Binding mechanism of spinosine and venenatine molecules with p300 HAT enzyme: Molecular screening,molecular dynamics and free-energy analysis

The chromatin modification is regulated by the histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) enzymes; abnormal function of these enzymes leads to several malignant diseases. The inhibition of these enzymes using natural ligand molecules is an emerging technique to cure these diseases. The in vitro analysis of natural molecules, venenatine, spinosine, palmatine and taxodione are giving the best inhibition rate against p300 HAT enzyme. However, the detailed understanding of binding and the stability of these molecules with p300 HAT is not yet known. The aim of the present study is focused to determine the binding strength of the molecules from molecular dynamics simulation analysis. The docking analysis confirms that, the venenatine (−6.97 kcal/mol - conformer 8), spinosine (−6.52 kcal/mol conformer −10), palmatine (−5.72 kcal/mol conformer-3) and taxodione (−4.99 kcal/mol conformer-4) molecules form strong hydrogen bonding interactions with the key amino acid residues (Arg1410, Thr1411 and Trp1466) present in the active site of p300. In the molecular dynamics (MD) simulation, the spinosine retain these key interactions with the active site amino acid residues (Arg1410, Thr1411, and Trp1466) than venenatine and are stable throughout the simulation. The RMSD value of spinosine (0.5 to 1.3 Å) and venenatine (0.3 to 1.3 Å) are almost equal during the MD simulation. However, during the MD simulation, the intermolecular interaction between venenatine and the active site amino acid residues (Arg1410, Thr1411, and Trp1466) decreased on comparing with the spinosine-p300 interaction. The binding free energy of the spinosine (−15.30 kcal/mol) is relatively higher than the venenatine (−11.8 kcal/mol); this increment is attributed to the strong hydrogen bonding interactions of spinosine molecule with the active site amino acid residues of p300.     

In silico docking and molecular dynamics simulation of 3-dehydroquinate synthase (DHQS) from <Emphasis Type="Italic">Mycobacterium tuberculosis</Emphasis>

The shikimate pathway is as an attractive target because it is present in bacteria, algae, fungi, and plants but does not occur in mammals. In Mycobacterium tuberculosis (MTB), the shikimate pathway is integral to the biosynthesis of naphthoquinones, menaquinones, and mycobactin. In these study, novel inhibitors of 3-dehydroquinate synthase (DHQS), an enzyme that catalyzes the second step of the shikimate pathway in MTB, were determined. 12,165 compounds were selected from two public databases through virtual screening and molecular docking analysis using PyRx 8.0 and Autodock 4.2, respectively. A total of 18 compounds with the best binding energies (?13.23 to ?8.22 kcal/mol) were then selected and screened for absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, and nine of those compounds were found to satisfy all of the ADME and toxicity criteria. Among those nine, the three compounds—ZINC633887?(binding energy =??10.29 kcal/mol), ZINC08983432?(?9.34 kcal/mol), and PubChem73393?(?8.61 kcal/mol)—with the best binding energies were further selected for molecular dynamics (MD) simulation analysis. The results of the 50-ns MD simulations showed that the two compounds ZINC633887 and PubChem73393 formed stable complexes with DHQS and that the structures of those two ligands remained largely unchanged at the ligand-binding site during the simulations. These two compounds identified through docking and MD simulation are potential candidates for the treatment of TB, and should undergo validation in vivo and in vitro.     

Structural basis of pesticide detection by enzymatic biosensing: a molecular docking and MD simulation study

Designing of rapid, facile, selective, and cost-effective biosensor technology is a growing area for the detection of various classes of pesticides. The biosensor with these features can be achieved only through the various bio-components using different transducers. This study, therefore, focuses on the usage of molecular docking, specificity tendencies, and capabilities of proteins for the detection of pesticides. Accordingly, the four transducers, acetylcholinesterase (ACH), cytochromes P450 (CYP), glutathione S-transferase (GST), and protein kinase C (PKC) were selected based on their applications including neurotransmitter, metabolism, detoxification enzyme, and protein phosphorylation. Then after molecular docking of the pesticides, fenobucarb, dichlorodiphenyltrichloroethane (DDT), and parathion onto each enzyme, the conformational behavior of the most stable complexes was further analyzed using 50 ns Molecular Dynamics (MD) simulations carried out under explicit water conditions. In the case of protein kinase C (PKC) and cytochrome P450 3A4 enzyme (CYP), the fenobucarb complex showed the most suitable combination of free energy of binding and inhibition constant ?4.42 kcal/mol (573.73 μM) and ?5.1 kcal/mol (183.49 μM), respectively. Parathion dominated for acetylcholinesterase (ACH) with ?4.57 kcal/mol (448.09 μM) and lastly dichlorodiphenyltrichloroethane for glutathione S-transferase (GST), ?5.43 kcal/mol (103.88 μM). The RMSD variations were critical for understanding the impact of pesticides as they distinctively influence the energetic attributes of the proteins. Overall, the outcomes from the extensive analysis provide an insight into the structural features of the proteins studied, thereby highlighting their potential use as a substrate in biorecognition sensing of pesticide compounds.     

Renin inhibition by soyasaponin I: a potent native anti-hypertensive compound

One way to control hypertension is inactivation of the Renin- Angiotensin- Aldosterone System (RAAS). Inhibition of renin as a rate-limiting step of this system is an effective way to stop up RAAS. It has been proved that soyasaponin I, an herbal compound obtained from soybeans, has anti-hypertensive effect via renin inhibition, so it has the potential of being an anti-hypertensive drug. Herein, some theoretical approaches such as Docking Simulation, Molecular Dynamics (MD) Simulation and MMPBSA analysis have been used to study how soyasaponin I inhibits renin at the structural level. The results of docking simulation and hydrogen bond pattern show that this ligand is able to bind to the active site of renin and a region near the active site. Results of MD simulation for renin – soyasaponin I complexes confirm that soyasaponin I binds to the active site of renin and has inhibition effect on it via competing with the substrate. Besides, according to MMPBSA analysis, the binding free energy for renin – soyasaponin I complex is ?42.61 kcal/mol when it binds to the active site. Comparing to the peptide obtained from angiotensinogen, ΔG = ?74.96 kcal/mol, it may inferred that although binding of soyasaponin I to the active site of renin does not have a complete competition with the substrate, it might attenuate the formation of renin – angiotensinogen complex and have partial non-competitive effect. The results of this survey might be helpful to design partial non – competitive renin inhibitors with pharmaceutical capability.     

Dynamics of fluoroquinolones induced resistance in DNA gyrase of Mycobacterium tuberculosis

DNA gyrase is a validated target of fluoroquinolones which are key components of multidrug resistance tuberculosis (TB) treatment. Most frequent occurring mutations associated with high level of resistance to fluoroquinolone in clinical isolates of TB patients are A90V, D94G, and A90V–D94G (double mutant [DM]), present in the larger subunit of DNA Gyrase. In order to explicate the molecular mechanism of drug resistance corresponding to these mutations, molecular dynamics (MD) and mechanics approach was applied. Structure-based molecular docking of complex comprised of DNA bound with Gyrase A (large subunit) and Gyrase C (small subunit) with moxifloxacin (MFX) revealed high binding affinity to wild type with considerably high Glide XP docking score of ?7.88 kcal/mol. MFX affinity decreases toward single mutants and was minimum toward the DM with a docking score of ?3.82 kcal/mol. Docking studies were also performed against 8-Methyl-moxifloxacin which exhibited higher binding affinity against wild and mutants DNA gyrase when compared to MFX. Molecular Mechanics/Generalized Born Surface Area method predicted the binding free energy of the wild, A90V, D94G, and DM complexes to be ?55.81, ?25.87, ?20.45, and ?12.29 kcal/mol, respectively. These complexes were further subjected to 30 ns long MD simulations to examine significant interactions and conformational flexibilities in terms of root mean square deviation, root mean square fluctuation, and strength of hydrogen bond formed. This comparative drug interaction analysis provides systematic insights into the mechanism behind drug resistance and also paves way toward identifying potent lead compounds that could combat drug resistance of DNA gyrase due to mutations.     

Drug targeted virtual screening and molecular dynamics of LipU protein of Mycobacterium tuberculosis and Mycobacterium leprae

The lipolytic protein LipU was conserved in mycobacterium sp. including M. tuberculosis (MTB LipU) and M. leprae (MLP LipU). The MTB LipU was identified in extracellular fraction and was reported to be essential for the survival of mycobacterium. Therefore to address the problem of drug resistance in pathogen, LipU was selected as a drug target and the viability of finding out some FDA approved drugs as LipU inhibitors in both the cases was explored. Three-dimensional (3D) model structures of MTB LipU and MLP LipU were generated and stabilized through molecular dynamics (MD). FDA approved drugs were screened against these proteins. The result showed that the top-scoring compounds for MTB LipU were Diosmin, Acarbose and Ouabain with the Glide XP score of ?12.8, ?11.9 and ?11.7 kcal/mol, respectively, whereas for MLP LipU protein, Digoxin (?9.2 kcal/mol), Indinavir (?8.2 kcal/mol) and Travoprost (?8.2 kcal/mol) showed highest affinity. These drugs remained bound in the active site pocket of MTB LipU and MLP LipU structure and interaction grew stronger after dynamics. RMSD, RMSF and Rg were found to be persistent throughout the simulation period. Hydrogen bonds along with large number of hydrophobic interactions stabilized the complex structures. Binding free energies obtained through Prime/MM-GBSA were found in the significant range from ?63.85 kcal/mol to ?34.57 kcal/mol for MTB LipU and ?71.33 kcal/mol to ?23.91 kcal/mol for MLP LipU. The report suggested high probability of these drugs to demolish the LipU activity and could be probable drug candidates to combat TB and leprosy disease.     

Molecular simulation of N-acetylneuraminic acid analogs and molecular dynamics studies of cholera toxin-Neu5Gc complex

Cholera toxin (CT) is an AB₅ protein complex secreted by the pathogen Vibrio cholera, which is responsible for cholera infection. N-acetylneuraminic acid (NeuNAc) is a derivative of neuraminic acid with nine-carbon backbone. NeuNAc is distributed on the cell surface mainly located in the terminal components of glycoconjugates, and also plays an important role in cell–cell interaction. In our current study, molecular docking and molecular dynamic (MD) simulations were implemented to identify the potent NeuNAc analogs with high-inhibitory activity against CT protein. Thirty-four NeuNAc analogs, modified in different positions C-1/C-2/C-4/C-5/C-7/C-8/C-9, were modeled and docked against the active site of CT protein. Among the 34 NeuNAc analogs, the analog Neu5Gc shows the least extra precision glide score of ?9.52 and glide energy of ?44.71?kcal/mol. NeuNAc analogs block the CT active site residues HIS:13, ASN:90, LYS:91, GLN:56, GLN:61, and TRP:88 through intermolecular hydrogen bonding. The MD simulation for CT-Neu5Gc docking complex was performed using Desmond. MD simulation of CT-Neu5Gc complex reveals the stable nature of docking interaction.     

Molecular modeling studies and anti-TB activity of trisubstituted indolizine analogues; molecular docking and dynamic inputs

A series of trisubstituted indolizine analogues has been designed as a result of a fragment-based approach to target the inhibition of mycobacterial enoyl-acyl carrier protein reductase. Anti-tuberculosis (TB) screening of the characterized compounds by a resazurin microplate assay method revealed that ethyl group at second position of indolizine nucleus exhibited activity against susceptible and multidrug-resistant strains of Mycobacterium tuberculosis at concentration of 5.5 and 11.3 μg/mL, respectively. A molecular docking study was also conducted to evaluate the stability of the active compounds, and compound with ethyl substitution at second position of indolizine nucleus showed the highest free binding energy of ΔG ?24.11 (kcal/mol), a low clash score of 3.04, and high lipo score of ?13.33. Indolizine analog with ethyl substitution at second position demonstrated Molecular Mechanics/Generalized Born Surface Area (?23.85 kcal/mol). Two molecular dynamics studies were computed (100 ps and 50 ns) to calculate the relationship between the potential and kinetic energies of the active anti-TB compound with time and temperature. The discovery of this lead may have a positive impact on anti-TB drug discovery.     

A computational study of binding between 3-(4-fluorophenyl)-N-((4-fluorophenyl)sulphonyl)acrylamide and tubulin

3-(4-Fluorophenyl)-N-((4-fluorophenyl)sulphonyl)acrylamide (FFSA) is a potential tubulin polymerisation inhibitor. In this article, a theoretical study of the binding between FFSA and tubulin in colchicine site was carried out by molecular docking, molecular dynamics (MD) simulation and binding free energy calculations. The docking calculations preliminarily indicate that there are three possible binding modes 1, 2 and 3; MD simulations and binding free energy calculations identify that binding mode 2 is the most favourable, with the lowest binding free energy of ? 29.54 kcal/mol. Moreover, our valuable results for the binding are as follows: the inhibitor FFSA is suitably located at the colchicine site of tubulin, where it not only interacts with residues Leu248β, Lys254β, Leu255β, Lys352β, Met259β and Val181a by hydrophilic interaction, but also interacts with Val181α and Thr179α by hydrogen bond interaction. These two factors are both essential for FFSA strongly binding to tubulin. These theoretical results help understanding the action mechanism and designing new compounds with higher affinity to tubulin.     

An explorative study on Staphylococcus aureus MurE inhibitor: induced fit docking,binding free energy calculation,and molecular dynamics

Staphylococcus aureus MurE enzyme catalyzes the addition of l-lysine as third residue of the peptidoglycan peptide moiety. Due to the high substrate specificity and its ubiquitous nature among bacteria, MurE enzyme is considered as one of the potential target for the development of new therapeutic agents. In the present work, induced fit docking (IFD), binding free energy calculation, and molecular dynamics (MD) simulation were carried out to elucidate the inhibition potential of 2-thioxothiazolidin-4-one based inhibitor 1 against S. aureus MurE enzyme. The inhibitor 1 formed majority of hydrogen bonds with the central domain residues Asn151, Thr152, Ser180, Arg187, and Lys219. Binding free-energy calculation by MM-GBSA approach showed that van der Waals (ΔG_vdW, ?57.30?kcal/mol) and electrostatic solvation (ΔG_solv, ?36.86?kcal/mol) energy terms are major contributors for the inhibitor binding. Further, 30-ns MD simulation was performed to validate the stability of ligand–protein complex and also to get structural insight into mode of binding. Based on the IFD and MD simulation results, we designed four new compounds D1–D4 with promising binding affinity for the S. aureus MurE enzyme. The designed compounds were subjected to the extra-precision docking and binding free energy was calculated for complexes. Further, a 30-ns MD simulation was performed for D1/4C13 complex.     

Induced fit docking,free energy calculation and molecular dynamics studies on Mycobacterium tuberculosis alanine racemase inhibitor

Alar, a Pyridoxal 5′-phosphate (PLP)-dependent bacterial enzyme is responsible for the racemisation of L-alanine into D-alanine which is essential for the peptidoglycan biosynthesis in both Gram-positive and Gram-negative bacteria. In the present study, we performed induced fit docking, binding free energy calculation and molecular dynamics simulation to elucidate the Alar inhibition potential of 1,2,4-thiadiazolidine-3,5-dione-based inhibitor 1. The inhibitor binds to the hydrophobic groove of Alar and the binding was found to be stable throughout 20-ns MD simulation. Induced fit docking result showed that Lys42, Tyr46, Tyr175 and Tyr364 residues are primarily responsible for the stabilisation of inhibitor–protein complex. Further, high negative van der Waals binding free energy value of –38.88 kcal/mol, indicated it as the main driving force for the inhibitor binding. Based on the information obtained from this study, we designed few molecules as potent Alar inhibitor. In order to gain structural insight and to validate the stability of complex, we performed 20-ns MD simulation of the designed molecule D1. Results obtained from this study can be used for the design of M. tuberculosis Alar potent inhibitors lacking affinity for the co-factor PLP.     

Possible binding sites and interactions of propanidid and AZD3043 within the γ-aminobutyric acid type A receptor (GABAAR)

Propanidid is an intravenous anesthetic with transient action and rapid recovery features, but it is clinically unacceptable due to its side effects. AZD-3043, an analog of propanidid with the methoxy group substituted by the ethoxy group, has become the focus of recent development efforts. Although propanidid and AZD-3043 are known to act by potentiating the γ-aminobutyric acid type A receptors (GABA_ARs), their action sites and binding modes in the recognition of target proteins still remain unclear. In this study, molecular docking and ONIOM calculations were performed to explore the possible binding sites and binding modes of propanidid and AZD-3043 with the GABA_AR. The predicted active region located in the transmembrane domain (TMD) of GABA_AR was identified as the most favorable binding site for propanidid and AZD-3043, with the highest docking score (?39.69 and ?39.44 kcal/mol, respectively) and the largest binding energy (?88.478 and ?78.439 kcal/mol, respectively). The important role of amino acids Asp245, Asp424, Asp425, Arg428, Phe307, and Ser308 in determining the binding modes of propanidid or AZD-3043 with GABA_AR was revealed. The detailed molecular interactions between propanidid and AZD-3043 and the GABA_AR were revealed for the first time. This could improve our understanding of the action mechanism of general anesthetics and will be helpful for the design of more potential lead-like molecules.     

Study on the binding mode of a pyrrolotriazin derivative with JAK2 by docking and MD simulation

The pyrrolotriazin derivative 2-(4-(4-((7-(3-(N-methylmethylsulfonamido)phenyl)pyrrolo [2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-1-yl)acetamide (PPA) is a potential Janus kinase 2 (JAK2) inhibitor. The binding mode between PPA and JAK2 was investigated by using a combined method of docking, molecular dynamics (MD) simulation and binding free-energy calculation. The docking calculations preliminarily indicated that there were two possible binding modes 1 and 2; MD simulations and binding free-energy calculations identified that binding mode 1 was more stable and favourable, with the lower MM-PBSA binding free energy of ?34.00?±?0.17?kcal/mol. Moreover, some valuable binding information is revealed as follows: the inhibitor PPA is suitably located at the ATP-binding site of JAK2 and the hydrophobic interaction plays an essential role. PPA not only interacts with residues Leu855, Val863, Ala880, Tyr931, Leu932 and Leu983 via hydrophobic interaction but also interacts with Ser936 and Asp994 by hydrogen bonds. These two factors are advantageous for PPA to strongly bind to JAK2. These results help to understand the action mechanisms and designing new compounds with a higher affinity to JAK2.     

Comparative docking of dual conformations in human fatty acid synthase thioesterase domain reveals potential binding cavity for virtual screening of ligands

Human fatty acid synthase (hFASN), a homo dimeric lipogenic enzyme with seven catalytic domains, is an important clinical target in cancer, metabolic syndrome and infections. Here, molecular modelling and docking methods were implemented to examine the inter-molecular interactions of thioesterase (TE) domain in hFASN with its physiological substrate, and to identify potential chemical inhibitors. TE catalyses the hydrolysis of thioester bond between palmitate and the 4’ phosphopantetheine of acyl carrier protein, releasing 16-carbon palmitate. The crystal structure of hFASN TE in two inhibitory conformations (A and B) were geometry-optimized and used for molecular docking with palmitate, orlistat (a known FASN inhibitor) and virtual screening against compounds from National Cancer Institute (NCI) database. Relatively, low binding affinity was observed during the complex formation of palmitate with A (?.164 kcal/mol) and B (?.332 kcal/mol) forms of TE, when compared with orlistat-docked TE (A form: ?5.872 kcal/mol and B form: ?5.484 kcal/mol), clearly indicating that the native inhibited conformation (crystal structure) was unfavourable for substrate binding. We used these orlistat dual binding modes as positive controls for prioritizing the ligands during virtual screening. From 2, 31,617 molecules in the NCI database, 916 high-scoring compounds (hit ligands) were obtained for A-form and 4582 for B-form of the TE-domain, which were then ranked according to glide docking score, XP H bond score, absorption, distribution, metabolism and excretion and binding free energy (Prime/MM-GBSA). Consequently, two top scoring ligands (NSC: 319661 and NSC: 153166) emerged as promising drug candidates that may be tested in FASN-over-expressing diseases.     

Characterization of human serum albumin's interactions with safranal and crocin using multi-spectroscopic and molecular docking techniques

Interaction mechanisms of human serum albumin (HSA) with safranal and crocin were studied using UV–Vis absorption, fluorescence quenching and circular dichroism (CD) spectroscopies as well as molecular docking techniques. Changes in absorbance and fluorescence of HSA upon interactions with both compounds were attributed to their binding to amino acid chromophores located in subdomains IIA and IIIA. Fluorescence secondary inner filter effect was excluded using 278 nm and 340 nm as the wavelengths of HSA's excitation and fluorescence while safranal and crocin absorbed at 320 nm and 445 nm, respectively. Stern-Volmer model revealed a static quenching mechanism involve the formation of non-fluorescent ground state complexes. Stern-Volmer, Hill, Benesi-Hilbrand and Scatchard models gave apparent binding constants ranged in 4.25 × 10³ - 2.15 × 10⁵ for safranal and 7.67 × 10³ - 4.23 × 10⁵ L mol^?1 for crocin. CD measurements indicated that 13 folds of safranal and crocin unfolded the α-helix structure of HSA by 7.47–21.20%. In-silico molecular docking revealed selective exothermic binding of safranal on eight binding sites with binding energies ranged in ?3.969 to ?6.6.913 kcal/mol. Crocin exothermally bound to a new large pocket located on subdomain IIA (sudlow 1) with binding energy of ?12.922 kcal/mol.These results confirmed the formation of HSA stable complexes with safranal and crocin and contributed to our understanding for their binding characteristics (affinities, sites, modes, forces … etc.) and structural changes upon interactions. They also proved that HSA can solubilize and transport both compounds in blood to target tissues. The results are of high importance in determining the pharmacological properties of the two phytochemical compounds and for their future developments as anticancer, antispasmodic, antidepressant or aphrodisiac therapeutic agents.     

Identification of selective MMP-9 inhibitors through multiple e-pharmacophore,ligand-based pharmacophore,molecular docking,and density functional theory approaches

Matrix metalloproteinase-9 (MMP-9) is a significant target for the development of drugs for the treatment of arthritis, CNS disorders, and cancer metastasis. The structure-based and ligand-based methods were used for the virtual screening (VS) of database compounds to obtain potent and selective MMP-9 inhibitors. Experimentally known MMP-9 inhibitors were used to grow up ligand-based three pharmacophore models utilizing Schrodinger suite. The X-ray crystallographic structures of MMP-9 with different inhibitors were used to develop five energy-optimized structure-based (e-pharmacophore) models. All developed pharmacophores were validated and applied to screen the Zinc database. Pharmacophore matched compounds were subjected to molecular docking to retrieve hits with novel scaffolds. The molecules with diverse structures, high docking scores and low binding energies for various crystal structures of MMP-9, were selected as final hits. The Induced fit docking (IFD) analysis provided significant information about the driving of inhibitor to approve a suitable bioactive conformational position in the active site of protein. Since charge transfer reaction occurs during receptor–ligand interaction, therefore, electronic features of hits (ligands) are interesting parameters to explain the binding interactions. Density functional theory (DFT) at B3LYP/6-31G* level was utilized to explore electronic features of hits. The docking study of hits using AutoDock was helpful to establish the binding interactions. The study illustrates that the combined pharmacophore approach is advantageous to identify diverse hits which have better binding affinity to the active site of the enzyme for all possible bioactive conformations. The approach used in the study is worthy to design drugs for other targets.     

3D structure generation,virtual screening and docking of human Ras-associated binding (Rab3A) protein involved in tumourigenesis

Rab3A is expressed predominantly in brain and synaptic vesicles. Rab3A is involved specifically in tethering and docking of synaptic vesicles prior to fusion which is a critical step in regulated release of neurotransmitters. The precise function of Rab3A is still not known. However, up-regulation of Rab3A has been reported in malignant neuroendocrine and breast cancer cells. In the present study, the structure of Rab3A protein was generated using MODELLER 9v8 software. The modeled protein structure was validated and subjected to molecular docking analyses. Docking with GTP was carried out on the binding site of Rab3A using GOLD software. The Rab3A-GTP complex has best GOLD fitness value of 77.73. Ligplot shows hydrogen bondings (S16, S17, V18, G19, K20, T21, S22, S31, T33, A35, S38, T39 and G65) and hydrophobic interacting residues (F25, F32, P34, F36, V37, D62 and A64) with the GTP ligands in the binding site of Rab3A protein. Here, the ligand molecules of NCI diversity set II from the ZINC database against the active site of the Rab3A protein were screened. For this purpose, the incremental construction algorithm of GLIDE and the genetic algorithm of GOLD were used. Docking results were analyzed for top ranking compounds using a consensus scoring function of X-Score to calculate the binding affinity and Ligplot was used to measure protein–ligand interactions. Five compounds which possess good inhibitory activity and may act as potential high affinity inhibitors against Rab3A active site were identified. The top ranking molecule (ZINC13152284) has a Glide score of ?6.65 kcal/mol, X-Score of ?3.02 kcal/mol and GOLD score of 64.54 with 03 hydrogen bonds and 09 hydrophobic contacts. This compound is thus a good starting point for further development of strong inhibitors.     

The effect of histidine residue modification on tyrosinase activity and conformation: inhibition kinetics and computational prediction

We found that the histidine chemical modification of tyrosinase conspicuously inactivated enzyme activity. The substrate reactions with diethylpyridinecarbamate showed slow-binding inhibition kinetics (K(I) = 0.24 +/- 0.03 mM). Bromoacetate, as another histidine modifier, was also applied in order to study inhibition kinetics. The bromoacetate directly induced the exposures of hydrophobic surfaces following by complete inactivation via ligand binding. For further insights, we predicted the 3D structure of tyrosinase and simulated the docking between tyrosinase and diethylpyridinecarbamate. The docking simulation was shown to the significant binding energy scores (-3.77 kcal/mol by AutoDock4 and -25.26 kcal/mol by Dock6). The computational prediction was informative to elucidate the role of free histidine residues at the active site, which are related to substrate accessibility during tyrosinase catalysis.     

In silico approaches to evaluate the molecular properties of organophosphate compounds to inhibit acetylcholinesterase activity in housefly

Organophosphate compounds (OPC) have become the primary choice as insecticides and are widely used across the world. Additionally, OPCs were also commonly used as a chemical warfare agent that triggers a great challenge to public safety. Exposure of OPCs to human causes immediate excitation of cholinergic neurotransmission through transient elevation of synaptic acetylcholine (ACh) levels and accumulations. Likewise, prolonged exposure of OPCs can affect the processes in immune response, carbohydrate metabolism, cardiovascular toxicity, and several others. Studies revealed that the toxicity of OPCs was provoked by inhibition of acetylcholinesterase (AChE). Therefore, combined in silico approaches – pharmacophore-based 3D-QSAR model; docking and Molecular Dynamics (MD) – were used to assess the precise and comprehensive effects of series of known OP-derived compounds together with its ?log LD₅₀ values. The selected five-featured pharmacophore model – AAHHR.61 – displayed the highest correlation (R² = .9166), cross-validated coefficient (Q² = .8221), F = 63.2, Pearson-R = .9615 with low RMSE = .2621 values obtained using five component PLS factors. Subsequently, the well-validated model was then used as a 3D query to search novel OPCs using a high-throughput virtual screening technique. Simultaneously, the docking studies predicted the binding pose of the most active OPC in the MdAChE binding pocket. Additionally, the stability of docking was verified using MD simulation. The results revealed that OP22 and predicted lead compounds bound tightly to S315 of MdAChE through potential hydrogen bond interaction over time. Overall, this study might provide valuable insight into binding mode of OPCs and hit compounds to inhibit AChE in housefly.