PDB Code Research Articles

Synthesis, spectral characterization of pyrazole derived Schiff base analogs: molecular dynamic simulation, antibacterial and DNA binding studies

We have synthesized the pyrazole-bearing Schiff base derivatives (5a–5e) and (6a–6h) then the structural confirmation was supported by various spectral analyses. The antibacterial activity of all analogs was screened against bacterial strains Staphylococcus aureus, Bacillus subtilis, Enterococcus faecalis, Escherichia coli, Klebsiella pneumonieae and Pseudomonas aeruginosa. In comparison to the reference drug ciprofloxacin, the lead analogs 5c and 6c showed potent activity, with MIC values of 64 µg/mL against E. coli and B. subtilis. Compound 5c showed a moderate effect with a MIC value of 128 µg/mL against B. subtilis, P. aeruginosa and K. pneumonieae, while compound 6c was against E. coli and P. aeruginosa. Furthermore, the compounds 5c and 6c displayed groove binding mode towards CT-DNA by absorption, emission, competitive fluorescence studies using EtBr, CD and time-resolved fluorescence studies. Thermodynamic parameters of analogs 5c and 6c with CT-DNA were also calculated at 298, 303 and 308K temperatures by UV–visible spectroscopy. The molecular docking studies give the docking score for all compounds with PDB codes: 1BNA and 2XCT. The MD simulation study of analogs 5c and 6c was also carried out. The pharmacokinetic and ADME properties were calculated for all of the synthesized analogs (5a–5e) and (6a–6h).Communicated by Ramaswamy H. Sarma

Synthesis, Molecular Docking, and Dynamic Simulation Targeting Main Protease (Mpro) of New, Thiazole Clubbed Pyridine Scaffolds as Potential COVID-19 Inhibitors

Many biological activities of pyridine and thiazole derivatives have been reported, including antiviral activity and, more recently, as COVID-19 inhibitors. Thus, in this paper, we designed, synthesized, and characterized a novel series of N-aminothiazole-hydrazineethyl-pyridines, beginning with a N'-(1-(pyridine-3-yl)ethylidene)hydrazinecarbothiohydrazide derivative and various hydrazonoyl chlorides and phenacyl bromides. Their Schiff bases were prepared from the condensation of N-aminothiazole derivatives with 4-methoxybenzaldehyde. FTIR, MS, NMR, and elemental studies were used to identify new products. The binding energy for non-bonding interactions between the ligand (studied compounds) and receptor was determined using molecular docking against the SARS-CoV-2 main protease (PDB code: 6LU7). Finally, the best docked pose with highest binding energy (8a = -8.6 kcal/mol) was selected for further molecular dynamics (MD) simulation studies to verify the outcomes and comprehend the thermodynamic properties of the binding. Through additional in vitro and in vivo research on the newly synthesized chemicals, it is envisaged that the achieved results will represent a significant advancement in the fight against COVID-19.

Molecular docking analysis of calcium channel blockers with ALR2 and RAGE.

A metabolic condition called diabetes mellitus is linked to a number of substantial challenges. Advanced Glycation End Products (AGEs) and Aldose reductase (ALR2) are crucial in the slow development of several secondary complications. Selected calcium channel blockers (CCB's-1, 4-dihydropyridines) were docked against ALR2 (PDB code: 1Z3N) and RAGE (PDB code: 3CJJ) in the current study. We report that 1, 4-dihydropyridine compounds, particularly Benidipine, bind to the active sites with good efficiency. Thus, 1,4 dihydropyridine derivatives can be considered for further confirmation in drug discovery.

Design and cytotoxic evaluation via apoptotic and antiproliferative activity for novel 11(4-aminophenylamino)neocryptolepine on hepatocellular and colorectal cancer cells.

The current study evaluated the cytotoxic activity of 11(4-Aminophenylamino)neocryptolepine (APAN), a novel derivative of neocryptolepine, on hepatocellular (HepG2) and colon (HCT-116) carcinoma cell lines as well as, the possible molecular mechanism through which it exerts its cytotoxic activity. The APAN was synthesized and characterized based on their spectral analyses. Scanning for anticancer target of APAN by Swiss software indicated that APAN had highest affinity for protein tyrosine kinase 6 enzyme. Furthermore, Super pred software indicated that APAN can be indicated in hepatic and colorectal cells with 92%. Molecular docking studies indicated that the binding affinity scores of APAN for protein PDB code: 6CZ4 of tyrosine kinase 6 recorded of - 6.6084 and RMSD value of 0.8891°A, while that for protein PDB: 7JL7 of caspase 3 was -6.1712 and RMSD of 0.8490°A. Treatment of HepG2 and HCT-116 cells with APAN induced cytotoxicity with IC50 of 2.6 and 1.82μg/mL respectively. In addition, it induced injury and serious morphological changes in cells including, disappearance of microvilli, membrane blebbing, cytoplasmic condensation, and shrunken nucleus with more condensed chromatin. Moreover, APAN significantly increased protein expression of annexin V (apoptotic marker). Furthermore, APAN significantly increased protein expression of caspase 3 and P53. However, it significantly reduced secretion of VEGF protein into the medium and decreased protein expression of PCNA and Ki67 in HepG2 and HCT-116 cells. This study indicated that APAN had cytotoxic activity against HepG2 and HCT-116 cells via increasing the expression of apoptotic proteins and reducing the expression of proliferative proteins.

Insight parameter drug design for human β-tryptase inhibition integrated molecular docking, QSAR, molecular dynamics simulation, and pharmacophore modelling studies of α-keto-[1,2,4]-oxadiazoles

Dengue hemorrhagic fever (DHF) is severe dengue with a hallmark of vascular leakage. β-tryptase has been found to promote vascular leakage in DHF patients, which could be a potential target for DHF treatment. This study aims to develop a theoretical background for designing and selecting human β-tryptase inhibitors through computational studies. Thirty-four α-keto-[1,2,3]-oxadiazoles scaffold-based compounds were used to generate 2D-QSAR models and for molecular docking studies with β-tryptase (PDB Code 4A6L). In addition, molecular dynamics (MD) simulation and molecular mechanics generalised born surface area (MM-GBSA) analysis on the binding of the reported most active compound, compound 11e, towards β-tryptase were performed. Finally, a structure-based pharmacophore model was generated. The selected 2D-QSAR models have statistically proven good models by internal and external validation as well as the y-randomization test. The docking results of compound 11e showed lower CDOCKER energy than the 4A6L co-crystallised ligand and a similar binding pattern as the 4A6L co-crystallised ligand. From molecular dynamics simulation, 4A6L in compound 11e bound state has RMSD below 2 Å throughout the 500 ns simulation, indicating the docked complex is stable. Besides, MM-GBSA analysis suggested the 4A6L-compound 11e docked complex (−66.04 Kcal/mol) is structurally as stable as the 4A6L-native ligand co-crystallized structure (−66.84 Kcal/mol). The best pharmacophore model identified features included hydrogen bond acceptor, ionic interaction, hydrophobic interaction, and aromatic ring, which contribute to the inhibitory potency of a compound. This study supplied insight and knowledge for developing novel chemical compounds with improved inhibition of β-tryptase. Communicated by Ramaswamy H. Sarma

3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer.

Overexpression of polo-like kinase 1 (PLK1) has been found in many different types of cancers. With its essential role in cell proliferation, PLK1 has been determined to be a broad-spectrum anti-cancer target. In this study, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations were applied on a series of novel pteridinone derivatives as PLK1 inhibitors to discover anti-cancer drug candidates. In this work, three models-CoMFA (Q² = 0.67, R² = 0.992), CoMSIA/SHE (Q² = 0.69, R² = 0.974), and CoMSIA/SEAH (Q² = 0.66, R² = 0.975)-of pteridinone derivatives were established. The three models that were established gave Rpred2 = 0.683, Rpred 2= 0.758, and Rpred 2= 0.767, respectively. Thus, the predictive abilities of the three proposed models were successfully evaluated. The relations between the different champs and activities were well-demonstrated by the contour chart of the CoMFA and CoMSIA/SEAH models. The results of molecular docking indicated that residues R136, R57, Y133, L69, L82, and Y139 were the active sites of the PLK1 protein (PDB code: 2RKU), in which the more active ligands can inhibit the enzyme of PLK1. The results of the molecular dynamic MD simulation diagram were obtained to reinforce the previous molecular docking results, which showed that both inhibitors remained stable in the active sites of the PLK1 protein (PDB code: 2RKU) for 50 ns. Finally, a check of the ADME-Tox properties of the two most active molecules showed that molecular N° 28 could represent a good drug candidate for the therapy of prostate cancer diseases.

IN SILICO STUDY OF NOVEL SULFONAMIDE DERIVATIVES BEARING A 1, 2, 4-TRIAZOLE MOIETY ACT AS CARBONIC ANHYDRASE INHIBITORS WITH PROMISING ANTI-CANCER ACTIVITY

Aim: To evaluate the theoretical binding affinities of four synthetic compounds that target the carbonic anhydrase IX enzyme in solid tumors. Materials and Methods: To accurately depict the molecular structure, we utilized the Chem Draw Professional 12.0 program. We downloaded the carbonic anhydrase IX enzyme (29.25 KDa) (PDB code: 4YWP) from the Protein Data Bank into the Molecular Operating Environment software. Then, the S-score and rmsd were calculated for the proposed compounds. Results: The theoretically synthesized compounds demonstrated good binding affinities with the receptor active pockets Sa, Sb, and Sd, with S-scores of -7.6491, -8.3789, and -8.3218, respectively. Substitutions improve compound orientation. The substituted triazoles ring increases flexibility and receptor interaction. In addition, the benzyl chloride derivatives play an important role in the interaction, with varying effects dependent on the groups substituted at position 4 of the benzene ring. Conclusions: The synthesized compounds Sb with para Br substitution (S-score = -8.37) and Sd with para Cl substitution (S-score = -8.32) are considered the best ones as they exhibit a high affinity for the receptor.

Design, synthesis and biological evaluation of phenanthridine amide and 1,2,3-triazole analogues against Mycobacterium tuberculosis.

The phenanthridine core exhibits antitubercular activity, according to reports from the literature. Several 1,2,3-triazole-based heterocyclic compounds are well-known antitubercular agents. A series of twenty-five phenanthridine amide and 1,2,3-triazole derivatives are synthesized and analyzed using ESI-MS, 1HNMR, and 13CNMR on the basis of our earlier findings that phenanthridine and 1,2,3-triazoles shown good antitubercular activity. The synthesized phenanthridine amide and 1,2,3-triazole analogues were tested in vitro against Mycobacterium tuberculosis H37Rv and minimum inhibitory concentration (MIC) values were determined utilizing non-replicating and replicating low-oxygen recovery assay (LORA) and microplate Alamar Blue assay (MABA) methodologies. The phenanthridine amide derivative PA-01 had an MIC of 61.31 μM in MABA and 62.09 μM in the LORA technique, showing intense anti-TB activity. Amongst the phenanthridine triazole derivatives, PT-09, with MICs of 41.47 and 78.75 μM against the tested strain of Mtb in both MABA and LORA was the most active one. The final analogues' drug-likeness is predicted using absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies. The most active compounds PA-01 and PT-09 were further subjected to in silico docking studies. Using the Glide module of Schrodinger, molecular docking analysis was carried out to estimate the plausible binding pattern of PA-01 and PT-09 at the active site of Mycobacterial DNA topoisomerase II (PDB code: 5BS8). Further, molecular dynamics studies of PA-01 and PT-09 were also carried out.

Design, synthesis, spectral characterization, multiple-biological activities, docking and in silico ADMET studies of thiazolidinones

A series of novel thiazolidinones (5a-5i) are synthesized and characterized by FT-IR, 1H NMR and 13C NMR spectral studies. Docking studies were carried out for the synthesised compound using the protein PDB Code 1HNY, 1VMP and 3A4A and it proved that all the synthesised compounds exhibit better binding affinity in all the above said proteins. Based on the docking results of all the newly synthesized compounds are screened for their anti-diabetic, anti-inflammatory and anti-oxidant activities. The synthesized compounds showed a very good potent activity towards anti-diabetic and anti-inflammatory properties compared with standard and exhibit moderate anti-oxidant activity than standard. Furthermore, to analysis the physiochemical and pharmacokinetic features of the compounds (5a-5i) are analysed using the SwissADME online application.

In silico Studies, Synthesis and Antibacterial Activity of Heterocyclic Compounds with Mannich Bases

Aim The present study aimed to identify the potent 123-triazole derivatives for synthesis and also assess their anti-bacterial activity.Methodology In silico design of novel analogues was carried out for ten derivatives using Auto Dock Vina and compared with standard drug Ciprofloxacin. Swiss ADME software was used to analyze lsquoLipinski Rule of Fiversquo and drug likeness properties. Three derivatives which obeyed rule of five having desired physicochemical properties and highest docking score were synthesized PDB code 2K35. The synthesis was carried out in two step process to determine their antibacterial activity. The synthesized compounds were structurally elucidated using Fourier-transform infrared spectroscopy FTIR Nuclear Magnetic Resonance 1H NMR and Mass spectroscopy .Results Antibacterial activity of different compounds was observed by disc diffusion method against two organisms E. coli and Streptococcus. Among the tested compounds 4A showed significant antibacterial activity. Compounds 6A and 8A also exhibited appreciable antibacterial activity against E. coli while compound 6A showed appreciable antibacterial activity against Streptococcus.Conclusion According to data obtained from the present study piperazine incorporated triazole derivatives were found to possess effective antibacterial activity. Further modifications of triazole based compounds at different positions to generate new molecules with potent anti-tumor activities will be described in future.

Structure, Quantum Chemical and In Silico Molecular Docking Analysis of some Di-Ortho-Substituted Halogenated Biphenyls

The structures of three di-ortho-substituted halogenated biphenyls have been revisited for their optimized geometry and other quantum chemical investigations. The X-ray data, in conjunction with quantum chemical investigations, reveals some interesting results. The Hirshfeld surface analysis helps visualize various intermolecular interactions and the energy frameworks dwell further on the dominant interaction energy component for each structure. To study the inhibitory behaviour of each biphenyl against Cytochrome-P450-14alpha-sterol demethylase fungal enzyme (PDB code: 1EA1), the results of molecular docking studies suggest that the di-ortho-substituted halogenated biphenyls may be regarded as effective and efficient antifungal drugs.

DESIGN, SYNTHESIS AND ANTIBACTERIAL EVALUATION OF SOME NEW COUMARIN FUSED OXAZOLE DERIVATIVES

A new series of dihydro-1, 2-oxazole coumarin derivatives (SR1-SR10) was prepared using a multi-step reaction. The syntheses of intermediates coumarinyl chalcones and final compounds were characterized by IR, Mass, and 1 H NMR spectra. The final compound’s SR1-SR10 binding mode and its inhibitor susceptibility were studied by molecular docking with the receptor DNA gyrase B (PDB code: 5L3J). It is responsible for catalyzing changes during DNA replication and validated targets for antibacterial molecules. The docking score of compounds SR1-SR10 ranges from -4.18 to -2.15 kcal mol-1. Among all these compounds, chloro-substituted dihydro isoxazole chromen-2-one (SR10) showed the best docking score with -4.18 kcal mol-1. SR10 interacted with the ATP-binding site of E. coli DNA gyrase B through a hydrogen bond with GLY77 and hydrophobic bond, charged negatives and polar interaction. SR1-SR10 antibacterial inhibitory property by tube dilution method was performed, and its minimum inhibitory concentrations (MIC) were observed. The MIC values of (SR1-SR10) range from 3.12 to 25 µg mL-1. Compounds SR3 and SR10 showed significant antibacterial activity with a MIC value of 3.12 µg mL-1

Difference in the Inhibitory Effect of Thiol Compounds and Demetallation Rates from the Zn(II) Active Site of Metallo-β-lactamases (IMP-1 and IMP-6) Associated with a Single Amino Acid Substitution

Gram-negative bacteria producing metallo-β-lactamases (MBLs) have become a considerable threat to public health. MBLs including the IMP, VIM, and NDM types are Zn(II) enzymes that hydrolyze the β-lactam ring present in a broad range of antibiotics, such as N-benzylpenicillin, meropenem, and imipenem. Among IMPs, IMP-1 and IMP-6 differ in a single amino acid substitution at position 262, where serine in IMP-1 is replaced by glycine in IMP-6, conferring a change in substrate specificity. To investigate how this mutation influences enzyme function, we examined lactamase inhibition by thiol compounds. Ethyl 3-mercaptopropionate acted as a competitive inhibitor of IMP-1, but a noncompetitive inhibitor of IMP-6. A comparison of the crystal structures previously reported for IMP-1 (PDB code: 5EV6) and IMP-6 (PDB code: 6LVJ) revealed a hydrogen bond between the side chain of Ser262 and Cys221 in IMP-1 but the absence of hydrogen bond in IMP-6, which affects the Zn2 coordination sphere in its active site. We investigated the demetallation rates of IMP-1 and IMP-6 in the presence of chelating agent ethylenediaminetetraacetic acid (EDTA) and found that the demetallation reactions had fast and slow phases with a first-order rate constant (kfast = 1.76 h-1, kslow = 0.108 h-1 for IMP-1, and kfast = 14.0 h-1 and kslow = 1.66 h-1 for IMP-6). The difference in the flexibility of the Zn2 coordination sphere between IMP-1 and IMP-6 may influence the demetallation rate, the catalytic efficiency against β-lactam antibiotics, and the inhibitory effect of thiol compounds.

Efficient Production of Epoxy-Norbornane from Norbornene by an Engineered P450 Peroxygenase.

Epoxy-norbornane (EPO-NBE) is a crucial building block for the synthesis of various biologically active heterocyclic systems. To develop an efficient protocol for producing EPO-NBE using norbornene (NBE) as a substrate, cytochrome P450 enzyme from Pseudomonas putida (CYP238A1) was examined and its crystal structure (PDB code: 7X53) was resolved. Molecular mechanism analysis showed a high energy barrier related to iron-alkoxy radical complex formation. Therefore, a protein engineering strategy was developed and an optimal CYP238A1NPV variant containing a local hydrophobic "fence" at the active site was obtained, which increased the H2 O2 -dependent epoxidation activity by 7.5-fold compared with that of CYP238A1WT . Among the "fence", Glu255 participates in an efficient proton transfer system. Whole-cell transformation using CYP238A1NPV achieved an EPO-NBE yield of 77.6 g ⋅ L-1 in a 30-L reactor with 66.3 % conversion. These results demonstrate the potential of this system for industrial production of EPO-NBE and provides a new biocatalytic platform for epoxidation chemistry.

Design, Synthesis, Docking Studies and Biological Evaluation of Novel Benzochromenopyrimidines via Silica Sulfuric Acid Catalyzed Reaction on Apoptosis in Human Cancer Cells

Via one-pot reaction of 2-naphthol, thiobarbituric acid and aldehyde in the presence of silica sulfuric acid (SSA) as a catalyst to synthesis benzochromenopyrimidines derivatives. Then we studied the reaction of benzochromenopyrimidines derivatives with bromoacetic acid to obtain benzo[5,6]chromeno[2,3-d]thiazolo[3,2-a]pyrimidine-11,13(10H,14H)-dione derivatives. Meanwhile, dichloroethane was reacted with 12-(4-fluorophenyl)-9-thioxo-9,10-dihydro-8H-benzo[5,6]chromeno[2,3-d]pyrimidin-11(12H)-one to form 14-(4-fluorophenyl)-10,11-dihydrobenzo[5,6]chromeno[2,3-d]thiazolo[3,2-a]pyrimidin-13(14H)-one. All new products structure was elucidated based on analytical and spectroscopic analyses. Anti-cancer activity of newly synthesized structures was investigated. Cancer cells (MDA-MB-231 and HepG2) were used to evaluate the anti-cancer activity of tested compounds using neutral red uptake assay. Treatment of MDA-MB-231 and HepG2 cells with tested compound 6h revealed more inhibitory influence after 48 h. The expression levels of BCL2, BAX, Caspase3, Survivin and P53 genes were investigated using QRT-PCR. This study exhibited that compound 6h revealed significant pro-apoptotic effect via down regulation of BCL2 and Survivin genes and up-regulation of BAX, Caspase3 and P53 genes when treated with MDA-MB-231 and HepG2 cells as compared to control values. The biological studies of these compounds were proved through molecular docking studies with human cyclin-dependent kinase 2 (PDB code: 2A4L) and compound 6h showed low binding energy and shortage bond length with different amino acids. Noteworthy, the tested compound 6h exhibited the most pronounced effect in this respect.

In silico studies and antimicrobial investigation of synthesised novel N-acylhydrazone derivatives of indole

Indole is an exceptional scaffold in the discovery and design of drugs with different mechanisms and biological activity. Numerous research has been conducted on N-acylhydrazones of indole and its derivatives, however, no account of the synthesis, molecular docking and the antimicrobial activities of the eleven synthesised compounds has never been reported. The study was therefore designed to synthesize, characterize, carry out molecular docking and determine the antimicrobial activities of novel N-acylhydrazone derivatives of indole.Aldol condensation of synthesised hydrazides with aromatic aldehydes led to the formation of the N-acylhydrazone derivatives of indole. The structure of the compounds were confirmed by proton nuclear magnetic Resonance (1H NMR) and electron impact mass spectrometry (EIMS). The N-acylhydrazones were screened against ten microbes (four fungi three Gram-positive bacteria, and three Gram-negative bacteria) at concentrations of 100 to 6.26 mg/mL, using agar well diffusion and fungi carpeted antimicrobial assays. Gentamicin (5 mg/mL) was the positive control for bacteria while tioconazole (70%) was used for fungi. The molecular docking studies was done and the docking scores recorded accordingly on four antimicrobial receptors with PDB codes (3CR7, 3FHV, 6L1L and 6SPC).The synthesised compounds displayed moderate activity against the test organisms with the zone of inhibitions range 24 ± 0.00 to 18 ± 0.70 mm at 100 mg/mL as compared to the standards (gentamicin 10 µg/mL (36 ± 1.41), tioconazole 70% (26 ± 4.24)). All synthesised N-acylhydrazone derivatives exhibited a good number of hydrophobic interactions, classical and non-classical hydrogen bonding with the docked protein enzymes. Compound 10 and 1 were predicted to exhibit highest binding energy of -9.7 and -9.2 kcal/mole respectively with the binding site of 6SPC. Other compounds were found to have higher predicted binding energies than the standard drugs. Previously, there has been no report on the synthesis of N-acylhydrazone derivatives of Indole used in this study, their molecular docking and antimicrobial analyses is being reported for the first time. Since microbial resistance poses a major threat to human health globally, this research screened the synthesised compounds on fungi and bacteria and were found to be active against the selected microbes. These compounds if ameliorated, will reduce the uncontrollable rise in the multidrug-resistant (MDR) bacteria in Africa and in the universe.Therefore, since the synthesised N-acylhydrazone derivatives have potential in inhibiting microbial growth and showed good binding parameters with the tested enzymes, they could be effectively developed into antimicrobial agents useful for treating a wide range of microbial infections. Further research should conducted on the drugability, toxicity, minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of the drug compounds.

Binding Properties of Photosynthetic Herbicides: Photosynthetic Activity and Molecular Docking Approach towards 1,4-Dihydropyridines Derivatives.

In the current work, we describe the synthesis of 1,4-dihydropyridine (1,4-DHP) derivatives via Hantzsch multicomponent reaction and their evaluation as photosystem II (PSII) inhibitors through chlorophyll a fluorescence bioassay. Among all the compounds tested, 1,1'-(2,4,6-trimethyl-1,4-dihydropyridine-3,5-diyl)bis(ethan-1-one) (4b) showed best results, reducing the parameters performance index on absorption basis (PIabs ) and electron transport per reaction center by 61 % and 49 %, respectively, as compared to the control. These results indicate the inhibitory activity of PSII over the electron transport chain. Additionally, a molecular docking approach using the protein D1 (PDB code 4V82) was performed in order to assess the structure-activity relationship among the 1,4-DHP derivatives over the PSII, which revealed that both, size of the group at position 4 and the carbonyl groups at the dihydropyridine ring are important for the ligand's interaction, particularly for the hydrogen-bonding interaction with the residues His215, Ser264, and Phe265. Thus, the optimization of these molecular features is the aim of our research group to extend the knowledge of PSII electron chain inhibitors and the establishment of new potent bioactive molecular scaffolds.

IN SILICO STUDY OF 12 PHYTOSTEROL COMPOUNDS IN MORINGA (MORINGA OLEIFERA LAMK.) SEED OIL ON 5Α-REDUCTASE ENZYME INHIBITION ACTIVITY AS ANTI-ALOPECIA

Objective: This study aimed to determine the interaction of 12 phytosterol compounds in moringa seed oil to the 5α-reductase enzyme (PDB code: 7BW1) as anti-alopecia by in silico.
 Methods: The research was conducted using a molecular docking approach using autodock Tools 1.5.6. Data analysis was carried out by looked at the binding affinity values ​​and inhibition constants (Ki) of 12 phytosterol compounds, as well as visualization of amino acid interactions using Biovia Discovery Studio 2021.
 Results: 12 Phytosterol compounds had the potential to be a candidate for anti-alopecia medicines based on in silico test simulations using auto dock with high binding affinity values ​​in the range of-11.47 to-12.76 kcal/mol and stable inhibition constants in the range of 1.87. nM–4.30 nM involving hydrogen bonds with Arg179, Tyr178, Arg105, Arg114, Ser177, Tyr98, Glu57, and Tyr91 amino acids.
 Conclusion: Ergostadienol compound in moringa seed oil was predicted to be a better anti-alopecia on the inhibition of 5α-reductase enzyme with binding energy value was-11.60 kcal/mol, inhibition constant was 3.17 nM and interaction of amino acid residues on the inhibition of 5α-reductase enzyme was similar with native finasteride ligands namely Glu57 and Tyr91.

Evaluation of anticancer activities, apoptosis, molecular docking, and antioxidant studies of new Ni(II), VO(IV), Cu(II) and Co(III) Schiff base complexes

New Schiff base complexes have been synthesized via appropriate conventional methods using 2-ethoxy-6-(E)-[(prop-2-em-1-yl)imino]methylphenol (HL) as a Schiff base ligand. The compounds obtained were characterized by spectral analysis and X-ray diffraction. Recrystallization from methanol provided single crystals with rod-shaped (1) and rhombus-shaped (2) shapes. The complexes were found to be composed of NiL2 and (VO)L2, with the anionic ligand L- acting as a bidentate ligand, coordinating to metal centers via imino N and hydroxyl oxygen atoms in all cases. Compound (1) crystallizes in the orthorhombic system with the Pccn space group, while compound (2) crystallizes in the monoclinic system with the P21/n space group. Cyclic voltammetry experiments in DMF show a metal-centered reduction peak at (−1.23), (−1.32), (−0.82, 1.36), and (−0.61, −1.55) V, corresponding to the Ni II/NiI, VO2+/VO+, CuII/CuI, and CoIII/II-CoII/I, respectively. The complexes were evaluated for anticancer activity in a human tumor cell line (HT-29). 5-fluorouracil was used as a standard drug. All tested compounds of Schiff base ligand and complexes (1–4) showed anticancer activity with inhibitory concentration (IC50) values of 85.28(HL), 15.13(1), 10.83(2), 28.53(3) and 30.21(4) (μM), respectively. The in vitro cytotoxicity screening results revealed that all compounds showed promising activity against colorectal cancer. In particular, compounds (1) and (2) showed excellent activity against tumor cell lines. The antioxidant activity of the synthesized Schiff base was determined using the DPPH method (1, 1-diphenyl-2- picryl hydrazyl). The effective concentration (EC50) indicates that all compounds have good antioxidant activity (EC50 = 143.02(HL), 168.03(1), 27.31(2), 160.3(3) and 173.41(4). The biological activity spectra of synthesized compounds are predicted by the Pass Online Web Resource. In addition to the PASS program's prediction, molecular docking studies were also performed to find bind affinity to protein cyclooxygenase inhibitor (the structure PDB code 1CX2).

Abstract B040: In silico drug design using KRASG12C as a theranostic target for pancreatic cancer

Abstract Pancreatic cancer is one of the most lethal malignancies worldwide, it often results in therapeutic failure and unfavorable outcome because of the absence of screening strategies, difficulties in tumor early detection due to the lack of specific signs/symptoms and aggressive behavior of the disease. Early detection of this cancer is a challenge with the technology we have, its late detection results in a poor outcome and reduced quality of life for the patient. The treatment success depends on surgical intervention, which is not always possible. Thus, trying to find alterations that occur in the early stages of pancreatic cancer is needed. Taking into consideration that the accumulation of genetic and epigenetic alterations results in a complex and heterogeneous disease, each patient has a unique tumor. The heterogeneity of cancer is not restricted to inter-patient differences but, intra-tumoral heterogeneity contributes to functional properties of tumor cell subclones, including proliferative capacity and progression to aggressive phenotypes such as drug tolerance and metastatic potential. Driver mutations are responsible for malignant transformation and tumor progression across different cancer types. One of the most common driver mutations are those leading to the constitutive activation of KRAS oncogene, a GTPase enzyme responsible for cell proliferation and survival that is frequently mutated in pancreatic cancer. Gain-of-function mutation of KRAS gene leads to a protein constitutively activated, which stimulates the proliferation of tumor cells. The c.34G>T missense mutation (rs121913530) causes the substitution of glycine for cysteine in the encoded protein KRASG12C; this mutation has been related to poorer prognosis and therapy resistance in lung cancer. As KRAS occurs before the progression of pancreatic cancer to invasive carcinoma, it is a promising target for new biomarker development. We design three near-infrared probe-drug conjugate directed to the KRASG12C and to predict in silico the best orientation and conformation of the test compounds bound to the KRAS G12C (PDB code: 6OIM), the PyRx program was used, which uses AutoDock Vina as docking software. Based on these profiles and structures of the compounds, AutoDock Vina infers the possible pharmacological interactions and allows the most promising compounds to be classified according to the studied biological activity, using the empirical score function for this classification. The AMG 510 (established inhibitor) and GDP (endogenous activator) were used as a reference to establish the docking box coordinates. The binding energy of the three compounds predicted by docking was analyzed and classified according to the binding affinity described in Kcal/mol. The tested compounds show an excellent affinity for this protein based on the binding energy results obtained by docking using the crystallized KRAS G12C protein. Therefore, they could be great candidates for further chemical synthesis studies aiming to improve diagnosis, treatment, and patient survival in pancreatic cancer. Citation Format: Barbara M. Barbosa, Allana C. F. Martins, Roberto S. Gomes, Claudia A. Rainho. In silico drug design using KRASG12C as a theranostic target for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B040.