Ebola virus causes severe and often fatal hemorrhagic fevers in humans. The 2014 Ebola epidemic affected multiple countries. The virus matrix protein (VP40) plays a central role in virus assembly and budding. Since there is no FDA-approved vaccine or medicine against Ebola viral infection, discovering new compounds with different binding patterns against it is required. Therefore, we aim to identify small molecules that target the Arg 134 RNA binding and active site of VP40 protein. 1800 molecules were retrieved from PubChem compound database based on Structure Similarity and Conformers of pyrimidine-2, 4-dione. Molecular docking approach using Lamarckian Genetic Algorithm was carried out to find the potent inhibitors for VP40 based on calculated ligand-protein pairwise interaction energies. The grid maps representing the protein were calculated using auto grid and grid size was set to 60*60*60 points with grid spacing of 0.375 Ǻ. Ten independent docking runs were carried out for each ligand and results were clustered according to the 1.0 Ǻ RMSD criteria. The post-docking analysis showed that binding energies ranged from -8.87 to 0.6 Kcal/mol. We report 7 molecules, which showed promising ADMET results, LD-50, as well as H-bond interaction in the binding pocket. The small molecules discovered could act as potential inhibitors for VP40 and could interfere with virus assembly and budding process.

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Tuberculosis causes more than two million deaths per year. Faced with this global threat it is crucial to better understand the physiology of the causative organism, Mycobacterium Tuberculosis, in order to develop efficient therapeutic strategies. PKnB from Mycobacterium tuberculosis is a crucial receptor-like protein kinase involved in signal transduction. M. tuberculosis PKnB is a trans-membrane Ser/Thr protein kinase (STPK) highly conserved in Gram-positive bacteria and apparently essential for Mycobacterial viability. We have attempted with the help of virtual screening and docking approach to expound the extent of specificity of protein kinase B towards different classes of Thiadiazoles (an anti-tubercular agent). The selected Thiadiazoles were selected on the basis of the structural specificity to the enzyme towards its substrate and inhibitors. Total number of Thiadiazoles were 5000 in number with the minimum binding energy of-10.46 kcal/mol with 10 molecules showing hydrogen bonds with the active site residue. The protein kinase B peptide contains two types of structural elements (Valine 95, Arginine 97) and basic residue ring constituted of glycine rich residue. The structure of the protein-ligand complex reveals that Thiadiazoles partially occupies the adenine-binding pocket in PKnB, providing a framework for the design of compounds with potential therapeutic applications. The study provides hints for the future design of new derivatives with higher potency and specificity.

Background: Calmodulin (CaM) is a ubiquitous, calcium-binding protein that can bind to and regulate a multitude of different protein targets, thereby affecting many different cellular functions. Binding ofsmall, hydrophobic molecules alter its function, as in the case of Phenothiazine (PTZ). PTZ isan organic compound with a history of use as an antihelminth and frequently quoted as a classic example of a pharmaceutical lead structure.Its derivatives are currently used as antipsychotic drugs. Triflouperazine (TFP) is a phenothiazine derivative and a dopamine antagonist, with antiemetic and antipsychotic activities. TFP exerts its antipsychotic effect by blocking central dopamine receptors, thereby preventing effects like delusions and hallucinations caused by an excess of dopamine. This agent also functions as a calmodulin inhibitor, thereby leading to an elevation of cytosolic calcium. We have attempted to screen the extent of CaM specificity towards different classes of TFP and PTZ. Methods: Molecular docking approach using the Lamarckian Genetic Algorithm was used to elucidate the basis of structural similarity of TFP and PTZ with CaM. In total, 3000 compounds were studied. All of the antagonists were taken from PubChem database on the basis of the structural similarity of TFP and PTZ. Results: The docking result of these molecules with CaM demonstrated favored binding energies in the range of -11.50 kcal/mol to -4.51 kcal/mol, with 8 molecules showing hydrogen bonds with the active site residue Met124. Compound 1 was found to be the best CaM inhibitor. The Drug like and chemical toxicity was also predicted for this compound. Conclusion: Computational docking is a feasible method to screen inhibitor compounds against a biomolecule of interest.

The tumor suppressor protein p53 is a transcription factor that plays a key role in the prevention of cancer development. The p53 cancer mutation Y220C induces formation of a cavity on the protein's surface that can accommodate stabilizing small molecules. We have attempted with the help of virtual screening and molecular docking approach using Lamarckian Genetic Algorithm to elucidate the extent of specificity of p53 cancer mutation Y220C towards different class of Phenothiazines (an anti-cancer agent).The 393 residue p53 tumor suppressor protein exists in a dynamic equilibrium to form homotetramers. Each chain comprises several functional domains. The N terminal part of the protein consists of the trans-activation domain (residues 1–63) followed by a proline rich region (64– 92). The central (core) domain (p53 core domain) is responsible for binding. The C terminal part of p53 contains the tetramerization domain (residues 326–355) and the negative regulatory domain at the extreme C terminus (363–393), which contains phosphorylation and acetylation sites and regulates the DNA binding activity of p53.The docking result of the study of 2,000 Phenothiazines demonstrated that the binding energies were in the range of -10.54 kcal/mol to -1.14 kcal/mol, with 8 molecules showing hydrogen bonds with the active site residues (Lys 164). All the selected 2000 inhibitors were selected on the basis of the structural specificity to the enzyme towards its substrate and inhibitors. Our research provides a blueprint for the design of more potent and specific drugs that rescue p53-Y220C.