In-silico studies on DegP protein of Plasmodium falciparum in search of anti-malarials

Abstract

Despite encouraging progress over the past decade, malaria caused by the Plasmodium parasite continues to pose an enormous disease burden and is one of the major global health problems. The extreme challenge in malaria management is the resistance of parasites to traditional monochemotherapies like chloroquine and sulfadoxine-pyrimethamine. No vaccine is yet in sight, and the foregoing effective drugs are also losing ground against the disease due to the resistivity of parasites. New antimalarials with novel mechanisms of action are needed to circumvent existing or emerging drug resistance. DegP protein, secretory in nature has been shown to be involved in regulation of thermo-oxidative stress generated during asexual life cycle of Plasmodium, probably required for survival of parasite in host. Considering the significance of protein, in this study, we have generated a three-dimensional structure of PfDegP followed by validation of the modeled structure using several tools like RAMPAGE, ERRAT, and others. We also performed an in-silico screening of small molecule database against PfDegP using Glide. Furthermore, molecular dynamics simulation of protein and protein-ligand complex was carried out using GROMACS. This study substantiated potential drug-like molecules and provides the scope for development of novel antimalarial drugs.

A systematic review: Application of in silico models for antimalarial drug discovery

“…The published in silico models were mostly applied for lead identification/optimization (13 articles) of the known Plasmodium targets (13 targets). Most articles are specific for P. falciparum targets (Campbell et al, 2014;Kumari et al, 2016;LaMonte et al, 2017;Lhouvum et al, 2013;MacDonald and Boyd, 2015;Raza et al, 2017;Ren et al, 2016;Sharma et al, 2016); 3 articles involved target for P. vivax (MacDonald et al, 2015;Rout et al, 2016;Bouillon et al, 2013) and 1 article involved target for liver stage of Plasmodium (Sullivan et al, 2015). Five articles were applied in silico modeling for target identification/validation (Lhouvum et al, 2013;Mehra et al, 2015;Paul et al, 2015;Rout et al, 2015;Pandey et al, 2014).…”

“…Five articles were applied in silico modeling for target identification/validation (Lhouvum et al, 2013;Mehra et al, 2015;Paul et al, 2015;Rout et al, 2015;Pandey et al, 2014). Both structure-based (Bouillon et al, 2013;LaMonte et al, 2017;MacDonald and Boyd, 2015;Raza et al, 2017;Ren et al, 2016;Rout and Mahapatra, 2016;Sullivan et al, 2015) and ligandbased (Villalobos et al, 2013;Kumari et al, 2016;Ren et al, 2016;Sharma et al, 2016) approaches were applied to obtain lead antimalarial candidates. Two articles also assessed ADMET properties (Ren et al, 2016;Rout and Mahapatra, 2016).…”

“…Lead identification/optimization involved identification of potent antimalarial candidate molecules which are inhibitors of known specific Plasmodium targets (13 targets) encoded by the malaria parasite genome. These included: inosine monophosphate dehydrogenase (IMPDH) (Raza et al, 2017), proteasome (LaMonte et al, 2017), lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) (Ren et al, 2016), heat shock regulated A (HrA or DegP) (Sharma et al, 2016), P. falciparum M18 (Kumari et al, 2016), P. falciparum aspartyl aminopeptidase (PfM18AAP) (Kumari et al, 2016), leucine amino peptidase (M17 LAP) (Rout and Mahapatra, 2016), P. falciparum glycogen synthase kinase-3 (PfGSK-3), P. falciparum CTP synthetase (PfCTPS), choline kinase (PfCK), and glutathione S-transferase (PfGST) (Verma et al, 2015), Plasmodium peptidyl-prolyl cis/trans isomerase (MacDonald and Boyd, 2015), Plasmodium phosphatases, cytochrome bc1 (Jimenez et al, 2013), and P. vivax subtilin-like serine protease (PvSUB1) (Bouillon et al, 2013). Application of the modeling for target identification/validation included Nmyristoyltransferase (NMT) (Paul et al, 2015), Plasmodium phosphatases (Campbell et al, 2014;Pandey et al, 2014), and PFI1625c metalloprotease (Lhouvum et al, 2013).…”

“…A multitude of databases of compounds were used as sources of chemical structures in one or more of the highlighted studies including ZINC (Rout et al, 2015;Rout and Mahapatra, 2016;Verma et al, 2015), ChEMBL-NTD (Sullivan et al, 2015), DrugBank (Ren et al, 2016;Rout et al, 2015;Rout and Mahapatra, 2016), PubChem (Kumari et al, 2016;Rout and Mahapatra, 2016), and ChemSpider (Rout and Mahapatra, 2016). For antimalarial protein targets, the databases applied included PlasmoDB 9.2 (Lhouvum et al, 2013;Pandey et al, 2014;Rout et al, 2015;Sharma et al, 2016), PFAM (Pandey et al, 2014;Rout et al, 2015), CDD [29], ZINC (Lhouvum et al, 2013;Pandey et al, 2014), and InterPro (Campbell et al, 2014;Rout et al, 2015). Protein structures were downloaded from these databases and validated using RAMPAGE (Paul et al, 2015;Sharma et al, 2016), PROCHECK (Bouillon et al, 2013;Campbell et al, 2014;Kruggel and Lemcke, 2009;Lhouvum et al, 2013;Mehra et al, 2015;Paul et al, 2015;Raza et al, 2017;Rout et al, 2015;Rout and Mahapatra, 2016), Verify-3D (Campbell et al, 2014;Lhouvum et al, 2013;Rout et al, 2015;Rout and Mahapatr...…”

“…For antimalarial protein targets, the databases applied included PlasmoDB 9.2 (Lhouvum et al, 2013;Pandey et al, 2014;Rout et al, 2015;Sharma et al, 2016), PFAM (Pandey et al, 2014;Rout et al, 2015), CDD [29], ZINC (Lhouvum et al, 2013;Pandey et al, 2014), and InterPro (Campbell et al, 2014;Rout et al, 2015). Protein structures were downloaded from these databases and validated using RAMPAGE (Paul et al, 2015;Sharma et al, 2016), PROCHECK (Bouillon et al, 2013;Campbell et al, 2014;Kruggel and Lemcke, 2009;Lhouvum et al, 2013;Mehra et al, 2015;Paul et al, 2015;Raza et al, 2017;Rout et al, 2015;Rout and Mahapatra, 2016), Verify-3D (Campbell et al, 2014;Lhouvum et al, 2013;Rout et al, 2015;Rout and Mahapatra, 2016;Sharma et al, 2016), ERRAT (Campbell et al, 2014;Lhouvum et al, 2013;Rout et al, 2015;Rout and Mahapatra, 2016;Sharma et al, 2016), CHIMERA (Paul et al, 2015), and PROSA (Rout et al, 2015;Rout and Mahapatra, 2016;Sharma et al, 2016;Verma et al, 2015). Stability check was performed using Gromacs (Lhouvum et...…”