Exploration of new drug-like inhibitors for serine/threonine protein phosphatase 5 ofPlasmodium falciparum: a docking and simulation study

Abstract

Protein phosphorylation is an important mechanism that implicates in physiology of any organism including parasitic protozoa. Metallic protein Ser/Thr protein phosphatase 5 (PP5) controls various cellular signaling pathways of Plasmodium falciparum. The structure and inhibitory mechanism of PP5 in P. falciparum is not known. In fact, no experimental structural data are available for P. falciparum Ser/Thr protein phosphatase 5 (PfPP5) till date. Hence, we have proposed computer-generated model of catalytic subunit of PfPP5 and its inhibitory mechanism was analyzed. A set of 42 known natural inhibitors of protein phosphate family were docked against metal-binding catalytic site of PfPP5 and we found that cantharidin and its derivatives shows better binding energy among them. Similarity search was performed by taking these compounds as lead compounds against PubChem and ChemBank. The search result provides 3703 similar compounds; out of which 2245 qualified the Lipinski rule of five. Further, virtual screening of these compounds was performed and selected top 25 were selected on the basis of binding energy. In continuation, rigid and flexible docking of these screened compounds was performed to get the insight of interactions. Finally, top 5 compounds were verified for ADMET properties, and then, all are subjected to MD simulations for 25 ns in order to validate their stability. Compounds CBI: 3554182, CID: 23561913, and CID: 21168680 showed most stable binding, although some of hydrogen bonds pairing varied throughout simulation. These finding would be helpful to the medicinal chemists for the development of antimalarial drugs to combat this deadly disease.

Transcriptomic Analysis of Soil Grown T. aestivum cv. Root to Reveal the Changes in Expression of Genes in Response to Multiple Nutrients Deficiency

“…Most of these functions directly depend on the transportation of potassium concentration across membrane-bound K transport proteins (Britto and Kronzucker, 2008). Interestingly, 2 transcripts expression encode cold responsive protein that indicates that Wlt10 gene of the wheat root is activated during ND condition, which enables root to survive at freezing temperatures (Thomashow, 1998; Gupta et al, 2015a). The expression of S-adenosylmethionine decarboxylase proenzyme (SAMDC, EC 4.1.1.50), as a key rate-limiting enzyme in the polyamine (PA) biosynthesis is required for plant growth and development (Hu et al, 2005).…”

Comparative Analysis of AGPase Genes and Encoded Proteins in Eight Monocots and Three Dicots with Emphasis on Wheat

“…The molecular function of proteins depends on their conformational behavior and structural stability, which can be studied in real time environment through atomic-level perturbations using Molecular Dynamics (MD) simulations (Gupta et al, 2015a,b). In the present study, MD simulations were performed using Desmond v4.2 and system generation and results were generated using Schrodinger's maestro v11 platform (Schrödinger, Inc.).…”

Analysis of non-peptidic compounds as potential malarial inhibitors against Plasmodial cysteine proteases via integrated virtual screening workflow

“…A formidable hurdle against successful elimination of malaria is the identification of a broad range of drugs targeting common druggable targets in both the active human forms of Plasmodium as well as the circulating wild species. Several Plasmodium drug targets including but not limited to falcipains (FPs) (Marco & Coteron, 2012), serine/threonine protein phosphatase 5 , serine repeat antigens, apicoplast-targeted tRNA-guanine transglycosylase (Gupta et al, 2015), Pf lactate dehydrogenase (Thillainayagam et al, 2014) and heat shock proteins (Hatherley, Blatch, & Tastan Bishop, 2014) have been identified. In the current study, our focus is on the falcipains which are validated drug targets (Teixeira, Gomes, & Gomes, 2011).…”