PfHslV, a homolog of b subunit of 20S proteasome forms the proteolytic core of the PfHslUV machin... more PfHslV, a homolog of b 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 b5 subunit of P. falciparum [3]. 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 s...
Biomedical Engineering and Computational Biology, 2011
There is an urgent need to develop novel anti-malarials in view of the increasing disease burden ... more There is an urgent need to develop novel anti-malarials in view of the increasing disease burden and growing resistance of the currently used drugs against the malarial parasites. Proliferation inhibitors targeting P. falciparum intraerythrocytic cycle are one of the important classes of compounds being explored for its potential to be novel antimalarials. Support Vector Machine (SVM) based model developed by us can facilitate rapid screening of large and diverse chemical libraries by reducing false hits and prioritising compounds before setting up expensive High Throughput Screening experiment. The SVM model, trained with molecular descriptors of proliferation inhibitors and non-inhibitors, displayed a satisfactory performance on cross validations and independent data set, with an average accuracy of 83% and AUC of 0.88. Intriguingly, the method displayed remarkable accuracy for the recently submitted P. falciparum whole cell screening datasets. The method also predicted several in...
Journal of Biomolecular Structure and Dynamics, 2009
The PfHslUV, a Plasmodium falciparum homolog of prokaryotic HslUV systems, is a newly identified ... more The PfHslUV, a Plasmodium falciparum homolog of prokaryotic HslUV systems, is a newly identified drug target. The HslUV complex is an assembly of Heat Shock Locus gene products U and V. The formation of complete complex is essential for the proteasome to carry out its biochemical and physiological role in the parasite, namely to degrade specific target proteins in an ATP-dependent chaperone assisted manner. PfHslV subunit, a protease, exhibits increased proteolytic activity in the presence of PfHslU, the subunit believed to be responsible for allosteric activation of PfHslV. In the present work, we have employed computational methods to simulate the interaction of PfHslU and PfHslV subunits. We have used three methods--namely homology modeling, molecular docking and computational alanine scanning to model the complex, to predict the binding mode of PfHslU-V interaction and to predict the binding-energy hot-spots in protein-protein interface, respectively. The three dimensional models of PfHslV and PfHslU have been generated using MODELLER, based on the crystal structures of prokaryotic HslUV complex as templates. The modeled structures were docked using PatchDock, a geometry-based molecular docking algorithm. Finally, a three-dimensional PfHslUV complex model was generated that helped in comparing protein-protein interface characteristics with that of crystal structures of prokaryotic HslUV. Further, computational alanine scanning analysis of the generated complex was performed to calculate the binding free energy changes (DeltaDeltaGbind), which helped in identifying residues crucial for PfHslU and PfHslV interactions.
Journal of Biomolecular Structure and Dynamics, 2013
Malaria is still one of the deadly diseases resulting in deaths of millions of people worldwide a... more Malaria is still one of the deadly diseases resulting in deaths of millions of people worldwide and situation has become worse due to alarming rise in anti-malarial drug resistance. Genome sequence availability of Plasmodium falciparum, the main causal organism of severe malaria in humans, has enabled identification of various parasite cell cycle regulators like several cyclins and cyclin dependent kinases or CDKs which are promising novel drug targets for Malaria. Here, we present in silico characterization of tertiary structure of Pfcyc-1, a P. falciparum cyclin homolog, which enables identification of key structural elements that contribute to its tertiary structure and function. We have investigated the structure and dynamics of Pfcyc-1 structural model by performing 10 ns molecular dynamics (MD) simulation. Our study indicates that despite poor sequence similarities with cyclin H and A, the characteristic structural cyclin domains are conserved in Pfcyc-1 too. The Pfcyc-1 model reveals a cyclin box, consisting of two tandemly repeating five-helix bundles separated by a linker hinge peptide. Furthermore, the amino acid residues in other known cyclins mediating cyclin-CDK interactions are conserved in Pfcyc-1. The model and its MD simulation offer a first ever structural annotation of any plasmodium cyclin, which along with sequence comparisons, helps in identification of important functional residues mediating the Pfcyc-1-CDK like interactions.
PfHslV, a homolog of b subunit of 20S proteasome forms the proteolytic core of the PfHslUV machin... more PfHslV, a homolog of b 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 b5 subunit of P. falciparum [3]. 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 s...
Biomedical Engineering and Computational Biology, 2011
There is an urgent need to develop novel anti-malarials in view of the increasing disease burden ... more There is an urgent need to develop novel anti-malarials in view of the increasing disease burden and growing resistance of the currently used drugs against the malarial parasites. Proliferation inhibitors targeting P. falciparum intraerythrocytic cycle are one of the important classes of compounds being explored for its potential to be novel antimalarials. Support Vector Machine (SVM) based model developed by us can facilitate rapid screening of large and diverse chemical libraries by reducing false hits and prioritising compounds before setting up expensive High Throughput Screening experiment. The SVM model, trained with molecular descriptors of proliferation inhibitors and non-inhibitors, displayed a satisfactory performance on cross validations and independent data set, with an average accuracy of 83% and AUC of 0.88. Intriguingly, the method displayed remarkable accuracy for the recently submitted P. falciparum whole cell screening datasets. The method also predicted several in...
Journal of Biomolecular Structure and Dynamics, 2009
The PfHslUV, a Plasmodium falciparum homolog of prokaryotic HslUV systems, is a newly identified ... more The PfHslUV, a Plasmodium falciparum homolog of prokaryotic HslUV systems, is a newly identified drug target. The HslUV complex is an assembly of Heat Shock Locus gene products U and V. The formation of complete complex is essential for the proteasome to carry out its biochemical and physiological role in the parasite, namely to degrade specific target proteins in an ATP-dependent chaperone assisted manner. PfHslV subunit, a protease, exhibits increased proteolytic activity in the presence of PfHslU, the subunit believed to be responsible for allosteric activation of PfHslV. In the present work, we have employed computational methods to simulate the interaction of PfHslU and PfHslV subunits. We have used three methods--namely homology modeling, molecular docking and computational alanine scanning to model the complex, to predict the binding mode of PfHslU-V interaction and to predict the binding-energy hot-spots in protein-protein interface, respectively. The three dimensional models of PfHslV and PfHslU have been generated using MODELLER, based on the crystal structures of prokaryotic HslUV complex as templates. The modeled structures were docked using PatchDock, a geometry-based molecular docking algorithm. Finally, a three-dimensional PfHslUV complex model was generated that helped in comparing protein-protein interface characteristics with that of crystal structures of prokaryotic HslUV. Further, computational alanine scanning analysis of the generated complex was performed to calculate the binding free energy changes (DeltaDeltaGbind), which helped in identifying residues crucial for PfHslU and PfHslV interactions.
Journal of Biomolecular Structure and Dynamics, 2013
Malaria is still one of the deadly diseases resulting in deaths of millions of people worldwide a... more Malaria is still one of the deadly diseases resulting in deaths of millions of people worldwide and situation has become worse due to alarming rise in anti-malarial drug resistance. Genome sequence availability of Plasmodium falciparum, the main causal organism of severe malaria in humans, has enabled identification of various parasite cell cycle regulators like several cyclins and cyclin dependent kinases or CDKs which are promising novel drug targets for Malaria. Here, we present in silico characterization of tertiary structure of Pfcyc-1, a P. falciparum cyclin homolog, which enables identification of key structural elements that contribute to its tertiary structure and function. We have investigated the structure and dynamics of Pfcyc-1 structural model by performing 10 ns molecular dynamics (MD) simulation. Our study indicates that despite poor sequence similarities with cyclin H and A, the characteristic structural cyclin domains are conserved in Pfcyc-1 too. The Pfcyc-1 model reveals a cyclin box, consisting of two tandemly repeating five-helix bundles separated by a linker hinge peptide. Furthermore, the amino acid residues in other known cyclins mediating cyclin-CDK interactions are conserved in Pfcyc-1. The model and its MD simulation offer a first ever structural annotation of any plasmodium cyclin, which along with sequence comparisons, helps in identification of important functional residues mediating the Pfcyc-1-CDK like interactions.
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Papers by Sangeetha Subramaniam