Computational analyses on delineating specificity of 2-hydroxy-3,5-dinitrobenzamide, a BH3-mimetic, towards anti-apoptotic proteins

We have herein computationally examined binding affinities and specificity of 2-hydroxy-3,5-dinitrobenzamide (HDNB), a small chemical molecular BH3-mimetic identified by means of peptidodynmimetic method, on the BH3-binding grooves of six anti-apoptotic proteins (Bcl-2, Bcl-B, Bcl-W, Bcl-XL, Bfl-1 and Mcl-1) from human beings. The HDNB ligand was found to interact on the BH3-binding grooves of Bcl-2, Bcl-B, Bcl-XL, Bfl-1 and Mcl-1, whereas it did not act as BH3-mimetic to Bcl-W. Moreover, binding affinities of the HDNB towards the anti-apoptotic proteins were significantly different from each other. The differential binding affinities and specificity of the HDNB towards the anti-apoptotic proteins have been chiefly attributed to the differences in the chemical properties of BH3-binding grooves of the proteins. Implications of the study to design efficient de novo antagonists to the anti-apoptotic proteins using the HDNB as seed molecule have been discussed

A COMPUTATIONAL APPROACH ON UNDERSTANDING STRUCTURAL INTERACTIONS OF ENVELOPE PROTEIN OF DENGUE VIRUS BOUND WITH SQUALENE, A PROTOTYPE ANTI-VIRAL COMPOUND

Objective: The objective of the work was to validate the structural binding affinity of Squalene with the envelope protein of Dengue virus by means of molecular simulations. Methods: Three-dimensional (3D) structure of dengue 2 virus envelope protein was retrieved from Protein Data Bank PDB and Squalene compound from the ZINC database. Molecular docking between the E protein and Squalene were carried out by means of Auto Dock 4.2. Results: Based on the study, it was observed that the binding/docking energy for the complex structure was calculated to be-5.55 kcal/mol. Critical residues to interact with E protein were scrutinized by analyzing the interface of the complex within 4 Å proximity. Residues such as Thr 48, Glu49, Ala 50, Val 130, Leu 135, Ser 186, Pro 187, Thr 189, Gly 190, Leu 191, Phe 193, Leu 198, Leu 207, Thr 268, Phe 279, Thr 280, Gly 281, His 282 and Leu 283 were found to be non-covalently located around the squalene. Conclusion: Scopes to design de novo anti-viral compounds to the dengue viruses by using squalene as a new class of template structure have also been concisely brought into fore

Structural characterizations of lead anticancer compounds from the methanolic extract of <i>Jatropha tanjorensis</i>

LC/ESI/MS/MS data analysis on the phytoconstituents of methanolic extract of Jatropha tanjorensis leaves revealed the presence of abundant flavone glucosides (homoorientin, kaempferol-3-o-rutinoside, luteolin-7-o-glucoside, 6-C-pentosyl-8-C-hexosyl apigenin, naringin and vitexin), flavonol (kaempferol and kaempferide) and flavones (baicalein and diosmetin). We, herein, demonstrated that methanolic extract of J. tanjorensis possess DPPH free-radical scavenging activity (IC50 of 49.7 µg/mL), inhibition of  lipid peroxidation activity (IC50 of 189.6 µg/mL) and anticancer activity through MTT assay against EAC cells (IC50 of 14.57 µg/mL) and Caco-2 cells (IC50 of 21.0 µg/mL). In silico analysis indicated that cytotoxic activity of the methanolic extract of J. tanjorensis could be attributed to the presence of vitexin and 6-C-pentosyl-8-C-hexosyl apigenin as evidenced by exhaustive molecular docking studies carried out against 8 proteins of Bcl-2 family that play essential role in apoptosis. Moreover, drug-likeness properties of the leads and scopes to develop them as potent anticancer compounds are discussed

OneG: A Computational Tool for Predicting Cryptic Intermediates in the Unfolding Kinetics of Proteins under Native Conditions

Understanding the relationships between conformations of proteins and their stabilities is one key to address the protein folding paradigm. The free energy change (ΔG) of unfolding reactions of proteins is measured by traditional denaturation methods and native hydrogen-deuterium (H/D) exchange methods. However, the free energy of unfolding (ΔGU) and the free energy of exchange (ΔGHX) of proteins are not in good agreement, though the experimental conditions of both methods are well matching to each other. The anomaly is due to any one or combinations of the following reasons: (i) effects of cis-trans proline isomerisation under equilibrium unfolding reactions of proteins (ii) inappropriateness in accounting the baselines of melting curves (iii) presence of cryptic intermediates, which may elude the melting curve analysis and (iv) existence of higher energy metastable states in the H/D exchange reactions of proteins. Herein, we have developed a novel computational tool, OneG, which accounts the discrepancy between ΔGU and ΔGHX of proteins by systematically accounting all the four factors mentioned above. The program is fully automated and requires four inputs: three-dimensional structures of proteins, ΔGU, ΔGU* and residue-specific ΔGHX determined under EX2-exchange conditions in the absence of denaturants. The robustness of the program has been validated using experimental data available for proteins such as cytochrome c and apocytochrome b562 and the data analyses revealed that cryptic intermediates of the proteins detected by the experimental methods and the cryptic intermediates predicted by the OneG for those proteins were in good agreement. Furthermore, using OneG, we have shown possible existence of cryptic intermediates and metastable states in the unfolding pathways of cardiotoxin III and cobrotoxin, respectively, which are homologous proteins. The unique application of the program to map the unfolding pathways of proteins under native conditions have been brought into fore and the program is publicly available at http://sblab.sastra.edu/oneg.htm