Deciphering the crucial residues involved in heterodimerization of Bak peptide and anti-apoptotic proteins for apoptosis

<p>B-cell lymphoma 2 (Bcl-2) family proteins are the central regulators of apoptosis, functioning via mitochondrial outer membrane permeabilization. The family members are involved in several stages of apoptosis regulation. The overexpression of the anti-apoptotic proteins leads to several cancer pathological conditions. This overexpression is modulated or inhibited by heterodimerization of pro-apoptotic BH3 domain or BH3-only peptides to the hydrophobic groove present at the surface of anti-apoptotic proteins. Additionally, the heterodimerization displayed differences in binding affinity profile among the pro-apoptotic peptides binding to anti-apoptotic proteins. In light of discovering the novel peptide/drug molecules that contain the potential to inhibit specific anti-apoptotic protein, it is necessary to understand the molecular basis of recognition between the protein and its binding partner (peptide or ligand) along with its binding energies. Therefore, the present work focused on deciphering the molecular basis of recognition between pro-apoptotic Bak peptide binding to different anti-apoptotic (Bcl-xL, Bfl-1, Bcl-W, Mcl-1, and Bcl-2) proteins using advanced Molecular Dynamics (MD) approach such as Molecular Mechanics-Generalized Born Solvent Accessible. The results from our investigation revealed that the predicted binding free energies showed excellent correlation with the experimental values (<i>r</i>² = .95). The electrostatic (Δ<i>G</i>_ele) contributions are the major component that drives the interaction between Bak peptides and different anti-apoptotic peptides. Additionally, van der Waals (Δ<i>G</i>_vdw) energies also play an indispensible role in determining the binding free energy. Furthermore, the decomposition analysis highlighted the comprehensive information about the energy contributions of hotspot residues involved in stabilizing the interaction between Bak peptide and different anti-apoptotic proteins.</p

Evolutionary Trace shows conserved consensus pattern, Vertical lines in dendrogram A to J shows different Partition Identity Cutoffs (PICs)

<p><b>Copyright information:</b></p><p>Taken from "Binding site prediction of galanin peptide using evolutionary trace method"</p><p></p><p>Bioinformation 2006;1(5):180-183.</p><p>Published online 25 Jul 2006</p><p>PMCID:PMC1891676.</p><p></p> Each PIC represents an individual group; A represents the most conserved 10 trace. As PIC increases from A to J, partition comprises decreased group from 10 to

Probing the binding mechanism of mercaptoguanine derivatives as inhibitors of HPPK by docking and molecular dynamics simulations

<p>6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a promising antimicrobial target involved in the folate biosynthesis pathway. Although, the results from crystallographic studies of HPPK have attracted a great interest in the design of novel HPPK inhibitors, the mechanism of action of HPPK due to inhibitor binding remains questionable. Recently, mercaptoguanine derivatives were reported to inhibit the pyrophosphoryl transfer mechanism of <i>Staphylococcus aureus</i> HPPK (SaHPPK). The present study is an attempt to understand the SaHPPK-inhibitors binding mechanism and to highlight the key residues that possibly involve in the complex formation. To decipher these questions, we used the state-of-the-art advanced <i>insilico</i> approach such as molecular docking, molecular dynamics (MD), molecular mechanics-generalized Born surface area approach. Domain cross correlation and principle component analysis were applied to the snapshots obtained from MD revealed that the compounds with high binding affinity stabilize the conformational dynamics of SaHPPK. The binding free energy estimation showed that the van der Waals and electrostatic interactions played a vital role for the binding mechanism. Additionally, the predicted binding free energy was in good agreement with the experimental values (<i>R</i>² = .78). Moreover, the free energy decomposition on per-residue confirms the key residues that significantly contribute to the complex formation. These results are expected to be useful for rational design of novel SaHPPK inhibitors.</p

Deciphering the crucial molecular properties of a series of Benzothiazole Hydrazone inhibitors that targets anti-apoptotic Bcl-xL protein

<p>The Bcl-2 family proteins are the central regulators of apoptosis. Due to its predominant role in cancer progression, the Bcl-2 family proteins act as attractive therapeutic targets. Recently, molecular series of Benzothiazole Hydrazone (BH) inhibitors that exhibits drug-likeness characteristics, which selectively targets Bcl-xL have been reported. In the present study, docking was used to explore the plausible binding mode of the highly active BH inhibitor with Bcl-xL; and Molecular Dynamics (MD) simulation was applied to investigate the stability of predicted conformation over time. Furthermore, the molecular properties of the series of BH inhibitors were extensively investigated by pharmacophore based 3D-QSAR model. The docking correctly predicted the binding mode of the inhibitor inside the Bcl-xL hydrophobic groove, whereas the MD-based free energy calculation exhibited the binding strength of the complex over the time period. Furthermore, the residue decomposition analysis revealed the major energy contributing residues – F105, L108, L130, N136, and R139 – involved in complex stability. Additionally, a six-featured pharmacophore model – AAADHR.89 – was developed using the series of BH inhibitors that exhibited high survival score. The statistically significant 3D-QSAR model exhibited high correlation co-efficient (<i>R</i>² = .9666) and cross validation co-efficient (<i>Q</i>² = .9015) values obtained from PLS regression analysis. The results obtained from the current investigation might provide valuable insights for rational drug design of Bcl-xL inhibitor synthesis.</p

Multispectroscopic and Computational Investigations on the Binding Mechanism of Dicaffeoylquinic Acids with Ovalbumin

Recently, studies on the interactions between ovalbumin (OVA) and polyphenols have received a great deal of interest. This study explored the conformational changes and the interaction mechanism of the binding between OVA and chlorogenic acid (CGA) isomers such as 3,4-dicaffeoylquinic acids (3,4-diCQA), 4,5-dicaffeoylquinic acids (4,5-diCQA), and 3,5-dicaffeoylquinic acids (3,5-diCQA) using multispectroscopic and in silico analyses. The emission spectra show that the diCQAs caused strong quenching of OVA fluorescence under different temperatures through a static quenching mechanism with hydrogen bond (H-bond) and van der Waals (vdW) interactions. The values of binding constants (OVA–3,4-diCQA = 6.123 × 105, OVA–3,5-diCQA = 2.485 × 105, OVA–4,5-diCQA = 4.698 × 105 dm3 mol–1 at 298 K) suggested that diCQAs had a strong binding affinity toward OVA, among which OVA–3,4-diCQA exhibits higher binding constant. The results of UV–vis absorption and synchronous fluorescence indicated that the binding of all three diCQAs to OVA induced conformational and micro-environmental changes in the protein. The findings of molecular modeling further validate the significant role of vdW force and H-bond interactions in ensuring the stable binding of OVA–diCQA complexes. Temperature-dependent molecular dynamics simulation studies allow estimation of the individual components that contribute to the total bound free energy value, which allows evaluation of the nature of the interactions involved. This research can provide information for future investigations on food proteins’ physicochemical stability and CGA bioavailability in vitro or in vivo

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

<p>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 <i>in silico</i> 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 (<i>R</i>² = .9166), cross-validated coefficient (<i>Q</i>² = .8221), <i>F</i> = 63.2, Pearson-<i>R</i> = .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.</p

DataSheet_1_Stilbenoid compounds inhibit NF-κB-mediated inflammatory responses in the Drosophila intestine.pdf

IntroductionStilbenoid compounds have been described to have anti-inflammatory properties in animal models in vivo, and have been shown to inhibit Ca2+-influx through the transient receptor potential ankyrin 1 (TrpA1).MethodsTo study how stilbenoid compounds affect inflammatory signaling in vivo, we have utilized the fruit fly, Drosophila melanogaster, as a model system. To induce intestinal inflammation in the fly, we have fed flies with the intestinal irritant dextran sodium sulphate (DSS).ResultsWe found that DSS induces severe changes in the bacteriome of the Drosophila intestine, and that this dysbiosis causes activation of the NF-κB transcription factor Relish. We have taken advantage of the DSS-model to study the anti-inflammatory properties of the stilbenoid compounds pinosylvin (PS) and pinosylvin monomethyl ether (PSMME). With the help of in vivo approaches, we have identified PS and PSMME to be transient receptor ankyrin 1 (TrpA1)-dependent antagonists of NF-κB-mediated intestinal immune responses in Drosophila. We have also computationally predicted the putative antagonist binding sites of these compounds at Drosophila TrpA1.DiscussionTaken together, we show that the stilbenoids PS and PSMME have anti-inflammatory properties in vivo in the intestine and can be used to alleviate chemically induced intestinal inflammation in Drosophila.</p