational study on the characterization of Ag-Threonine complex

The current manuscript is emphasized on the vibrational spectroscopic study of l-Threonine-TCA (LTh-TCA) complex and metal-based complexes such as (l-Threonine-TCA)Ag [(LTh-TCA)Ag] and (l-Threonine-TCA)Ag2 [(LTh-TCA)Ag2] investigated under the Raman, FTIR and UV–vis techniques. The most favourable binding sites of the mentioned complexes were predicted under the density functional theory (DFT) evaluated using the B3LYP method and LANL2DZ basis set. The quantum chemical parameters of the complexes calculated under the DFT method affirm the chemical reactivity, bioactive property and distribution of electrons within the atoms of the molecules. The electronic transition of the atoms are analysed using the UV–vis simulation method performed under the IEFPCM solvation model by employing methanol as solvent. The AIM analysis is carried out to understand the interaction types manifested by the mentioned complexes. The bioactivity score and drug-likeness properties of the complexes are also analysed. The theoretical and experimental vibrational wave numbers of L-Th-TCA complex and its metal-based complexes are compared with each other and are found in good agreement with each other. The potential binding regions of the mentioned compounds with 1QCY collagen receptor is evaluated using the molecular docking analysis.

In-silico prediction of highly promising natural fungicides against the destructive blast fungus Magnaportheoryzae

Magnaporthe oryzae causes destructive blast disease in more than 50 species of the major cereal crops rice, wheat and maize and destroys food of millions of people worldwide. Application of synthetic chemical fungicides are environmentally hazardous and unreliable in controlling M. oryzae. Conversely, naturally occurring biofungicides with multiple modes of actions are needed to be discovered for combatting the blast fungus. To find the effective biofungicides, we performed molecular docking study of some potential antifungal natural compounds targeting two proteins including a single-stranded DNA binding protein MoSub1 (4AGH), and an effector protein AVR-Pik (5E9G) of M. oryzae that regulates transcription in fungus and/or suppresses the host cell immunity. The thirty-nine natural compounds previously shown to inhibit M. oryzae growth and reproduction were put under molecular docking against these two proteins followed by simulation, free energy, and interaction analysis of protein-ligand complexes. The virtual screening revealed that two alkaloidal metabolites, camptothecin and GKK1032A2 showed excellent binding energy with any of these target proteins compared to reference commercial fungicides, azoxystrobin and strobilurin. Of the detected compounds, GKK1032A2 bound to both target proteins of M. oryzae. Both compounds showed excellent bioactivity scores as compared to the reference fungicides. Results of our computational biological study suggest that both camptothecin and GKK1032A2 are potential fungicides that could also be considered as lead compounds to design novel fungicides against the blast fungus. Furthermore, the GKK1032A2 acted as a multi-site mode of action fungicide against M. oryzae.

Comparative anti-Diabetic potential of phytocompounds from Dr. Duke's phytochemical and ethnobotanical database and standard antidiabetic drugs against diabetes hyperglycemic target proteins: an in silico validation

In the current investigation, the antidiabetic potential of 40 phytocompounds from Dr. Dukes phytochemical and ethanobotanical database and three antidiabetic pharmaceuticals from the market comparatively validated against hyperglycemic target proteins. Silymarin, proanthocyanidins, merremoside, rutin, mangiferin-7-O-beta-glucoside, and gymnemic acid exhibited good binding affinity toward protein targets of diabetes among the 40 phytocompounds from Dr.Dukes database over three chosen antidiabetic pharmaceutical compounds. Further these phytocompounds and sitagliptin are validated for its ADMET and bioactivity score to screen its pharmacological and pharmacokinetics properties. Silymarin, proanthocyanidins, rutin along with sitagliptin screened for DFT analysis found that phytocompounds have great Homo–Lumo orbital energies over commercial pharmaceutical sitagliptin. Finally, four complexes of alpha amylase-silymarin, alpha amylase-sitagliptin, aldose reductase-proanthocyanidins, and aldose reductase-sitagliptin screened for MD simulation and MMGBSA analysis, results shown that the phytocompounds silymarin and proanthocyanidins have strong affinities for binding to the binding pockets of alpha amylase and aldose reductase respectively over antidiabetic pharmaceuticals. Our current study proven proanthocyanidins and silymarin act as novel antidiabetic compounds toward diabetic target protein but it require clinical trial to evaluate its clinical pertinence toward diabetic target proteins. Communicated by Ramaswamy Sarma

Chemometric-guided chemical marker selection: A case study of the heat-clearing herb Scrophularia ningpoensis.

The selection of medicinal plants' chemical markers focuses on bioactivity as the primary goal, followed by the nature of secondary metabolites, their stability, and availability. However, herbal medicines are valued for their complex and holistic pharmacological effects. A correct chemical marker can be carefully selected by a systematic clarification of their chemical-biological relationships. In the current study, the multi-informative molecular networking (MIMN) approach was employed to construct the anti-inflammatory metabolomic pattern of a heat-clearing herb, Scrophularia ningpoensis Hemsl. (S. ningpoensis). The MIMN molecular families characterized by cinnamic acid glycosides showed a higher bioactivity score compared with the other two major chemical classes (iridoid glycosides and iridoid-cinnamic acid glycosides). The Global Natural Product Social Molecular Networking (GNPS) and Reaxys database were used to assist in the putative annotation of eighteen metabolites from the bioactive and non-bioactive molecular families. The anti-inflammatory validation step was based on the detection of reactive oxygen species (ROS) generation by activated human neutrophils. All compounds from the bioactive MIMN molecular families dose-dependently inhibited the total ROS generation promoted by fMLF (IC50: 0.04-0.42 μM), while the compounds from non-bioactive MIMN clusters did not show any significant anti-inflammatory effect. The ROS-dependent anti-inflammatory activity of these cinnamic acid glycosides was attributed to their oxygen radical scavenging ability. The most abundant cinnamic acid glycoside, angoroside C (IC50: 0.34 μM) was suggested to be selected as a chemical marker for S. ningpoensis. In this study, the MIMN platform was applied to assist in the chemical marker selection of S. ningpoensis. The correct selection of markers will aid in the compilation and revision of herbal monographs and pharmacopeias resulting in the precise analysis and classification of medicinal plants on a scientific basis.

Anti-quorum sensing effects of batatasin III: in vitro and in silico studies

The spread of multidrug resistant bacteria has fueled the development of new antibiotics to combat bacterial infections. Disrupting the quorum sensing (QS) mechanism with biomolecules is a promising approach against bacterial infections. Plants used in Traditional Chinese Medicine (TCM) represent a valuable resource for the identification of QS inhibitors. In this study, the in vitro anti-QS activity of 50 TCM-derived phytochemicals against the biosensor Chromobacterium violaceum CV026 was tested. Among the 50 phytochemicals, 7-methoxycoumarin, flavone, batatasin III, resveratrol, psoralen, isopsoralen, and rhein inhibited violacein production and showed good QS inhibitory effects. Batatasin III was selected as the best QS inhibitor based on drug-likeness, physicochemical properties, toxicity, and bioactivity score prediction analyses using SwissADME, PreADMET, ProtoxII, and Molinspiration. At 30 μg/ mL, Batatasin III inhibited violacein production and biofilm formation in C. violaceum CV026 by more than 69% and 54% respectively without affecting bacterial growth. The in vitro cytotoxicity evaluation by MTT assay demonstrated that batatasin III reduced the viability of 3T3 mouse fibroblast cells to 60% at 100 μg/mL. Furthermore, molecular docking studies showed that batatasin III has strong binding interactions with the QS-associated proteins CViR, LasR, RhlR, PqsE, and PqsR. Molecular dynamic simulation studies showed that batatasin III has strong binding interactions with 3QP1, a structural variant of CViR protein. The binding free energy value of batatasin III-3QP1 complex was −146.295 ± 10.800 KJ/mol. Overall results suggested that batatasin III could serve as a lead molecule that could be developed into a potent QS inhibitor. Communicated by Ramaswamy H. Sarma

Molecular Docking Studies of Ocimum Americanum Secondary Metabolites Against SARS-Cov-2 Spike Protein

Introduction and Aim: The outbreak of Covid-19 pandemic since December 2019 has raised serious global health concern. Because of rapid human to human transmission and non-availability of clinically proven drugs or vaccines, this Covid-19 pandemic has created a great threat to mankind. Many naturally derived molecules are being investigated for the treatment of Covid-19. Ocimum americanum is one such significant medicinal plant possessing a variety of biological activities. Materials and Methods: In the present study, seven phytochemicals were selected from O. americanum and were docked against SARS-CoV-2 spike protein which is an important site for virus to enter the host cell. Docking was performed using Autodock Vina and the ADME properties of all these seven ligands were predicted using the Swiss-ADME tool. The bioactivity score was also predicted using the Molinspiration tool. Besides the secondary metabolites, all these analyses were also performed for well-known antiviral drugs namely lopinavir and ritonavir. Results: The binding energy obtained from the docking studies of SARS-CoV-2 spike protein with Lopinavir, Ritonavir, Alpha-farnesene, Beta-farnesene, Eugenol, Linalool, Estragole, Limonene and 1,8-Cineole was found to be -5.2, -5.1, -4.7, -4.5, -4.3, -4.1, -4, -3.9 and -3.8 Kcal/Mol respectively. Swiss-ADME results also suggest that all the selected ligands follow the drug likeness properties and hence they could be taken for further drug discovery process. Conclusion: From the present in silico study, it can be concluded that secondary metabolites of O. americanum have potential inhibiting activity against spike protein of SARS-CoV-2. Isolation and efficacy studies in vitro may provide an insight into the drug discovery to fight Covid-19.

DFT calculations, molecular docking, in vitro antimicrobial and antidiabetic studies of green synthesized Schiff bases: as Covid-19 inhibitor

In this investigation, we synthesized Schiff bases 2-(2-methoxyphenoxy)-N-(4-methylbenzylidene)ethanamine, N-(4-methoxybenzylidene)-2-(2-methoxyphenoxy)ethanamine and 2-(2-methoxyphenoxy)-N-(4-nitrobenzylidene)ethanamine from 2-(2-methoxyphenoxy)ethanamine and various aromatic aldehydes by the environmentally friendly sonication method. The B3LYP method with a 6-311++G (d, p) basis set was used in the DFT calculation to obtain the optimized structure of the Schiff base MPEA-NIT. The compounds were tested in vitro for inhibition of bacterial growth (disc well method) and inhibition of α-amylase (starch-iodine method). The compounds tested showed inhibitory activities. In addition, they were subjected to PASS analysis, drug likeness, and bioactivity score predictions using online software. To confirm the experimental findings, molecular docking analyses of synthesized compounds on α-amylase (PDB ID: 1SMD), tRNA threonylcarbamoyladenosine (PDB ID: 5MVR), glycosyl transferase (PDB ID: 6D9T), and peptididoglycan D,D-transpeptidase (PDB ID: 6HZQ) were performed. The emergence of a new coronavirus epidemic necessitates the development of antiviral medications (SARS-CoV-2). Docking active site interactions were investigated to predict compounds’ activity against COVID-19 by binding with the SARS-CoV-2 (PDB ID: 6Y84). Communicated by Ramaswamy H. Sarma

Theoretical insights into Zn2+chelated complexes of herbacetin for the application in Alzheimer's disease

Herbacetin is a potential phytochemical that is proposed to treat various diseases. In this study, density functional theory is used to characterize the metal-chelating ability of herbacetin, with Zn2+ ion in various solvents like DMSO, acetone, CCl4, and toluene. In general, metal chelation improved the reactivity of herbacetin. Interaction energies suggest Zn2+ is preferably coordinated to O6 and O4 atoms of herbacetin and the higher affinity of herbacetin for Zn2+ is found in CCl4 solvent. The metal chelation enhanced the anti-oxidant activity of herbacetin for scavenging ·OH and ·OOH. Further, the anti-Alzheimer's property of herbacetin was explained using molecular docking technique. Our results suggest that herbacetin is a potential contender in chelation therapy for the treatment of Alzheimer's disease due to its metal chelating and antioxidant properties. More importantly, an outstanding bioactivity score of 0.55 was obtained for the herbacetin molecule.

Design, synthesis, and anti-bacterial activities of piperazine based phthalimide derivatives against superbug-Methicillin-Resistant Staphylococcus aureus

A series of piperazine-based phthalimide derivatives 5 (a-l) were synthesized and extensively characterized using a variety of spectrum methods, including LC-MS, 1H-NMR, 13C-NMR, and FT-IR. All the derivatives were examined for their physicochemical, pharmacokinetic, bio-activity score, and PASS analysis. The 5e piperazine-based phthalimide derivative demonstrated promising antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) in the in vitro antibacterial studies. In comparison to streptomycin and bacitracin (10 µg/mL), the minimum inhibitory concentration of 5e against MRSA was discovered to be 45±0.15 micro g/ml. The anti-MRSA activity was validated with membrane damage studies by using SEM, and in silico docking studies were against 3VMT and 6FTB proteins of MRSA. In the toxicity study, 5e derivatives were evaluated against L6 cell lines. The results of the studies show the synthesized 2-(2-(4-((4-chlorophenyl) sulfonyl) piperazin-1-yl) ethyl) isoindoline-1,3-dione (5e) can be used for the development of anti-MRSA drugs.

Molecular docking and ADMET studies to predict the anti-breast cancer effect of aloin by targeting estrogen and progesterone receptors

The existing anti-cancer drugs are known for their adverse effects. Hence, it calls for an urgent need to explore the alternative therapies that are safer and efficient with no or minimal side effects. This approach points towards the utilization of traditional medicinal herbs to formulate naturally-derived drugs. So, aloin is a bioactive compound of Aloe Vera and known to exhibit an anticancerous effect on different cancer types. However, limited studies are indicating its possible interaction with estrogen receptors (ER) and progesterone receptors (PGR), that are the most targeted receptors in breast cancer therapeutics. Our study aims to predict the possible interactions of ER and PGR with aloin. We also analysed the drug likeliness properties of aloin for its anti-breast cancer activity. Hence, we performed molecular docking study of aloin against both these receptors using AutodockVina. Drug-like properties and bioactivity score for aloin was also predicted, using Molinspiration tool. The results suggest that aloin exhibit better interaction with ER than PGR with a binding affinity of −8.0 Kcal/mol. Molinspiration assay further suggested the aloin to carry drug-like property and behave as a good ligand for nuclear receptors. Our study indicates that aloin may behave as a potential anti-breast cancer agent by targeting the ER in breast cancer cells.

In Silico Method for the Screening of Phytochemicals against Methicillin-Resistant Staphylococcus Aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) has evolved resistance even against the last resort β-lactam antibiotics. This is because of the acquisition of an additional penicillin-binding protein 2a (PBP2a) which is a resistance determinant in MRSA. Currently, available PBP2a inhibitors are ineffective against life-threatening and fatal infections caused by microorganisms. Therefore, there is an urgent need to screen natural compounds that could overpass the resistance issue alone or in combination with antibacterial drugs. We studied the interactions of different phytochemicals with PBP2a so that crosslinking of peptidoglycans could be inhibited. In structure-based drug designing, in silico approach plays a key role in determining phytochemical interactions with PBP2a. In this study, a total of 284 antimicrobial phytochemicals were screened using the molecular docking approach. The binding affinity of methicillin, -11.241 kcal/mol, was used as the threshold value. The phytochemicals having binding affinities with PBP2a stronger than methicillin were identified, and the drug-likeness properties and toxicities of the screened phytochemicals were calculated. Out of the multiple phytochemicals screened, nine were found as good inhibitors to be PBP2a, among which cyanidin, tetrandrine, cyclomorusin, lipomycin, and morusin showed strong binding potential with the receptor protein. These best-selected phytochemicals were also docked to the allosteric site of PBP2a, and most of the compounds revealed strong interactions with the allosteric site. These compounds were safe to be used as drugs because they did not show any toxicity and had good bioactivity scores. Cyanidin had the highest binding affinity (S-score of -16.061 kcal/mol) with PBP2a and with high gastrointestinal (GI) absorption. Our findings suggest that cyanidin can be used as a drug against MRSA infection either in purified form or that its structure can lead to the development of more potent anti-MRSA medicines. However, experimental studies are required to evaluate the inhibitory potential of these phytochemicals against MRSA.

Chemical Characterization, In-silico Evaluation, and Molecular Docking Analysis of Antiproliferative Compounds Isolated from the Bark of Anthocephalus cadamba Miq.

The present study aimed to isolate and characterize chemical compounds from Anthocephalus cadamba Miq. bark and evaluate their anticancer activity by in silico, molecular docking, and in vitro studies. Anthocephalus cadamba is a traditionally used Indian medicinal plant. The anticancer and phytochemical properties of this plant remain unexplored except for a few studies. The objective of the study was to evaluate the antiproliferative activity of extract and fractions against breast cancer and prostate cancer cell lines and isolate and characterize active compounds from bio-active guided fractions. Moreover, the anticancer activity of isolated compounds against breast and prostate cancer cell lines was also evaluated, in addition to in silico and molecular docking interactions of isolated compounds with VEGFR2 and PDGFRα target proteins. The compounds were isolated and purified with the help of repeated column chromatography, and spectral techniques, such as 1D, 2D NMR, and GC-MS/MS, were used to identify and elucidate the structure of the compounds. Moreover, prediction of activity spectra for substances, physiochemical properties, bioactivity radar prediction, bioactivity score, natural-product likeness, ADME, and toxicity parameters of isolated compounds (AC-1 to AC-4) was performed through various in-silico databases and servers. To evaluate the docking interaction profile and binding energies of compounds, three docking tools were utilized, such as AutoDock, AutoDock Vina, and iGEMDOCK, against two targets VEGFR2 and PDGFRα. MD simulation was performed through ligand and receptor molecular dynamic server (LARMD). It was found that the A. cadamba bark chloroform fraction demonstrated a significant inhibitory effect against MDA-MB-231, MCF-7, and PC-3 cells in a dose-time-dependent manner. The bioassay-guided isolation afforded four molecules AC-1 to AC-4 from chloroform fraction. Moreover, the GC-MS/MS profiling identified fourteen new molecules which were not reported earlier from A. cadamba. The in-silico study showed that the isolated compounds (AC-1 to AC-4) followed Lipinski's rule and had good oral bioavailability. While compound AC-4 had positive bioactivity scores except for kinase inhibitor activity. The ADMET profiling revealed that AC-4 was non-toxic and easily absorbed in the human intestine, and transportable in the blood-brain barrier compared to AC-1, AC-2, AC-3, and standard drug doxorubicin. Molecular docking and MD simulation assessment also signified AC-4 anticancer activity with dual inhibitory action against the target proteins VEGFR2 and PDGFRα amongst the studied compounds. The in vitro cell viability assay of isolated compounds demonstrated that AC-1 showed IC50 (μg/mL) value of 34.96 ±3.91, 47.76±3.80 69.1±4.96, AC-2; 68.26±4.22, 54.03±5.14, >100, AC-3; 35.34±4.14, 51.5±51.5, 70.8±5.25 and AC-4; 44.2±3.57, 24.2±2.67, 51.2±2.54 for MDA-MB-231, MCF-7, and PC-3 cancer cell lines, respectively and compared with standard drug doxorubicin. Moreover, fluorescence microscopy confirmed the apoptogenic property of compounds. We also found that AC-4 exhibited significant intracellular ROS production in breast cancer cells, thereby inducing apoptosis and eventually cell death. In conclusion, A. cadamba afforded four pure molecules AC-1 to AC-4 with the identification of fourteen new compounds. The entire in-silico studies concluded that the AC-4 compound had better oral bioavailability, bioactivity score, and ADMET profile among studied molecules. Molecular docking analysis and MD simulation also supported AC-4 dual inhibitory action against both VEGFR2 and PDGFRα receptors. Moreover, the isolated molecules AC-1, AC-2, AC-3, and AC-4 were found to be active against MDA-MB-231, MCF-7, and PC-3 cancer cells. The molecule AC-4 was found to induce ROS-mediated apoptosis in breast cancer cells. It was found that the anticancer inhibitory potentiality of AC-4 is directed to its molecular stereochemistry which specifically binds to the target proteins of breast cancer cells with no toxicological effect. Therefore, AC-4 is suggested to be an effective aspirant for novel drug design and discovery.

Strychnos alkaloids: total synthesis, characterization, DFT investigations, and molecular docking with AChE, BuChE, and HSA

An efficient five steps, the protection-deprotection synthetic a novel synthetic routes to(±) noruleine (±)-uleine, are reported starting from tetrahydrocarbazole fused monoalkyl nitrile at C-2 position that is prepared on multigram scale from 2-(3-ethyl-1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetonitrile (1) as well as the key azocino[4,3-b]indole skeleton is constructed via the tetrafluoro-1,4-benzoquinone (TFB)-mediated cyclization of a tetrahydrocarbazole derivative possessing direct amide synthesis from nitrile. As a result, Total synthesis of noruleine and uleine has been developed, which is accomplished in 4 and 5- steps synthesis of the ABCD tetracyclic of the strychnos alkaloids with an overall yield of 44% and 39%, respectively. The DFT computations were performed with B3LYP/6-311g(d,p) level to determine inter and intramolecular interactions and reactivity features of the compound 3–6. Also, TD-DFT computations were performed to characterize the electronic absorption spectra of all compounds. Last, the interactions of compounds 3–6 with selected targets AChE, BuChE, and HSA were evaluated in light of the molecular dockings. The bioactivity and drug-likeness scores revealed that compound 6 3–6 can be proper candidate for future drug-design studies more than the other compounds.

Highly potent natural fungicides identified in silico against the cereal killer fungus Magnaporthe oryzae

Magnaporthe oryzae is one of the most notorious fungal pathogens that causes blast disease in cereals, and results in enormous loss of grain production. Many chemical fungicides are being used to control the pathogen but none of them are fully effective in controlling blast disease. Therefore, there is a demand for the discovery of a new natural biofungicide to manage the blast disease efficiently. A large number of new natural products showed inhibitory activities against M. oryzae in vitro. To find out effective biofungicides, we performed in silico molecular docking analysis of some of the potent natural compounds targeting four enzymes namely, scytalone dehydratase, SDH1 (PDB ID:1STD), trihydroxynaphthalene reductase, 3HNR (PDB ID:1YBV), trehalose-6-phosphate synthase, Tps1 (PDB ID:6JBI) and isocitrate lyase, ICL1 (PDB ID:5E9G) of M. oryzae fungus that regulate melanin biosynthesis and/or appresorium formation. Thirty-nine natural compounds that were previously reported to inhibit the growth of M. oryzae were subjected to rigid and flexible molecular docking against aforementioned enzymes followed by molecular dynamic simulation. The results of virtual screening showed that out of 39, eight compounds showed good binding energy with any one of the target enzymes as compared to reference commercial fungicides, azoxystrobin and strobilurin. Among the compounds, camptothecin, GKK1032A2 and chaetoviridin-A bind with more than one target enzymes of M. oryzae. All of the compounds except tricyclazole showed good bioactivity score. Taken together, our results suggest that all of the eight compounds have the potential to develop new fungicides, and remarkably, camptothecin, GKK1032A2 and chaetoviridin-A could act as multi-site mode of action fungicides against the blast fungus M. oryzae.

Analyzing Indole-fused benzooxazepines as inhibitors of apoptosis pathway-related proteins using multifaceted computational medicinal chemistry

In this study, quantum chemical (QC) investigations, virtual screening, molecular docking, and molecular dynamics analysis of indole-fused benzooxazepines derivatives (IFBOs) are presented. The ab-initio density function theory (DFT) using Becke's three parameters hybrid functional (B3LYP) and Hartree-Fock (HF) with 6-311+G(d) level of theory were used to optimize IFBOs. The most suitable level is determined as DFT(B3LYP)6-311+G(d) by correlation of observed and calculated results of IFBOs (1-8). IR, NMR, quantum chemical descriptors, and frontier molecular orbitals (FMOs) were examined in detail. Similarly, virtual drug-likeness screening of IFBOs (1-8) was also performed including molecular descriptors (MDs) and bioactivity score (BS) along with absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were computed to reveal their biological activity. Moreover, their potential anticancer activity target was explored by molecular docking and molecular dynamics analyses. Mainly apoptosis pathway-related protein targets including caspase 8, caspase 3, Bcl-2, Bcl-xl, BAD, BAX and poly-ADP-ribose-polymerase-1 (PARP1) were studied to find the most prominent target of IFBOs to display their potential anticancer activity. As a result, IFBO-7 revealed the best molecular interaction profile with PARP1 and showed its potent inhibitory activity.