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Development of target focused library against drug target of P. falciparumusing SVM and Molecular docking
Journal of Cheminformatics volume 4, Article number: P48 (2012)
PfHslV, a homolog of β subunit of 20S proteasome forms the proteolytic core of the PfHslUV machinery in P. falciparum [1, 2]. PfHslV has no homolog in the human host and it is a promising drug target essential to the plasmodial metabolism. The use of single proteasome inhibitor targeting these threonine proteases has a potential to be antimalarial drug candidate. One of our recent studies identified several promising inhibitors against 20S β5 subunit of P. falciparum . The present study adopts a similar knowledge based virtual screening strategy using Support Vector Machines (SVM) and molecular docking to build a focused library of potential PfHslV inhibitors. SVM model has been trained using 170 molecular descriptors of 64 inhibitors and 208 putative non-inhibitors. The non-linear classifier based on Radial Basis Function (RBF) kernel yielded classification accuracy of 97%. The SVM model rapidly predicted inhibitors from NCI library and were subsequently docked in to the active site of an optimised three-dimensional model of PfHslV. The novel drug-like PfHslV inhibitors with very good binding affinity and novel scaffold can be a good starting point to develop new antimalarial drugs.
Ramasamy G, Gupta D, Mohmmed A, Chauhan VS: Characterization and localization of Plasmodium falciparum homolog of prokaryotic ClpQ/HslV protease. Mol Biochem Parasitol. 2007, 152: 139-148. 10.1016/j.molbiopara.2007.01.002.
Subramaniam S, Mohmmed A, Gupta D: Molecular modeling studies of the interaction between Plasmodium falciparum HslU and HslV Subunits. J Biomol Struct Dyn. 2009, 26: 403-524.
Subramaniam S, Mehrotra M, Gupta D: Support Vector Machine based prediction of P. falciparum proteasome inhibitors and development of focused library by molecular docking. Comb Chem High Throughput Screen. 2011, 14 (10): 898-907. 10.2174/138620711797537058.
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Subramaniam, S., Mehrotra, M. & Gupta, D. Development of target focused library against drug target of P. falciparumusing SVM and Molecular docking. J Cheminform 4 (Suppl 1), P48 (2012). https://doi.org/10.1186/1758-2946-4-S1-P48
- Support Vector Machine
- Radial Basis Function
- Molecular Docking
- Antimalarial Drug