Biology subjects

Sandhu, K. K.

Publications and source records attributed to Sandhu, K. K..

3 recordsLinked to original sources

bioRxiv2023

Exploring the interaction of inhibitor YM-1 with Plasmodium falciparum HSP70s through in silico methods

YM-1 belongs to the rhodacyanine class of the 70kDa heat shock protein (Hsp70) inhibitors. It antagonizes nucleotide exchange factor (NEF) BAG3 to block the critical ATPase cycle of HSP70 chaperones thereby disabling them. The anti-cancer potential of this small molecule derivative of MKT-077 is attributed to its improved solubility and stability over its parent. In the current study, we have used bioinformatics tools including molecular docking to study the binding strength of YM-1 for Plasmodium falciparum (Pf) HSP70s. Of the four PfHSP70 homologs, the mitochondrial counterpart was predicted to bind most efficiently with YM-1 at a previously reported inhibitor binding site. The interaction of YM-1 with mitochondrial PfHSP70 was significantly better than with any of the other Pf homologs. Further analysis of this PfHSP70-YM-1 complex helped us to predict not just the types of interactions, but also specific residues of the protein involved in inhibitor engagement. Information reported in this article is important from the standpoint of design and development of newer rhodacyanine based drugs against malaria.

bioinformatics↗

bioRxiv2023

Analyzing interaction of rhodacyanine inhibitor MKT-077 with Plasmodium falciparum HSP70 nucleotide binding domains

MKT-077 and its derivatives are rhodacyanine inhibitors that hold potential in treatment of cancer, neurodegenerative diseases and malaria. These allosteric drugs act by inhibiting the ATPase action of heat shock proteins of 70kDa (HSP70). MKT-077 accumulates in the mitochondria and displays differential activity against HSP70 homologs. The four Plasmodium falciparum HSP70s (PfHSP70) are present at various subcellular locations to perform distinct functions. In the present study, we have used bioinformatics tools to understand interactions between MKT-077 and PfHSP70s. Nature of the identified interactions is primarily hydrophobic with different PfHSP70 homologs showing variable propensity to bind MKT-077. Our molecular docking approach has helped us to predict the binding pocket and specific residues on PfHSP70s that are involved in interacting with MKT-077. Information derived from this article may form the foundation for design and development of MKT-077 based drugs against malaria.

bioinformatics↗

bioRxiv2023

Understanding the structural basis for differential binding of lapachol with PfHSP70s

The 70 kDa heat shock proteins from Plasmodium falciparum (PfHSP70) are an important family of proteins that may be exploited for antimalarial design. Plant derived inhibitor lapachol is reported to efficiently inhibit the exported PfHSP70-x while having poor activity against the parasite PfHSP70-1. In the present study, we have used in silico tools including molecular docking to understand the molecular basis for the above differences in lapachol inhibition activity against PfHSP70s. We found a significant gap in the binding energies and hence affinity of PfHSP70-1 and PfHSP70-x for lapachol with the latter having a better binding propensity. Our data highlight notable differences in the type of interactions between the two complexes. Detailed molecular analysis of the complexes has helped us to predict specific amino acid residues from both these PfHSP70 homologs that may be involved in lapachol binding. The above information may be utilized for design of PfHSP70 inhibitors with antimalarial potential.

bioinformatics↗