Sulfonamide derivatives as Mycobacterium tuberculosis inhibitors: in silico approach
- 9 Downloads
Both DHPS (dihydropteroate synthase) and DHFR (dihydrofolate reductase) play important physiological roles in the survivability of Mycobacterium tuberculosis (MTB). Sulfonamides are the potent drugs to monitor growth and proliferation of MTBs by inhibiting the activity of DHPS and DHFR which could explain the mechanism of action of these molecules. In this work, 102 heterocyclic sulfonamides (HSF) have been screened by discovery studio molecular docking programme to search the best suitable molecule for the treatment of MTBs. Lipinski’s rule of five protocols is followed to screen drug likeness of these molecules and ADMET (absorption, distribution, metabolism, excretion and toxicity) filtration has been used to value their toxicity. Only fourteen molecules are found to obey the Lipinski’s rule and able to cross the ADMET filter. A small difference between HOMO and LUMO energy signifies the electronic excitation energy which is essential to calculate molecular reactivity and stability of the best docked compound and easy activation of drug in the protein environment. Both 4-amino-N-(6-hydroxypyridin-2-yl)benzenesulfonamide (M1) and 4-amino-N-(9H-carbazol-2-yl)benzenesulfonamide (M2) show the best theoretical efficiency with DHPS and DHFR, respectively. These compounds are also found to bind to the adenine–thymine region of tuberculosis DNA.
KeywordsDHPS and DHFR inhibitors Heterocyclic sulfonamide compounds Structure based drug design Molecular docking ADMET
We sincerely thank the Council of Scientific and Industrial Research, New Delhi, India [Grant number 01(2894)/17/EMR-II] for funding.
Compliance with ethical standards
Conflict of interest
The authors confirm that this article content has no conflicts of interest.
- Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark MJ, Heyd J, Brothers EN, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam NJ, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09. Gaussian Inc., WallingfordGoogle Scholar
- Pradhan S, Mondal S, Sinha C (2016) In search of Tuberculosis drug design: an in silico approach to azoimidazolyl derivatives as antagonist for cytochrome P450. J Indian Chem Soc 93(9):1067–1084Google Scholar
- Rozhenko AB (2014) Density functional theory calculations of enzyme-inhibitor interactions in medicinal chemistry and drug design. In: Gorb L, Kuz’min V, Muratov E (eds) Application of computational techniques in pharmacy and medicine. Springer, Dordrecht, pp 207–240Google Scholar
- Winum J-Y, Dogné J-M, Casini A, de Leval X, Montero J-L, Scozzafava A, Vullo D, Innocenti A, Supuran CT (2005) Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/membrane-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating hydrazino moieties. J Med Chem 48(6):2121–2125CrossRefPubMedGoogle Scholar
- Zhao YH, Le J, Abraham MH, Hersey A, Eddershaw PJ, Luscombe CN, Boutina D, Beck G, Sherborne B, Cooper I (2001) Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure–activity relationship (QSAR) with the Abraham descriptors. J Pharm Sci 90(6):749–784CrossRefPubMedGoogle Scholar