MolDock Score Research Articles

In silico study of phytochemicals contained in Brucea javanica in inhibiting the InhA enzyme as antituberculosis.

Currently Mycobacterium tuberculosis is found to be resistant to the treatment of tuberculosis with rifampin and isoniazid (INH) and often stated as multi-drug resistance (MDR). Knowledge and determination of biological properties of plant extracts is a source of drug candidates in various health fields. Therefore, natural products are important in the discovery of new drugs, especially in disease therapy, particularly for tropical diseases, tuberculosis. Brucea javanica, known as Buah Makasar, is found in many Asian countries including Indonesia. This plant fruit has a very bitter taste so it cannot be directly consumed and is often used as a traditional medicine to prevent some diseases, especially malaria. There has been no research on the effectiveness of Buah Makasar in tuberculosis. This study aims to identify compounds contained in Brucea javanica, namely bruceines, bruceosides and yadanziosides in inhibiting the InhA enzyme found in the wall of Mycobacterium tuberculosis. This in-silico study is using Molegro Virtual Docker (MVD) Ver. 5.5. We compared it to the native ligand, namely N-(4- Methylbenzoyl)-4-Benzylpiperidine (code: 4PI) and the reference drug standard, INH. In-silico results show that yadanziosides found in Brucea javanica have the potential to inhibit the InhA enzyme. Bruceoside F (-190.76 Kcal/mol) has the lowest MolDock score among the 27 other compounds. It is also having lower MolDock score than the native ligand 4PI (-120.61 Kcal/mol) and INH (- 54.44 Kcal/mol). Brucea javanica can be considered as source of drug development for againts tuberculosis.

Computational design, molecular properties, ADME, and toxicological analysis of substituted 2,6-diarylidene cyclohexanone analogs as potent pyridoxal kinase inhibitors.

Leishmaniasis is one of the tropical diseases which affects over 12 million people mainly in the tropical regions of the world and is caused by the leishmanial parasites transmitted by the female sand fly. The lack of vaccines to prevent leishmaniasis, as well as limitations of existing therapies necessitated this study which was focused on a combined virtual docking screening and 3-D QSAR modeling approach to design some diarylidene cyclohexanone analogs, while also performing pharmacokinetic analysis and Molecular Dynamic (MD) simulation to ascertain their drug-ability. As a result, the built 3-D QSAR model was found to satisfy the requirement of a good model with R2 = 0.9777, SDEC = 0.0593, F-test = 105.028, and Q2 LOO = 0.6592. The template (compound 9, MolDock score = - 161.064) and all seven newly designed analogs were found to possess higher docking scores than the reference drug (Pentamidine, Moldock score = - 137.827). The results of the pharmacokinetic analysis suggest 9 and the new molecules (9a, b, c, e, and f) as orally bioavailable with good ADME and safe toxicological profiles. These molecules also showed good binding interactions with the receptor (pyridoxal kinase). Additionally, the MD simulation result confirmed the stability of the tested protein-ligand complexes, with an estimated ∆G binding (MM/GBSA) of - 65.2177kcal/mol and -58.433kcal/mol for 9_6K91 and 9a_6K91 respectively. Hence, the new compounds, especially 9a could be considered potential anti-leishmanial inhibitors.

Polypyridyl Coordinated Re(I) complexes for human tenascin-C (TNC) as an Antibreast Cancer Agent: An Intuition from Molecular Modeling and Simulations

Breast cancer continues to be the biggest cause of mortality for women worldwide, taking the lives of millions each year. As a result, scientists are now exploring the possibility of metal-based complexes as anticancer therapies. Notwithstanding, polypyridyl coordinated Re(I) complexes have demonstrated tremendous promise as cancer-fighting medications. Therefore, the intent of this research is to investigate theoretically the spectral properties, compute density functional theory (DFT), and simulate molecular docking of polypyridyl coordinated Re(I) complexes containing functionalized 2,2′-bipyridine N,N′-donor bidentate ligands: 5,5′-DiMBpy coordinated in (1a), 4,4′-DiMBpy coordinated in (2a), and 4,4′-DiMoxBp coordinated in (3a) for cancer therapy application. Intriguingly, the complex Re(2a) achieved the greatest MolDock score and H-bond energy following interactions with the target receptors utilized, followed by Re(1a) and Re(3), respectively. Thus elucidating the studied compounds to be efficient in the mitigation of breast cancer.

Novel 1, 3, 4-Oxadiazole-pyridine hybrids as potential DNA gyrase B inhibitors (5D7R): ADMET prediction and molecular docking study

A small molecule (ligand) is placed in the binding site of its macromolecular target (receptor) using a computational process called molecular docking, which also calculates the binding affinity of the small molecule. With the use of PyRx software, the current study tried a high-throughput in-silico screening of 16 compounds docked with the crystal structure of DNA gyrase B receptors (PDB ID: 5D7R). In the range of -8.0 and -8.1, 3 of these 16 compounds displayed very good mol dock scores. As a typical medicine, amoxicillin medications have a mol dock score of -7.1. According to the results, all of the investigated ligands occupy similar positions and directions within the putative binding site of DNA gyrase B receptors (PDB ID: 5D7R), which reveals a sizable area surrounded by a membrane binding domain that acts as a pathway for substrate entry into the active site. Additionally, any small molecule's affinity can be viewed as a special instrument in the field of drug design and provide a possibility for future study to create an antibacterial activity. Additionally, ADME evaluations must be used to confirm compounds that are candidates for oral administration. The findings demonstrated that compound 4a, 4b, 4c, 4d, 4i, 4j, and 4k absorbed from GIT and compound 4i, 4j, and 4k fulfilled the Lipinski rule.
 Keywords: 1, 3, 4-Oxadiazole, ADME Evaluation, molecular docking, antimicrobial activity

New flavone-based arylamides as potential V600E-BRAF inhibitors: Molecular docking, DFT, and pharmacokinetic properties

ObjectivesThe V600E-BRAF protein kinase is an attractive and essential therapeutic target in melanoma and other tumors. However, because of its resistance to the known inhibitors and side effects of some identified inhibitors, new potent inhibitors need to be identified. MethodsIn the present work, in silico strategies such as the molecular docking simulation, DFT (Density-Functional-Theory) computations, and pharmacokinetic evaluation were used to determine potential V600E-BRAF inhibitors from a set of 31 synthesized novel flavone-based arylamides. ResultsThe docking result demonstrated that four compounds (10, 11, 28, and 31) had acceptable docking scores (MolDock score of −167.523 kcal mol−1, −158.168 kcal mol−1, −160.581 kcal mol−1,−162.302 kcal mol−1, and a Rerank score of −124.365, −129.365, −135.878 and −117.081, respectively) appeared as most active and potent V600E-BRAF inhibitors that topped vemurafenib (−158.139 and −118.607 kcal mol−1). The appearance of H-bonds and hydrophobic interactions with essential residues for V600E-BRAF proved the high stability of these complexes. The energy for the frontier molecular orbitals such as HOMO, LUMO, energy gap, and other reactivity parameters was computed using DFT. The frontier molecular-orbital surfaces and electrostatic potentials (EPs) were investigated to demonstrate the charge-density distributions that might be linked to anticancer activity. Similarly, the chosen compounds revealed superior pharmacological properties according to the drug-likeness rules (bioavailability) and pharmacokinetic properties. ConclusionThe chosen compounds were recognized as potent V600E-BRAF inhibitors with superior pharmacokinetic properties and could be promising cancer drug candidates.

Molecular Docking Investigation, Pharmacokinetic Analysis, and Molecular Dynamic Simulation of Some Benzoxaborole-Benzimidazole Hybrids: An Approach to Identifying Superior Onchocerca Inhibitors

Onchocerciasis is one of the major neglected tropical diseases caused by the filarial worm (Onchocerca volvulus), affecting an estimated population of about 37 million people living predominantly in tropical Africa. The major treatment approach has been based on the use of Ivermectin, which kills the microfilariae or the less effective Doxycycline targeting Wolbachia, endosymbiont of filarial nematodes. Flubendazole (FBZ) has proved effective in treating adult worms but with threatening adverse effects. Against this backdrop, therefore, a combined molecular docking study and pharmacokinetic screening were conducted on a series of benzimidazole-benzoxaborole hybrids to find more potent analogs with attributes that address the limitations of existing therapies. All the nineteen analogs were found to possess better docking scores than the reference drug (FBZ, Moldock scores = -120.466 and -125.359). The results of pharmacokinetic testing suggest that four molecules (14, 16, 19, and 20) are orally bioavailable and showed better ADMET properties than FBZ. These molecules and FBZ showed good binding interactions with the receptors’ active sites. Also, the molecular dynamic simulation performed on the docked complexes of 20 and FBZ confirmed the rigidity and stability of their interactions. Based on the results of this study, the selected molecules (especially 20) could be considered superior drug candidates for the treatment of Onchocerciasis.

Carboxylate‐ and Sulfonate‐Containing Quinazolin‐4(3H)‐one Rings: Synthesis, Characterization, and Carbonic Anhydrase I–II and Acetylcholinesterase Inhibition Properties

AbstractQuinazolines are a group of bioactive heterocyclic compounds with a wide range of biological activities and have gained an important place in the design of active drugs with various targets due to their pharmacological properties. Carbonic anhydrase (CA) and acetylcholinesterase (AChE) inhibitors are very important pharmacologically. In this study, inhibition effects of newly synthesized quinazolin‐4(3H)‐one derivatives on human erythrocyte CA‐I (hCA‐I) and CA‐II (hCA‐II) isoenzyme and AChE activity were investigated. The structures of the novel compounds were characterized by fourier‐transform infrared (FTIR), nuclear magnetic resonance (NMR), and high‐resolution mass spectroscopy (HRMS). All molecules showed strong inhibitory effect in all three enzymes. 4‐[(4‐Oxo‐2‐(phenoxymethyl)quinazolin‐3(4H)‐ylimino)methyl]phenyl furan‐2‐carboxylate for hCA‐I (IC50: 205 nM), 4‐[(4‐oxo‐2‐(phenoxymethyl)quinazolin‐3(4H)‐ylimino)methyl]phenyl isobutyrate for hCA‐II (IC50: 209 nM), and 4‐[(4‐oxo‐2‐(phenoxymethyl)quinazolin‐3(4H)‐ylimino)methyl]phenyl propionate for AChE (IC50: 14.2 nM) were the molecules that showed the strongest inhibitory effect. Molecular docking studies were carried out to elucidate the possible interaction mechanism of the molecules in the active site of the enzymes. The affinity scores of the most active compounds for hCA‐I, hCA‐II, and AChE were determined as −134.765, −147.423, and −175.354 MolDock Score, respectively.

Virtual screening, pharmacokinetic, and DFT studies of anticancer compounds as potential V600E-BRAF kinaseinhibitors

ObjectivesV600E-BRAF kinase is an essential therapeutic target in melanoma and other types of tumors. Because of its resistance to known inhibitors and the adverse effects of some identified inhibitors, investigation of new potent inhibitors is necessary. MethodsIn the present work, in silico strategies such as molecular docking simulation, pharmacokinetic evaluation, and density functional theory (DFT) computations were used to identify potential V600E-BRAF inhibitors from a set of 72 anticancer compounds in the PubChem database. ResultsFive top-ranked molecules (12, 15, 30, 31, and 35) with excellent docking scores (MolDock score ≥90 kcal mol−1, Rerank score ≥60 kcal mol−1) were selected. Several potential binding interactions were discovered between the molecules and V600E-BRAF. The formation of H-bonds and hydrophobic interactions with essential residues of V600E-BRAF suggested the high stability of these complexes. The selected compounds had excellent pharmacological properties according to the drug likeness rules (bioavailability) and pharmacokinetic properties. Similarly, the energy for the frontier molecular orbitals, such as the HOMO, LUMO, energy gap, and other reactivity parameters, was computed with DFT. The frontier molecular orbital surfaces and electrostatic potentials were investigated to demonstrate the charge-density distributions potentially associated with anticancer activity. ConclusionThe identified compounds were found to be potent hit compounds for V600E-BRAF inhibition with superior pharmacokinetic properties; therefore, they may be promising cancer drug candidates.

Acetylacetone and imidazole coordinated Re(I) tricarbonyl complexes: Experimental, DFT studies, and molecular docking approach

The research work presents the synthesis, spectral characterization (UV, FT-IR, and NMR), and modelling of tricarbonyl rhenium complexes (R1, R2, R3, R4, and R5) bearing the β-diketone ligand and acetylacetone (Acac) for potential application as cancer drugs. The theoretical investigation was carried out within the framework of density functional theory (DFT) computation at the ωB97XD/Gen/6–311++G (d,p)/LanL2DZ level of theory. The studied rhenium complexes: fac-[Re(Acac)(CO)3(H2O)] (R1),fac-[Re(Acac)(CO)3(Py)] (R2), fac-[Re(Acac)(CO)3(Im)] (R3), fac-[Re(Acac)(CO)3(1-CH3Im)] (R4),fac-[Re(Acac)(CO)3(Pz)] (R5) follows an increasing pattern of stability: R5 < R4 < R2 < R3 < R1, with energy gap values of 6.4487, 6.6281, 7.6758, 7.7487 and 8.0608 eV respectively. The MolDock score ranges from -65.769 to -42.141 kcal/mol compared to the much smaller value of -13.191 kcal/mol for Cisplatin (Cispt) interaction with 2ES3, indicating that the rhenium complex ligands exhibit higher inhibitory activities against TNC to promote apoptosis and regulate cell cycle associated with breast cancer compared to Cispt. The highest score is R4 at -115.954 with HBond energy of -2.923 kcal/mol, then followed by R2 with a score of -103.773 and H-Bond energy bond of -0.392 kcal/mol due to only Steric interaction and R3 with a score of -102.885 and H-bond of -0.2259 kcal/mol due to steric interaction with Phe16(I), Val17(I), Cys53(B) amino acid similar to R2. Due to their stability and MolDock score, R2 and R3 complexes exhibit the potency to be used as potential anti-breast cancer drug participants.

Computational Method on Hydroxychloroquine and Azithromycin for SARS-CoV-2: Binding Affinity Studies

World is facing a new pandemic called covid-19SARS-CoV-2) since a year ago. Unfortunately there is no treatment for Covid 19 nowadays as well as no potential therapies has been developed to overcome from coronavirus pandemic. Some potential drug molecules with combination have ability to respond for covid19 virus. From the research it was found that the reduction of viral load can be treated with hydroxychloroquine and azithromycin combination. We evaluate the mode of interactions of hydroxychloroquine and azithromycin with the dynamic site of SARS-CoV-2 coronavirus main protease. Molecular Structure-based computational approach viz. molecular docking simulations were performed to scale up their affinity and binding fitness of the docked complex of novel SARS-CoV-2 coronavirus protease and hydroxychloroquine and azithromycin. The natural inhibitor N3 of novel SARS-CoV-2 coronavirus protease were exhibited highest affinity in terms of MolDock score (-167.203Kcal/mol), and hydroxychloroquine was found with lowest target affinity (-55.917 Kcal/mol).The amino acid residue cysteine 145 and histidine 41 is bound covalently and formed hydrogen bond interaction with SARS-CoV-2 inhibitor known as inhibitor N3 as such, hydroxychloroquine and azithromycin also formed hydrogen bond interaction. The binding patterns of the inhibitor N3 of SARS-CoV-2 coronavirus main protease could be used as a guideline for medicinal chemist to explore their SARS-CoV-2 inhibitory potential.

Molecular modelling, synthesis and in vitro evaluation of quinazolinone hybrid analogues as potential pancreatic lipase inhibitors

Obesity is a multifactorial metabolic disorder, growing in an alarming rate across the world. Amongst the numerous targets explored for obesity management, inhibition of pancreatic lipase (PL) is considered as one of the promising approaches. Orlistat is the only PL inhibitory drug approved for long term treatment of obesity. However, it is reported to possess hepatotoxicity and nephrotoxicity. Thus, novel drug candidates that act through PL inhibition are considered the hour’s need. Based on this aim, a series of quinazolinone hybrid analogues have been synthesized, characterized and evaluated for their PL inhibitory potential. The physicochemical properties and toxicity parameters suggested that these parameters are in an acceptable range for the screened analogues. Amongst the synthesised analogues, QH-25 exerted potential PL inhibition (IC50 = 16.99 ± 0.54 µM). Further, enzyme inhibition studies suggested a reversible competitive inhibition. Molecular docking of these analogues was in line with in vitro results, wherein the obtained MolDock scores exhibited a significant correlation with their inhibitory activity (Pearson’s r = 0.6629). To further confirm the stability of the QH-25-PL complex in a dynamic environment, a molecular dynamics study (100 ns) was carried out and the results suggested that this complex is stable at dynamic conditions. Overall, these results shed light on the quinazolinone hybrids as potential PL inhibitors. Further structural modification may result in the development of potent anti-obesity agents which acts through PL inhibition. Communicated by Ramaswamy H. Sarma

Synthesis, Characterisation and Docking Studies of Thioxoquinoline Derivatives as Potential Anti-Alzheimer Agents.

Alzheimer's Disease (AD) is related to the total loss of presynaptic neurotransmitters of the cholinergic system in regions of the brain related to memory. Approximately 15% of the population beyond the age of 65 years are suffering from dementia due to AD and the rate is rising exponentially with age. The objective of this research was the synthesis of a series of 1-(4-substituted-2- thioxoquinolin-1(2H)-yl)-2-substituted ethanoneV (a-c(1-4)) by undergoing acetylation at the nitrogen of 4-hydroxyquinolin-2-(1H)-one and replacing its oxygen atom with sulphur moiety via the process of thionation. To carry out-docking studies of the title compounds were carried out using Molegro Virtual Docker (MVD-2013, 6.0) software and in-vitro screening of anti-alzheimer's activity by Ellman assay method. The synthesis of the title compounds was carried out via the sequential reaction from the initial dianilide to ring closure to the substituted quinoline-2-ones using polyphosphoric acid as a cyclising agent. These substituted quinoline-2-ones on thionation by phosphorous pentasulphide in aluminium trioxide gave quinoline-2-thiones and on further condensation with chloroacetyl chloride, they resulted in compounds with a leaving group. Nucleophilic substitution reaction of chloroacetylquinoline- 2-thiones with secondary amines resulted in the title compounds 1-(4-substituted-2- thioxoquinolin-1(2H)-yl)-2-substituted ethanone V(a-c(1-4)). The pharmacophore mapping of synthesized compounds was performed by using Molegro Virtual Docker (MVD-2013,6.0). The title compounds were tested for their in vitro anti-Alzheimer's activity using the Ellman assay method. All the synthesized compounds were characterized by IR, 1H NMR, 13C NMR, and Mass spectral data. Docking studies of all the synthesized compounds were carried out using a structural mechanism for the inhibition of CDK5-p25 by roscovitine, aloisine, and indirubin (PDB ID: 1UNG), showed favourable results, with compound (Vb3) showing a MolDock score of -85.9788 that was comparable to that of the active ligand (ALH_1288 [B]) with MolDock score of - 87.7609. The synthesized derivatives possessed the potential to bind with some of the amino acid residues of the active site. Compound 2-(6-chloro-4-hydroxy-2-thioxoquinolin-1(2H)-yl-1-piperazin- 1-ethanone (Vb3) was found to be the most active among the synthesized derivatives, with IC50 values of 32 ± 0.1681. All the synthesized compounds showed potent to moderate activity in comparison to the reference standard donepezil.

Design and Synthesis of Echitamine-inspired Hybrid Analogues Containing Thiazolidinediones as Potential Pancreatic Lipase Inhibitors

Background: Obesity is a multifactorial metabolic disease characterised by excessive accumulation of triglycerides. The prevalence and morbidity rates associated with obesity are increasing tremendously, posing a significant risk to society. Pancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary triglycerides; hence its inhibition is considered an attractive target in obesity. Methods: In this present work, a new series of echitamine-inspired indole-based thiazolidinedione hybrid analogues were designed, synthesized, and evaluated for their in vitro PL inhibitory potential. The nature of inhibition has been identified by enzyme kinetic analysis, whereas in silico molecular modelling tools (molecular docking and dynamic studies) were used for the identification of the mode of action at the catalytic site of PL (PDB ID: 1LPB). Fluorescence quenching was used for the identification of the interaction between the potent analogues with PL. Results: The condensation reaction of substituted indole derivatives with TZD in the presence of aqueous KOH resulted in the formation of the titled analogues. Analogues 7k and 7p displayed a potential PL inhibitory activity (IC50 = 11.36 and 11.87 μM, respectively). A competitive mode of PL inhibition was revealed in the enzyme kinetic analysis. A static quenching mechanism was exhibited by the screened agents on PL. The obtained MolDock scores were aligned with the in vitro PL inhibitory activity (Pearson’s r - 0.7575, p &lt; 0.05). Moreover, the PL-ligand complexes were stable in the dynamic conditions. Conclusion: Analogue 7k exerted the potential activity, and further studies might result in novel lead molecules.

Docking and Molecular Dynamics Simulations of Flavonoids as Inhibitors of Infectious Agents: Rutin as a Coronavirus Protease Inhibitor

Abstract3CL protease as the main protease (Mpro) of coronavirus is investigated as a potential target in medicine. Flavonoid compounds with polyphenolic structures exhibited anti‐viral, anti‐bacterial, immunomodulatory and anti‐inflammatory effects against infectious agents. In this study, the inhibitory effect of flavonoid‐based compounds was evaluated against coronavirus Mpro using molecular docking and dynamic simulations. Molegro Virtual Docker 6.0 (MVD) software was used to ensure the accuracy of the docking analysis. Eventually, four compounds including two herbal‐based (Rutin and Quercetin) and two chemical‐based (2‐Iodoadenosine‐5’‐O‐[(phosphonomethyl)phosphonic Acid] and Camostat) are selected based on the interaction energies and docking scores of the investigated structures. The values of MolDock Score for Rutin was −174.355 docked to Mpro enzyme. The molecular dynamics was performed by using GROMACS in 100 ns to refine the docking simulation results and evaluated the binding stability of Rutin. Potential energy of Rutin/Mpro complex stabilization was measured approximately −1.11×106 kcal/mol for 100 ns. As a result, Rutin is suggested as a potent inhibitor for Mpro and can be used as an effective drug in the treatment and prevention of covid.

Ligand-based drug design, molecular docking and pharmacokinetic studies of some series of 1,4 - dihydropyridines derivatives as human intestinal maltase-glucoamylase inhibitor

Quantitative Structure Activity Relationship (QSAR) was employed to predict the inhibitory activities of some series of 1,4–dihydropyridines derivatives as potent C-terminal human intestinal maltase-glucoamylase inhibitor (MGAM-C). The Density Functional Theory utilizing B3LYP/6–31G* as the basis set was employed to optimize the chemical structure of 1,4–dihydropyridines derivatives. four models were generated using Genetic Function Approximation with model three having internal validation parameters of R 2 (trng set) = 0.899, R 2 adj = 0.869, Q 2 cv = 0.769, LOF = 0.0129 selected as the best since it has the highest external validation parameter of R 2 (test set) = 0.885. Five potent compounds designed using the ligand-based approach were found to be more enhanced than the template. furthermore, binding interactions of the designed compounds within the active site of (MGAM-C) showed a fascinating MolDock scores with good pharmacokinetic profiles. This study, provide a useful information for the design of new α-glucosidase inhibitors.

In silico and invitro Antidiabetic Characterization and ADME Studies of Rhus parviflora

The study was planned to trace out connection among receptors responsible for the development of diabetes mellitus and active constituents of Rhus parviflora by in silico and in vitro methods. A molecular docking study was carried out for selected compounds after screening of all chemical constituents present in plant. Initial screening was carried through Lipinski’s rule of five along with ADME study of the reported phytoconstituents. For estimation of Antidiabetic potential of all selected constituent total 6 PDB namely 1IR3 (Insulin receptor), 1US0 (Aldose Reductase), 2FV6 (Protein tyrosine phosphatase 1), 2OQV (Human Dipeptidyl Peptidase IV) 2QV4 (α-amylase), 5NN6 (α- glucosidase) were selected. Molegro Virtual Docker tool was employed for the Molecular Docking studies. 4’-O-beta-D-Glucosyl-cis-p-coumaric acid, Kaempferol, Myrecetin, Quercetin, Taxifolin, and Isorhamnetin exhibited efficient hydrogen bonding as well as mol dock score with all selected 6 receptor PDB in contrast to standard drug Glibenclamide. In vitro study results of RPME exhibited 60.58±0.6, 54.64±2.46 percent inhibition in α- Glucosidase Inhibition Assay and α- Amylase Inhibition Assay, in contrast standard acarbose exhibited 71.35±1.84 and 67.76±1.97 percent inhibition respectively. The entire study gives understanding that chosen plant presumably has antidiabetic potential because of considered biomarkers.

Biotransformation of Modified Benzylisoquinoline Alkaloids: Boldine and Berberine and In Silico Molecular Docking Studies of Metabolites on Telomerase and Human Protein Tyrosine Phosphatase 1B.

Natural nitrogen heterocycles biotransformation has been extensively used to prepare synthetic drugs and explore the fate of therapeutic agents inside the body. Herein, the ability of filamentous fungi to biotransform boldine and berberine was investigated. Docking simulation studies of boldine, berberine and their metabolites on the target enzymes: telomerase (TERT) and human protein tyrosine phosphatase 1B (PTP-1B) were also performed to investigate the anticancer and antidiabetic potentials of compounds in silico. The biotransformation of boldine and berberine with Cunninghamella elegans NRRL 2310, Rhodotorula rubra NRRL y1592, Penicillium chrysogeneum ATCC 10002, Cunninghamella blackesleeana MR198 and Cunninghamella blackesleeana NRRL 1369 via demethylation, N- oxidation, glucosidation, oxidation and hydroxylation reactions produced seven metabolites, namely: 1,10-didesmethyl-boldine (1), laurolitsine (2), 1,10-didesmethyl-norboldine (3), boldine-9-O-β-D-glucoside (4), tridesmethyl berberine (5), demethylene berberine (6), and lambertine (7). Primarily, the structures of the metabolites were established by one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) analyses and mass spectrometry. In silico molecular docking simulation of the metabolites of boldine and berberine to the proteins TERT and PTP-1B, respectively, revealed good binding MolDock scores comparable to boldine and berberine and favorable interactions with the catalytic sites of the proteins. In conclusion, this study presented promising biologically prepared nitrogen scaffolds (isoquinolines) of boldine and berberine.

Flavonoids as promising anticancer agents: an in silico investigation of ADMET, binding affinity by molecular docking and molecular dynamics simulations

Cancer is one of the most concerning diseases to humankind. Various treatment strategies are being employed for its treatment, out of which use of natural products is an essential one. Flavonoids have proven to be promising anticancer targets since decades. Also, tubulin is a significant biological target for the development of anticancer agents due to its crucial role in mitosis and abundance throughout the body. In the current study, in silico ADMET parameters of 104 flavonoids were examined, followed by molecular docking with the colchicine binding site of Tubulin protein (PDB; Id 4O2B). The best conformation from each flavonoid subcategory with the best docking score (MolDock score) was further subjected to 100 ns of molecular dynamics to investigate the protein-ligand complex’s stability. Different parameters such as RMSD, RMSF, rGy and SASA were calculated for the six flavonoids using molecular dynamic studies. The top most compound from all the six subcategories of flavonoids elicited best behavior in the colchicine binding site of Tubulin protein. This in silico study employing molecular docking and molecular dynamics simulation provides strong evidence for flavonoids to be excellent anti-tubulin agents for the treatment of cancer. Communicated by Ramaswamy H. Sarma

2D-QSAR, molecular docking, drug-likeness, and ADMET/pharmacokinetic predictions of some non-small cell lung cancer therapeutic agents

ObjectivesNon-small cell lung cancer (NSCLC) is the most common type of lung cancer, with nearly 2 million diagnoses and a 17% 5-year survival rate. The aim of this study was to use computer-aided techniques to identify potential therapeutic agents for NSCLC. MethodsThe two dimensional-quantitative structure–activity relationship (2D-QSAR) modeling was employed on some potential NSCLC therapeutic agents to develop a highly predictive model. Molecular docking-based virtual screening were conducted on the same set of compounds to identify potential hit compounds. The pharmacokinetic features of the best hits were evaluated using SWISSADME and pkCSM online web servers, respectively. ResultsThe model generated via 2D-QSAR modeling was highly predictive with R2= 0.798, R2adj = 0.754, Q2CV = 0.673, R2 test = 0.531, and cRp2 = 0.627 assessment parameters. Molecular docking-based virtual screening identified compounds 25, 32, 15, 21, and 23 with the highest MolDock scores as the best hits, of which compound 25 had the highest MolDock score of −138.329 kcal/mol. All of the identified hits had higher MolDock scores than the standard drug (osimertinib). The best hit compounds were ascertained to be drug-like in nature following the Lipinski’s rule of five. Also, their ADMET features displayed average pharmacokinetic profiles. ConclusionAfter successful preclinical testing, the hit compounds identified in this study may serve as potential NSCLC therapeutic agents due to their safety and efficacy with the exception of compound 23, which was found to be toxic. They can also serve as a template for designing novel NSCLC therapeutic agents.

Design, synthesis, and activity of 2-aminochromone core N,N-bis-1,2,3-triazole derivatives using click chemistry.

A new series of 2-aminochromone-based N,N-di-1,2,3-triazole hybrid heterocycles were synthesized in one pot from N,N-terminal dialkyne 2-aminochromone with various organo azides by following the click strategy using classical Cu(I)-catalyzed azide-alkyne [3 + 2] annulation reaction. The synthesized compounds were well characterized by using various spectral analyses such as IR, 1H NMR, 13C NMR, and HRMS data for their structural elucidation. All newly synthesized compounds have been investigated for anti-microbial activity against Gram-positive, Gram-negative bacteria, and fungal strains and exhibited high activity against microbial growth when compared with standard anti-bacterial agents. These derivatives were tested for anti-cancer activity against HeLa cell lines and found that all compounds exhibit good activity with IC50 values ranging from 0.11 to 1.04 µM than standard curcumin (IC50 4.83 ± 0.44 µM). The molecular docking studies of the synthesized compounds with the affinity of ligands toward the target protein dual-specificity tyrosine-regulated kinase 2, DYRK2 (PDB id: 5ZTN) molecular docking were shown a better Moldock score performed compared to standard.Graphic abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s11696-022-02449-w.