Human immunodeficiency virus type 1 protease (HIV-1 PR) is an essential enzyme for the replication cycle of HIV. HIV-1 PR inhibitors have been extensively investigated as anti-AIDS drugs. In the presence of HIV-1 protease inhibitors, the virion is unable to mature. Natural compounds are important sources of drugs. The present investigation concentrates on discovering anti-HIV compounds that are present in Mappia foetida, a medicinal plant belonging to Icacinaceae family. Here, we selected Phytochemicals of Mappia foetida-Root identified by the method of Gas chromatography-mass spectrometry (GC-MS Method) to dock against the enzyme HIV-1 protease (PDB ID: 3HAU). The resulted enzyme-substrate interaction energies shows that those compounds are active against HIV-1 protease and further research on plant Mappia foetida will be useful in drug designing against HIV.
Source of material 0.29 mmol (100 mg) of 2,2¢-biquinoline-4,4¢-dicarboxylic acid (H 2 BQDC) and 0.58 mmol (150 mg )ofMn(NO 3 ) 2 ·4H 2 Owere suspendedin8mLof1:1 ethanol/watermixture, heated to 180°C over two hoursand kept at that temperature for 2h.The reaction mixture was cooled down to 80°Co ver 120 h. It was finally cooled down to 25°Co ver 72 h. Ay ellow crystalline product (yield 96 mg, 40 %) was obtained after washing with ethanol. Experimental detailsThe Hatoms attached to the water molecule were not found. Discussion 2,2¢-Biquinoline-4,4¢-dicarboxylica cid has rarely been considered as asupramolecularbuilding block. Coordination polymers containing BQDC are known [1,2]. In continuation of our work on metal organic frameworks using bipyridyldicarboxylate ligand [3-5], we report aMncoordinationpolymer containing BQDC as ligand. The crystal structure of the title compound revealed infinite zigzag chain structureinwhich manganese ions are linked by m 1,1 -OCO bridges (d(Mn···Mn) =3 .702 Å). Each Mn ion is coordinated by six oxygen atomscoming from three different BQDC 2-ions and aw ater molecule,f orming ad istorted octahedral environment. The ligand utilizes both of its carboxylic groups for coordination with the metal ion. It is interesting to note that the coordination mode of each of the carboxylic groups is different. One of the carboxylic group binds in ac helating mode (d(Mn-O1) =2.295(8) Å and d(Mn-O2) =2.179(8) Å)and another in abridging mode towards manganese ions (d(Mn-O3) = 2.197(7) Å). Thus the ligand displays ab ridging and chelating bis-bidentate mode, coordinating to three metalatoms. It is noteworthy that the other oxygen atom in the bridgingc arboxylic group coordinates to one of the manganese atoms that are bridged by that carboxylic group (d(Mn-O4) =2.153(8) Å). This coordination further extends to generate a2Ddiamondoid structure of (4,4) topology.The coordinated water molecules form H-bonds withone of the nitrogen atomsofthe ligand (2.958 Å)and the oxygen atom of the chelating carboxylgroup (2.812 Å).
Nicotinamide phosphoribosyl transferase (NAMPT) is the enzyme that catalyzes the rate-limiting step in the salvage pathway of Nicotinamide Adenine Dinucleotide (NAD) biosynthesis. NAMPT is overexpressed in a number of cancers, and inhibition of NAMPT has been shown to result in anti-tumor efficacy in preclinical models. Clinical development to first generation NAMPT inhibitors has been hindered because of their poor pharmacological profile, high cytochrome inhibition and possibly mechanism-based toxicities. Therefore, we sought to develop NAMPT inhibitors with the “best-in-class” profile for overcoming mechanism-based toxicities and/or resistance to current therapies. Utilizing structure-guided drug design including determination of co-crystal structures and SAR-based approaches, we have identified a novel chemical series of inhibitors of NAMPT. Optimization of the series for transient target inhibition as a result of reduced binding strength coupled with desirable pharmacokinetic profile to minimize mechanism based toxicity resulted in identification of AU-4869 as the Lead compound.AU-4869 showed potent cross-species activity and reduced strength of binding in comparison with first generation NAMPT inhibitors. Anti-proliferative activity of AU-4869 correlated well with NAD depletion in multiple cell lines derived from multiple myeloma and Pancreatic cancers. The anti-proliferative activities were rescued in NAPRT-proficient cell lines with the addition of NA due to the NAMPT independent salvage pathway for biosynthesis of NAD, confirming the mechanism of action through NAD depletion. AU-4869 exhibited desirable drug-like properties including solubility, permeability, metabolic stability, lack of CYP & hERG inhibition and pharmacokinetic exposure upon oral dosing. At well-tolerated doses, AU-4869 exhibited superior efficacy at MTD doses in mice xenograft models (pancreatic cancer and multiple myeloma) as compared to FK866 and GNE-617. In view of the ability of NAMPT inhibitors to enhance sensitivity to a number of targeted agents and overcome resistance to available therapies such as bortezomib in multiple myeloma, further pre-clinical development of AU-4869 for multiple myeloma is ongoing. Citation Format: Dinesh Chikkanna, Anirudha Lakshminarasimhan, Vinayak Khairnar, Sunil panigrahi, Anuradha Ramanathan, Sumalatha Rani, Narasimha Rao, Karthikeyan S, Kishore Narayanan, Sreevalsam Gopinath, Raghuveer Ramachandra, Charamanna K B, Shekar Chelur, Chetan Pandit, Murali Ramachandra. Discovery of dihydro-isoxazole derivatives as novel inhibitors of NAMPT for the treatment of multiple myeloma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5367. doi:10.1158/1538-7445.AM2015-5367
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