Comparative Molecular Docking Studies Research Articles

Possible inhibitory effects of hoslundal, hoslundin and hoslunddiol on human lactate dehydrogenases: a bioinformatics proof

The development of anti-malarial drugs is of great importance due to the detrimental effects of this disease all around the world. In recent years, bioinformatics tools provide considerable contributions to develop new small molecules which have important bioactivities against many bio-targets. However, biases in the methodologies or aims of the studies in which in silico tools are used may reveal problematic cases. Hoslundal, hoslundin, and hoslunddiol were proposed by Shadrack et al. (2016) to inhibit Plasmodium falciparum lactate dehydrogenase (Pf-LDH) to fight malaria. But these molecules may have potential to inhibit mammalian LDHs. To investigate whether these molecules have inhibitions on mammalian LDHs or not, we studied a comprehensive and comparative molecular docking studies as described in the present paper. According to the results, the vina scores of hoslundal without NADH for Pf-LDH, HM-LDH, HH-LDH were found as -7.5, -7.6 and -8.2 kJ/mol, respectively. Moreover, multiple sequence alignment analysis reveals high similarities among sequences. In the light of molecular studies, hoslundal were found to be connected to Pf-LDH, HM-LDH, HH-LDH (31, 26, 34), (2, -7, 154), (11, 41, 54), respectively. In conclusion, novel small molecules which are developed via in silico tools could show excellent activities against bio-targets of the pathogenic microorganisms. However, it should not be forgotten that active site of the enzymes is conserved, therefore, after a possible proposal of small molecule, its molecular docking and also Swiss-ADME studies should be necessarily carried out.

Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays.

Trace amine-associated receptor 1 (TAAR1) is an attractive target for the design of innovative drugs to be applied in diverse pharmacological settings. Due to a non-negligible structural similarity with endogenous ligands, most of the agonists developed so far resulted in being affected by a low selectivity for TAAR1 with respect to other monoaminergic G protein-coupled receptors, like the adrenoreceptors. This study utilized comparative molecular docking studies and quantitative-structure activity relationship (QSAR) analyses to unveil key structural differences between TAAR1 and alpha2-adrenoreceptor (α2-ADR), with the aim to design novel TAAR1 agonists characterized by a higher selectivity profile and reduced off-target effects. While the presence of hydrophobic motives is encouraged towards both the two receptors, the introduction of polar/positively charged groups and the ligand conformation deeply affect the TAAR1 or α2-ADR putative selectivity. These computational methods allowed the identification of the α2A-ADR agonist guanfacine as an attractive TAAR1-targeting lead compound, demonstrating nanomolar activity in vitro. In vivo exploration of the efficacy of guanfacine showed that it is able to decrease the locomotor activity of dopamine transporter knockout (DAT-KO) rats. Therefore, guanfacine can be considered as an interesting template molecule worthy of structural optimization. The dual activity of guanfacine on both α2-ADR and TAAR1 signaling and the related crosstalk between the two pathways will deserve more in-depth investigation.

Synthesis, Characterization, Molecular Docking and Biological Evaluation of 1,4-Bis(aryl-1H- 1,2,3-triazole-4yl)methoxy)benzaldehyde Derivatives as Potential Anticancer Agents

A series of novel analogues of 1,4-bis((aryl-1H-1,2,3-triazole-4-yl)methoxy)benzaldehydes were synthesized efficiently by click reaction via conventional method using 2,4-dipropyloxy benzaldehyde and aryl azides characterized by spectroscopic methods including 1H NMR, 13C NMR, mass and IR spectrometry. Comparative molecular docking studies were carried out for all the synthesized compounds (4a-l) using cancer therapeutics levatinib and vandetanib targeting the VEGFR2 protein’s active region using the Glide tool in the Schrödinger suite. Among these, compounds 4b, 4f and 4h showed better drug likeness functions than current cancer inhibitors of VEGFR2 protein. Furthermore, to determine ADME and toxicity properties, the pkCSM server and the QikProp module were used. Glide scores and binding free energy analyses were used to determine the lead molecules. Compounds 4b, 4f and 4h revealed from docking exhibited potential in vitro cytotoxic activity against both MCF7 and HepG2 cell lines.

Comparative Molecular Field Analysis (CoMFA), Molecular Docking and ADMET Study on Thiazolidine-4-carboxylic acid Derivatives as New Neuraminidase Inhibitors

The objective of this research was to create a 3D-QSAR CoMFA model for a set of twenty-five neuraminidase inhibitors containing thiazolidine-4-carboxylic acid derivatives and to identify a new potent neuraminidase inhibitor for the treatment of influenza. The statistical parameters of the generated model are excellent: Q2 = 0.708, R2 = 0.997. The external validation results were (r2 0 = 0.922, K= 1.016, R2 pred = 0.674, r2 m= 0.778) indicating that the constructed model has good predictive power. Based on the contour map of the CoMFA model, we were able to propose six novel compounds with higher neuraminidase inhibitory activity than the most active compound. The six proposed molecules were submitted to molecular docking to analyse the bindings formed between the newly designed molecules and the neuraminidase. All of the proposed molecules were found to be more stable on the active site of neuraminidase than the reference molecule (1SJ). SwissADME was used to estimate the pharmacokinetic properties of each proposed molecule, while ProToxII and VEGA QSAR were used to investigate any potential toxicity. Finally, a reaction mechanism for synthesizing the six proposed compounds was described, which could potentially be explored further in the search for novel neuraminidase inhibitors. In conclusion, this study has identified potential candidates for the development of more effective neuraminidase inhibitors for the treatment of influenza.

In silico elucidation of potential drug targets against oxygenase domain of Human eNOS Dysfunction.

Nitric Oxide (NO) signaling pathway plays a vital role in various physiological and pathophysiological processes including vasodilation, neurogenesis, inflammation, translation and protein regulation. NO signaling pathway is associated with various diseases such as cardiovascular diseases, vision impairment, hypertension and Alzheimer's disease. Human Endothelial Nitric Oxide Synthase (eNOS) bound with calcium regulatory protein (calmodulin (CaM)) to produce NO which initiates cGMP pathway. The current study employs to screen the novel compounds against human eNOS independent of calcium regulatory protein (CaM). The current effort emphasized that the deficiency of CaM leads to dysfunction of cGMP signaling pathway. In this work, a hybrid approach of high-throughput virtual screening and comparative molecular docking studies followed by molecular dynamic simulation analyses were applied. The screening of top ranked two novel compounds against eNOS were reported that showed effective binding affinity, retrieved through the DrugBank and ZINC database libraries. Comparative molecular docking analyses revealed that Val-104, Phe-105, Gln-247, Arg-250, Ala-266, Trp-330, Tyr-331, Pro-334, Ala-335, Val-336, Tyr-357, Met-358, Thr-360, Glu-361, Ile-362, Arg-365, Asn-366, Asp-369, Arg-372, Trp-447 and Tyr-475 are potent residues for interactional studies. High-throughput virtual screening approach coupled with molecular dynamic simulation and drug likeness rules depicted that ZINC59677432 and DB00456 are potent compounds to target eNOS. In conclusion, the proposed compounds are potent against eNOS based on extensive in silico analyses. Overall, the findings of this study may be helpful to design therapeutic targets against eNOS.

Palbociclib (PD 0332991) Interaction with Kinases. Theoretical and Comparative Molecular Docking Study.

The optimized geometry of palbociclib, (PD 0332991) (8-cyclopentyl-6-ethanoyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one), electrostatic potential map, molecular orbitals were calculated using the density functional theory. The geometry was used in a molecular docking study of palbociclib-kinase complexes, results could be explained by the charge of the nitrogen and oxygen atoms within the palbociclib. Energy gap of HOMO-LUMO surfaces, could help to explain the reactivity of the ligand and the hydrogen bonding with three different kinases, two of CDK6 and one of CDK4 type. Docking results are similar and complementary with literature reports using molecular dynamics, were hydrogen bonding was obtained and analyzed. The promiscuity of three kinases with palbociclib was detected by the docking results, thus, palbociclib could be used in other types of cancer besides myeloid leukemia. Some similarities are found with CDK4/CDK6 kinases which allow us to determine that palbociclib could be used to control other resistant inhibitor types of cancer.

A comparative molecular docking study of phytocompounds of Ziziphus jujuba lam. with multiple receptors for the cardioprotective activity

A comparative molecular docking study of phytocompounds of Ziziphus jujuba lam. with multiple receptors for the cardioprotective activity

COMPUTATIONAL DRUG REPROPOSING TO IDENTIFY SARS-COV-2 MPRO INHIBITORS: MOLECULAR DOCKING, ADMET ANALYSIS, AND IN-SILICO/IN-VITRO TOXICITY STUDY

Aim and Objective: After the COVID-19 outbreak, drug repurposing has emerged as an effective and fast approach for combating the SARS-CoV-2 crisis. in this work, computational drug repurposing has been utilized to identify new SARS-CoV-2Mpro inhibitors. Methods: Comparative molecular docking studies were used to evaluate the activity of the commercially available oral antiviral drug simeprevir and its degradation products (compounds 1–5) against the main protease (Mpro)of SARS-CoV-2 (PDB ID: 6lu7; resolution: 2.16 Å). Moreover, the ADMET and in-silico toxicity properties of the acidic (compounds 1–3) and oxidative (compounds 4 and 5) degradation products of simeprevir were predicted. Results: Docking studies revealed good binding affinities for compounds (1–5) against Mpro of SARS-CoV-2, with binding free energies ranging from −6.23 to −7.65 kcal/mol. The acidic degradant 2 exhibited the best affinity and was superior to simeprevir and a natural ligand. All compounds were expected to be safe to the CNS. Conclusion: Compounds 1, 4, and 5 were expected to possess good human intestinal absorption, whereas compounds 2 and 3 appeared to have moderate intestinal absorption. Peer Review History: Received: 1 September 2022; Revised: 11 October; Accepted: 6 November, Available online: 15 November 2022 Academic Editor: Dr. DANIYAN Oluwatoyin Michael, Obafemi Awolowo University, ILE-IFE, Nigeria, toyinpharm@gmail.com Received file: Reviewer's Comments: Average Peer review marks at initial stage: 5.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. Gehan Fawzy Abdel Raoof Kandeel, Pharmacognosy Department, National Research Centre, Dokki, 12622, Giza, Egypt, gehankandeel9@yahoo.com Dr. Nicola Micale, University of Messina, Italy, nmicale@unime.it Prof. Cyprian Ogbonna ONYEJI, Obafemi Awolowo University, Ile-Ife, Nigeria, conyeji@oauife.edu.ng Similar Articles: USE OF COLCHICINE TO COUNTERACT THE STRONG HYPERINFLAMMATORY STATE INDUCED BY SARS-COV-2 THE ROLE OF ANTICOAGULANTS AND ANTIPLATELETS IN PROPHYLAXIS AND/OR TREATMENT OF SEVERE SARS-COV-2 INFECTION

Potential Epha2 Receptor Blockers Involved in Cerebral Malaria from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis and Ocimum basilicum: A Computational Approach.

Cerebral malaria (CM) is a severe manifestation of parasite infection caused by Plasmodium species. In 2018, there were approximately 228 million malaria cases worldwide, resulting in about 405,000 deaths. Survivors of CM may live with lifelong post-CM consequences apart from an increased risk of childhood neurodisability. EphA2 receptors have been linked to several neurological disorders and have a vital role in the CM-associated breakdown of the blood-brain barrier. Molecular docking (MD) studies of phytochemicals from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis, Ocimum basilicum, and the native ligand ephrin-A were conducted to identify the potential blockers of the EphA2 receptor. The software program Autodock Vina 1.1.2 in PyRx-Virtual Screening Tool and BIOVIA Discovery Studio visualizer was used for this MD study. The present work showed that blocking the EphA2 receptor by these phytochemicals prevents endothelial cell apoptosis by averting ephrin-A ligand-expressing CD8+ T cell bioadhesion. These phytochemicals showed excellent docking scores and binding affinity, demonstrating hydrogen bond, electrostatic, Pi-sigma, and pi alkyl hydrophobic binding interactions when compared with native ligands at the EphA2 receptor. The comparative MD study using two PDB IDs showed that isocolumbin, carnosol, luteolin, and taraxasterol have better binding affinities (viz. -9.3, -9.0, -9.5, and -9.2 kcal/mol, respectively). Ocimum basilicum phytochemicals showed a lower docking score but more binding interactions than native ligands at the EphA2 receptor for both PDB IDs. This suggests that these phytochemicals may serve as potential drug candidates in the management of CM. We consider that the present MD study provides leads in drug development by targeting the EphA2 receptor in managing CM. The approach is innovative because a role for EphA2 receptors in CM has never been highlighted.

Design, synthesis, and biological evaluation of novel quinoline derivatives as small molecule mutant EGFR inhibitors targeting resistance in NSCLC: In vitro screening and ADME predictions

Here in, we report the design, synthesis and in vitro anticancer activity of a novel series of 24 quinoline analogues of substituted amide and sulphonamide derivatives. The anticancer activity of the synthesised compounds was evaluated against the HCC827, H1975 (L858R/T790 M), A549 (WT EGFR), A-549 and BEAS-2B cell lines. The majority of quinoline compounds demonstrated a significant cytotoxic effect. Compound 21 was found to be the most potent, with IC50 values of 0.010 μM, 0.21 μM, 0.99 μM and 2.99 μM as compared to Osimertinib with IC50 values with of 0.0042 μM, 0.04 μM, 0.92 μM and 2.67 μM. Compound 21 exhibited promising inhibitory enzymatic activity against the EGFR L858R/T790 M with IC50 value of 138 nM, comparable to Osimertinib's 110 nM. Employing a Western blot assay on the phosphorylation of EGFR and the signalling pathways transmission in HCC827 cells, the anticancer activity of the synthesised compounds 18 and 21 was evaluated in terms of its mechanism of action. All the compounds were subjected to a comparative molecular docking study against various EGFR enzyme types, including the wild-type (PDB: 4I23) and T790 M mutant (PDB: 2JIV) enzymes. Furthermore, compounds were examined at the allosteric binding site of the EGFR enzyme with the L858R/T790 M/C797S mutation (PDB ID: 5D41). The MD simulation study was also performed for EGFR-compound 21 complex which indicates the stability compound 21 in both ATP and allosteric site of enzyme. Further, in silico ADME prediction studies of all derivatives were found promising, signifying the drug like properties.

Comparative modelling, molecular docking and immobilization studies on Rhizopus oryzae lipase: evaluation of potentials for fatty acid methyl esters synthesis

Elucidation of lipase–substrate interactions will guide the proper industrial use and applicability of the enzyme. The aim of this study was to predict the 3 D structure of Rhizopus oryzae ZAC3 (RoZAC3) lipase, study its interactions with some natural substrates and evaluate the feasibility of fatty acid methyl esters (FAME) production by the immobilized lipase. Protein identification of RoZAC3 lipase was carried out using LC-MS/MS. The 3 D structure of the lipase was built using homology modelling and natural substrates such as tributyrin, tripalmitin and triolein were docked to the optimized 3 D model for investigation of enzyme-ligand interactions. RoZAC3 lipase, immobilized by adsorption on Lewatit VP OC 1600 was applied in the synthesis of fatty acid methyl esters (FAME). From the phylogenetic analysis, it was observed that RoZAC3 lipase was closely related (48%) to Rhizopus javanicus lipase (Q7M4U7). The predicted 3 D model was validated using the SWISS model validation server. Ramachandran and ERRAT plots were used to assess the amino acid environment and overall quality of the model. From the docking studies, the values of the binding energies obtained for tributyrin, tripalmitin and triolein were − 5.37, −5.27 and −5.77 respectively. At an enzyme:immobilization support ratio of 50 mg/g, transesterification reaction duration of 18 h and a temperature of 40 oC, the conversion reached above 80%. The molecular docking studies provided information on the interaction/modifications between the RoZAC3 lipase and triacylglycerols that can be exploited for numerous applications. The immobilized lipase could serve in hydro-esterification reactions adaptable for biodiesel production. Communicated by Ramaswamy H. Sarma

New benzimidazole based hybrids: Synthesis, molecular modeling study and anticancer evaluation as TopoII inhibitors

Three series of new benzimidazole hybrids were designed and synthesized as promising human TopoII inhibitors. They were characterized by different spectroscopic techniques (1H, 13C NMR, ESI-MS and IR). All hybrids (6–23) were screened for their in vitro antiproliferative activity against five human cancer cell lines namely; HepG-2, MCF-7, PC-3, HCT-116 and Hela. Compound 21 showed the most potent anticancer activity against all cancer cell lines, with IC50 range of 2.82 to 12.59 µM, while proving safe towards normal cells WI-38 (IC50 = 31.89 µM) compared to the reference drug doxorubicin (IC50 = 6.72 µM). The most active candidates 13, 20, 21, 22 and 23 were further assessed for their human TopoII inhibition. The best of which, compounds 13 and 20 showed IC50 of 6.72 and 8.18 µM respectively compared to staurosporine (IC50 = 4.64 µM). Further mechanistic studies for compound 13 showed cell cycle arrest at S-phase by 51.29 % and a significant increase in the total apoptosis by 62.5 folds. Furthermore, apoptosis study proved that it induced apoptosis by decreasing both IAP and Bcl-2, activating caspases 3, 8 and 9, and increasing accumulation of ROS in HepG-2 cells. Besides, it decreased transcription factors’ binding activity to DNA. Comparative molecular docking study was performed between the most potent TopoII inhibitors 13 and 20, and the least potent one 23 to relate the binding pattern with TopoII catalytic active site to the biological activity, where all results came in agreement with the biological results. Additional molecular modeling studies including surface mapping and contact preferences were performed to emphasize the importance of hydrophobicity. Physicochemical calculations were assessed where compounds 13 and 20 represented very promising orally active drug candidates.

The Impact of D614G Mutation of SARS-COV-2 on the Efficacy of Anti-viral Drugs: A Comparative Molecular Docking and Molecular Dynamics Study.

D614G is one of the most reported mutations in the spike protein of SARS-COV-2 that has altered some crucial characteristics of coronaviruses, such as rate of infection and binding affinities. The binding affinity of different antiviral drugs was evaluated using rigid molecular docking. The reliability of the docking results was evaluated with the induced-fit docking method, and a better understanding of the drug-protein interactions was performed using molecular dynamics simulation. The results show that the D614G variant could change the binding affinity of antiviral drugs and spike protein remarkably. Although Cytarabine showed an appropriate interaction with the wild spike protein, Ribavirin and PMEG diphosphate exhibited a significant binding affinity to the mutated spike protein. The parameters of the ADME/T analysis showed that these drugs are suitable for further in-vitro and in-vivo investigation. D614G alteration affected the binding affinity of the RBD and its receptor on the cell surface.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00284-022-02921-6.

Comparative modeling, comparative molecular docking analyses, and revealing of potential binding pockets of MDM-2: A candidate cancer gene

MDM-2 is also known as E3 ubiquitin-protein ligase encoded by Mdm-2. MDM-2 is an important negative regulator of p53 tumor suppressor and performs key function as an inhibitor of p53 transcriptional activation and E3 ubiquitin ligase. MDM-2 also plays significant role in human cancers and therapeutic target. Hundred different structures were predicted through comparative modeling, threading and ab initio approaches followed by the evaluation of predicted structures through various evaluation tools including ERRAT, ProSa-web, Rampage, molprobidity, verify3D and Anolea. The selected 3D structure of MDM-2 showed 13 α- helix chains, 2 β-pleated sheets along with 97.4468% overall quality factor of the predicted structure. Interestingly, it was observed that only 4.5% residues were present in outlier region and the observed errors were fixed. Moreover, 91.1% residues of the selected structure were present in favored region and 8.9% in allowed region having -6.0 Z-score. High throughput virtual screening and comparative molecular docking studies was performed. Four novel compounds have been reported that showed minimum binding energy (-8.1 Kcal/mol) and maximum binding affinity against MDM-2. Molecular docking analyses revealed that Ser154, Arg155, Pro156, Ser157, Lys185, Ser186, Ser188, Ser190, Ile189, Val247, Glu257, Asp173, Glu174, Glu178, Arg161, Ard181, Lys182, Arg183 and His184 residues are significant residues for therapeutic drug targets. The reported compounds showed effective energy scores. In addition, the site-directed mutagenesis may be helpful for further analyses. The reported compounds may act like potent drug compounds against MDM-2.

Fermentation medium optimization, molecular modelling and docking analysis of the alginate lyase of a novel Pseudomonas sp. LB56 isolated from seaweed waste

Alginate lyase has the potential for the ecofriendly depolymerization of alginate and generation of value-added products important in agriculture, bioenergy, food processing, medical diagnostic and pharmaceutical industries. Substantial research has focused on the cost-effective production of alginate lyase via screening of potent microbial isolates for use as biocatalysts and the optimization of fermentation media with low-cost feedstocks. This study evaluated the alginate lyase-producing efficacy of a novel Pseudomonas sp. LB56 (GenBank accession no. MT176182) isolated from Sargassum seaweed waste. The feedstock for solid-state fermentation (SSF) was decomposed Sargassum biomass amended with cow dung. The production of alginate lyase was maximal using 9.5 g Sargassum, 14 g cow dung and at pH 8 after optimization via a 23–factorial central composite design. Comparative modelling and molecular docking studies were conducted to elucidate the 3D structure of the alginate lyase of this novel isolate, as well as to investigate its catalytic interactions with different polymeric sizes of alginate [polymannuronate (mannuronate disaccharide and mannuronate trisaccharide), polyguluronate (guluronate disaccharide and guluronate trisaccharide) and alginate]. The overall results suggest that biowaste (Sargassum seaweed amended with cow dung) can be used as a feedstock for economical production of alginate lyase. Additionally, the identified active site residues of alginate lyase, which were shared by different polymers of alginate, can be tailored via rational and/or combinatorial approaches for efficient biotransformation of alginate-enriched wastes into biologically active alginate oligomers and third generation biofuels.

A comparative molecular docking study of crocetin with multiple receptors for the treatment of alzheimer's disease

A comparative molecular docking study of crocetin with multiple receptors for the treatment of alzheimer's disease

Design, synthesis, biological evaluation, and molecular docking studies of some novel N,N‐dimethylaminopropoxy‐substituted aurones

AbstractIn continuation of our ongoing research on the discovery of novel and potentially bioactive aurones, we have designed and synthesized some novel N,N‐dimethylaminopropoxy‐substituted pyrazole‐based aurones 10(a‐l). These pyrazole‐benzofuranone hybrid compounds were characterized by using their IR, 1H‐NMR, 13C‐NMR, and mass spectrometry data. Compound 10c was used as a model to further explicate the structure of tilted compounds by means of 1H‐1H COSY, 1H‐13C HMQC, 1H‐13C HMBC, 1H‐1H TOCSY, 1H‐1H NOSEY, DEPT‐45°, DEPT‐90°, and DEPT‐135° NMR spectra. The comparative molecular docking study of N,N‐dimethylaminopropoxy‐substituted pyrazole‐based aurones and standard drugs (Ampicillin and Chloramphenicol) against Bacillus subtilis (PDB: 6tzp) active site was performed to determine the binding interactions, binding energy, and orientation of the molecules at the active site of the target protein. Out of these synthesized compounds, five best analogs (10b, 10f, 10h, 10k, and 10l) of docking results were also evaluated for their in vitro antibacterial potential against Bacillus subtilis to validate the docking results.

Free energy perturbation guided Synthesis with Biological Evaluation of Substituted Quinoline derivatives as small molecule L858R/T790M/C797S mutant EGFR inhibitors targeting resistance in Non-Small Cell Lung Cancer (NSCLC)

Two different schemes of novel substituted quinoline derivatives were designed and synthesized via simple reaction steps and conditions. A comparative molecular docking study was carried out on two different types of EGFR enzymes which include wild-type (PDB: 4I23) and T790M mutated (PDB: 2JIV) respectively. Compounds were also validated upon T790M/C797S mutated (PDB ID: 5D41) EGFR enzyme at the allosteric binding site. Free energy perturbations were carried out to determine the absolute binding free energy of a protein–ligand complex in the form of ΔGbinding, which in turn provided 4ab and 5ad as the most potential contenders through the structural enhancement in the determined initial scaffolds. Anticancer activity of the synthesized derivatives was examined against HCC827, H1975 (L858R/T790M), A549, and HT-29 cell lines by standard MTT assay. Compound 4ad (6-chloro-2-(isoindolin-2-yl)-4-methylquinoline) has shown excellent inhibitory activities against mutant EGFR kinase with IC50 value 0.91 µM. The potency of compounds 4ab, 4ad and 5adwas compared throughan insilicoADMET study.

Synthesis, Spectroscopic, Conceptual DFT Characterization and Molecular Docking Studies of Two Versatile di-Bromobenzaldehyde Derived Compounds

(E)-4,6-dibromo-2-[(2-chlorophenylimino)methyl]-3-methoxyphenol (I) and (E)-4,6-dibromo-2-[(2,5-difluorophenylimino)methyl]-3-methoxyphenol (II) Schiff base compounds were synthesized and characterized by using experimental XRD, FT-IR, UV-Vis. spectroscopic methods and computational methods. Geometry optimizations were done by using Gaussian type orbitals in Gaussian 09 W and Slater type orbitals in ADF2009 software. Spectroscopic studies show that the compounds prefer enol form in both solid and solvent. Scan calculations revealed that the reason for the enol form preference and the energy for prototropic tautomerism. From the biological activity estimations, it was determined that the compounds could be a Monoamine Oxidase Type B inhibitor, and comparative in-silico molecular docking studies with reverse docking of human monoamine oxidase type B protein were performed. Theoretical NLO calculations show that the second-order polarizability values of I and II were over 18 and 13 times that of the urea. Conceptual DFT studies were carried out to determine the reactivity descriptors of the molecules.

Differential specificities of polyphenol oxidase from lotus seeds (Nelumbo nucifera Gaertn.) toward stereoisomers, (−)-epicatechin and (+)-catechin: Insights from comparative molecular docking studies

Lotus seeds are highly susceptible to browning because of the catalysis of polyphenol oxidase (PPO), which caused a tremendous waste of lotus resources, so it is urgent to investigate the PPO in lotus seeds. In this study, lotus seed PPO was gradually purified with 26.92 times fold and a 1.43% yield. The molecular weight of lotus seed PPO was tested at 58 kDa, and its three-dimensional (3D) model consisted of eight α-helices, ten β-sheets, and random coils. A total of 14 phenolic compounds were identified in lotus seeds. However, lotus seed PPO showed different affinity towards these phenolic substrates. Even the stereoisomers, (+)-catechin and (−)-epicatechin, demonstrated disparate Km and Vmax values. Thus, the catalytic mechanism between PPO and these stereoisomeric substrates was explored using comparative molecular docking. In contrast to (+)-catechin, (−)-epicatechin formed more Pi-Alkyl interactions and hydrogen bonds with amino acid residues in the hydrophobic pocket of PPO. (−)-Epicatechin had a lower HOMO-LUMO energy gap and higher molecular ovality after entering the active pocket of PPO than (+)-catechin. To conclude, the catalytic mechanism of lotus seed PPO was clarified by comparative molecular docking studies, and (−)-epicatechin was evidenced as the optimal substrate of lotus seed PPO.