Cancer is a class of diseases characterized by uncontrolled cell growth. Every year more than 2 million people are affected by the disease. Rho family proteins are actively involved in cytoskeleton regulation. Over-expression of Rho family proteins show oncogenic activity and promote cancer progression. In the present work RhoG protein is considered as novel target of cancer. It is a member of Rho family and Rac subfamily protein, which plays pivotal role in regulation of microtubule formation, cell migration and contributes in cancer progression. In order to understand the binding interaction between RhoG protein and the DH domain of Ephexin-4 protein, the 3D structure of RhoG was evaluated and Molecular Dynamic Simulations was performed to stabilize the structure. The 3D structure of RhoG protein was validated and active site identified using standard computational protocols. Protein-protein docking of RhoG with Ephexin-4 was done to understand binding interactions and the active site structure. Virtual screening was carried out with ligand databases against the active site of RhoG protein. The efficiency of virtual screening is analysed with enrichment factor and area under curve values. The binding free energy of docked complexes was calculated using prime MM-GBSA module. The SASA, FOSA, FISA, PISA and PSA values of ligands were carried out. New ligands with high docking score, glide energy and acceptable ADME properties were prioritized as potential inhibitors of RhoG protein.

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Multidrug efflux mechanism is the main cause of intrinsic drug resistance in bacteria. Mycobacterium multidrug resistant (MMR) protein belongs to small multidrug resistant family proteins (SMR), causing multidrug resistance to proton (H(+))-linked lipophilic cationic drug efflux across the cell membrane. In the present work, MMR is treated as a novel target to identify new molecular entities as inhibitors for drug resistance in Mycobacterium tuberculosis. In silico techniques are applied to evaluate the 3D structure of MMR protein. The putative amino acid residues present in the active site of MMR protein are predicted. Protein-ligand interactions are studied by docking cationic ligands transported by MMR protein. Virtual screening is carried out with an in-house library of small molecules against the grid created at the predicted active site residues in the MMR protein. Absorption distribution metabolism and elimination (ADME) properties of the molecules with best docking scores are predicted. The studies with cationic ligands and those of virtual screening are analysed for identification of new lead molecules as inhibitors for drug resistance caused by the MMR protein.

Background & Objective: A facile and efficient method for the synthesis of novel derivatives of FQ citrate conjugates with 1,2,4-triazoles and 1,3,4-oxadiazole scaffolds 8-11 using conventional as well as microwave irradiation methods was reported. Based on these original building blocks the new derivatives of 3, 7-disubstituted fluoroquinolones bearing the oxadiazolyl-triazole groups were obtained. These invaluable derivatives are of great interest in medicinal and pharmaceutical studies because of their important biological properties. Methods: All the reactions were examined under conventional as well as microwave mediated conditions. The structures of obtained compounds were confirmed by 1H NMR, 13C NMR, IR HRMS spectroscopy and elemental analysis. The antibacterial, antifungal activity of these compounds was screened against Gram-positive, Gram-negative bacteria and fungal stains by agar well diffusion method. Cytotoxic assay of the title compounds was evaluated against cervical carcinoma cell line (HeLa) by using MTT assay. The crystal structure of Quinolone-DNA cleavage complex of type IV topoisomerase from S. pneumoniae (PDB ID: 3RAE) complex were obtained from the Protein Database (PDB, http://www.rcsb.org). Molecular properties prediction-drug likeness by Molinspiration and Molsoft software, lipophilicity and solubility parameters using Osiris program. Results: A novel approach to the synthesis of benzylthio-1,2,4-triazole, 1,3,4-oxadiazoles core with regioisomeric norfloxacin citrate conjugates was developed. Among the title compounds 11b, 10a reveals pronounced activity against S. pneumoniae with minimum inhibitory concentrations 0.89, 0.96 mg/mL and MBCs of 2.95, 2.80 mg/mL respectively. Minimum fungicidal concentration (MFC) have been determined for each compound against two fungal strains. Compound 11b showed maximum anticancer activity against HeLa cell line with IC50 value 11.3 ± 0.41 comparable to standard drug DXN. For binding mode active site residues and docking energies (ΔG =-7.9 Kcal/mol) for ligand 9b exhibited highest hydrogen bonding (3.59274 A˚), Pi–Alkyl (5.14468 A˚) interactions with amino acid LEU479 of 3RAE protein. The compounds followed the Lipinski ‘Rule of five’ were synthesized for antimicrobial and anticancer screening as oral bioavailable drugs/leads. Maximum drug likeness model score 1.52, 1.41 was found for compounds 10d, 11b. Conclusion: The present work, through simple synthetic approaches, led to the development of novel hybrids of fluoroquinolone containing citrate-triazole-oxadiazole pharmacophores that exhibited remarkable biological activities against different microorganisms and cell line. The compounds showed suitable drug like properties and are expected to present good bioavailability profile. An efficient combination of molecular modeling and biological activity provided an insight into QSAR guide lines that could aid in further development and optimization of the norfloxacin derivatives.

Mycobacterium tuberculosis (Mtb) is an intracellular human parasite that causes tuberculosis (TB). The parasite is capable of surviving under stress conditions. The gene expression in Mtb is regulated by sigma factor family of proteins. The SigF protein belongs to the sigma factor family, expressed during stationary and growth phase, 14 genes are directly regulated by SigF and has a role in the expression of the principal sigma factor SigB as well. The interacting partner Usfx, the anti SigF protein, controls the regulation of SigF. The structures of SigF and Usfx were evaluated using comparative modelling techniques and validated. The active sites of the two proteins were identified. The protein-protein interaction studies between SigF and Usfx reveal His53, Phe226 and Asp227 residues of SigF protein to be involved in binding with Arg108, Arg130 and Glu140 amino acids of Usfx. The present study focuses on identification of important residues involved in binding of SigF protein with Usfx, which are essential in the inhibition of transcription initiation and survival of Mtb.