This is a call for creating a tuberculosis research community.
Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb), infects approximately two billion people. The World Health Organization estimates that about two million people die each year from TB due to the lack of and inability to afford proper health care.1 Overcrowding and ill-nourishment of poor people living in large cities leads to a high incidence of the disease due to the ease at which the infection can be transferred.2 This contributes to the accelerated speed at which TB spreads in underdeveloped countries. There is also an alarming increase in cases of TB caused by multidrug-resistant strains of Mycobacterium tuberculosis (Mtb), due in part to inadequate drug therapy as a result of incorrectly selected medications or suboptimal drug dosing.3 Thus, there is a need for new drugs targeting enzymes essential to mycobacterial survival.
My lab is focusing on the inhibition of type II NADH-menaquinone dehydrogenase (ndh-2). By inhibiting ndh-2, the electron transport chain in Mtb becomes blocked and shuts down. Ndh-2 is the only NADH dehydrogenase enzyme expressed in Mtb and is thus vital to its survival.4 Ndh-2 is also found in a number of other bacteria such as Staphylococcus aureus and Enterococcus faecalis but is not expressed in humans.5 Humans rely only on type I NADH dehydrogenase (ndh-1) and thus minimal toxicity in humans is predicted with ndh-2 inhibitors.
Current State of Affairs
My lab has discovered two quaternized promazine derivatives (QPDs), 1 and 2, that both have an MIC (minimum inhbitory concentration) of 3.13 μg/mL vs. Mycobacterium tuberculosis H37Rv and SI values (IC50 vs. human Vero cells/MIC) of 7.6 and 4.1, respectively.
Changing the para substituent to H, CH3O, or NO2 (or replacing benzyl by allyl) raises the MIC. The pharmacophore definitely needs something aromatic on the quaternized N (84% inhibition for benzyl at 6.25 μg/mL; only 47% inhibition for allyl at 6.25 μg/mL). Our goal: MIC ≤ 3.13 μg/mL against both current drug regimen-sensitive and multidrug-resistant Mtb and SI ≥ 30.
Although my lab can do good synthetic work, we are solely a post-doc free, undergraduate chemistry department and need assistance in several areas:
This is my first time freely discussing yet to be published medicinal chem research. It is both daunting and invigorating. I hope that there are some allies in this effort to stop TB.
1. Maher, D. & Raviglionem, M. C. (1999) in Tuberculosis and Nontuberculous
Mycobacterial Infections, ed. Schlossberg, D. (Saunders, Philadelphia), 4th Ed., pp.104-115.
2. Lowell, A. M. (1999) in Tuberculosis and Nontuberculous Mycobacterial Infections, ed. Schlossberg, D. (Saunders, Philidelphia), 4th Ed., pp. 3-15.
3. Bearing, S. E.; Peloquin, C.A.; Patel, K.B. (1999) in Tuberculosis and Nontuberculous Mycobacterial Infections, ed. Schlossberg, D. (Saunders,
Philadelphia), 4th Ed., pp. 83-91.
4. Weinstein, E.A.; Yano, T.; Li, L.S.; Avarbock, D.; Avarbock, A.; Helm, D.; McColm, A.A.; Duncan, K.; Lonsdale, J.T.; Rubin, H. PNAS 2005, 102, 4548-4553.
5. Melo, A. M. P.; Bandeiras, T. M.; Teixeira, M. Microbiol. Mol. Biol. Rev. 2004, 68, 603-616.
The idea is to design Potential Kinase inhibitors using Pharmacophore search, Docking, Semantic link association prediction, VROCS and fragment based approach to find novel molecules against Kinases.PASS Prediction
The project is divided into several sections Each section would result in different compounds. The final docking is done in Moldock and the compounds are ranked according to the rerank scores .After ranking compounds by several methods final ranking would be done using data fusion methods. ADMET filters would be applied to check whether the compounds are feasible to test in wet labs.
Identification of Pharmacophore , fragment based approach, docking and scoring.
I did use the some Ligand based Techniques to identify Novel Inhibitors of PkNb and this will get extended further for other kinase Inhbitors. Finding the Ligand binding pattern of Kinase inhibitors.