Computational modeling of some oxazolyl thiosemicarbazone derivatives against multidrug-resistant tuberculosis via 2-D QSAR and molecular docking simulation Ngo Hanna Joelle University of Douala, Cameroon In order to develop new potent, selective and novel antitubercular agents against MDR-TB, we performed a QSAR investigation on a series of oxazolyl thiosemicarbazones, which have been reported to be active with MIC values ranging from 0.05 to 25.00 microgram per millitre. We geometrically optimized the oxazolyl thiosemicarbazones, at the B3LYP/6-311+G(d,p) level of theory using the Gaussian 09W software. The Molecular descriptors included in the model for the QSAR were XlogP, molecular refractivity (MR), dipole moment, chemical hardness, electrophilicity, 2DPSA, and E. A QSAR equation was derived r 2 = 0.9553, q 2 =0.4573, F=21.37, SDEP=0.4573, from a training set of 16 randomly selected compounds from the series. The results obtained indicated the robust and predictivity of developed QSAR models. This was used to adequately predict the MIC values of 4 compounds in a validation set which were not included in the initial model. We intend to use the derived pharmacophore from the ligand-based design to screen a virtual database for potentially active compounds against MDR-TB. The molecules were also virtually screened based on their binding scores via molecular docking simulation with active site protein target which also confirms their potency. Based on these results, we proposed new oxazolyl thiosemicarbazones derivatives with potent biological activity. The obtained results can be further used by pharmaceutical and medicinal chemists to design new drugs against MDR-TB. References 1. Molecular Operating Environment Software . Chemical Computing Group Inc., Montreal, Canada, 2007 . http://www. chemcomp.com BROOD 2.0.0, OEChem , version 1.4.2; OpenEye Scientific Software, Inc. Santa Fe, NM, 2006 ; www. eyeopen.com. GaussView 5.0.8 , Revision 5, Gaussian, Inc.: Wllingford, CT, USA, 2009 . 2. Gaussian 09 , revision A.02, Frisch, M.J.; trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.P.; Izmaylov, A.F.; Bloino, J.; Zheng, G.; Sonnenberg, J.L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; T. Nakajima, Y.; Honda, O.; Kitao, H.; Nakai, T.; Vreven, J.A.; Montgomery, Jr.; Peralta, J.E.; Ogliaro, F.; Bearpark, M.; Heyd, J.J.; Brothers, E.; Kudin, K.N.; Staroverov, V.N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J.C.; Iyengar, S.S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J.M.; Klene, M.; Knox, J.E.; Cross, J.B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E., Yazyev, O.; Austin, A.J.; Cammi, R.; Pomelli, C.; Ochterski, J.W.; Dapprich, S.; Daniels, A.D.; Farkas, O.; Foresman, J.B.; Ortiz, J.V.; Cioslowski, J.; Fox, D.J. Gaussian, Inc., Wallingford CT, 2009 . 3. Duda-Seiman, C.; Duda-Seiman, D.; Dragos, D.; Medeleanu, M.; Careja, V.; V. Putz, M.; Lacrama, A.M.; Chiriac, A.; Nutiu, R.; Ciubotariu, D. Design of anti-HIV ligands by means of minimal topological difference (MTD) method. Int. J. Mol. Sci . 2006 , 7, 537-555. 4. Cramer, R.D. III; Bunce, J.D.; Patterson, D.E.; Frank, I.E. Bootstrapping, crossvalidation and partial least squares. Quant. Struct.-Act. Relat ., 1988 , 7, 18-25. 5. Sriram, D.; Yogeeswari, P.; Thirumurugan, R.; Pavana, R.K. Discovery of new antitubercular oxazolyl thiosemicarbazones. J. Med. Chem. 2006 , 49, 3448-3450.
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