Identification of Plasmodium falciparum heat shock 90 inhibitors via molecular docking

Everson, Nikalet; Bach, Jordan; Hammill, Jared T.; Falade, Mofolusho O.; Rice, Amy L.; Guy, R. Kiplin; Eagon, Scott

doi:10.1016/j.bmcl.2021.127818

Cited by 6 publications

(13 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A total of 20 hypotheses were generated and ranked based on several statistical metrics, which include vector, volume, site, and survival scores. Hypothesis was validated by taking the 31 compounds from literature , that were used to develop the model and compounds from the DUD database as a subset of decoys. The validation of the model was used to assess the ability of the generated hypothesis to differentiate between active and decoy compounds and provide a quality estimation of the hypothesis.…”

Section: Methodsmentioning

confidence: 99%

“…Using surface plasmon resonance and site-directed mutagenesis, it was previously demonstrated that Arg98 was responsible for the selectivity of harmine . In other studies, rational design strategies implementing molecular docking and molecular dynamics simulations were used to identify novel, potent, and selective inhibitors of PfHsp90. , We used the gains and information from previous studies to develop a pharmacophore model trained using the structures of the selective inhibitors of PfHsp90 obtained from the literature. The hypothesis generated was used to investigate pharmacophores of compounds obtained from commercial databases to enable the identification of selective inhibitors of PfHsp90.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacophore Model-Based Virtual Screening Workflow for Discovery of Inhibitors Targeting Plasmodium falciparum Hsp90

Mafethe,

Ntseane,

Dongola

et al. 2023

ACS Omega

View full text Add to dashboard Cite

Plasmodium falciparum causes the most lethal and widespread form of malaria. Eradication of malaria remains a priority due to the increasing number of cases of drug resistance. The heat shock protein 90 of P. falciparum (PfHsp90) is a validated drug target essential for parasite survival. Most PfHsp90 inhibitors bind at the ATP binding pocket found in its N-terminal domain, abolishing the chaperone's activities, which leads to parasite death. The challenge is that the NTD of PfHsp90 is highly conserved, and its disruption requires selective inhibitors that can act without causing off-target human Hsp90 activities. We endeavored to discover selective inhibitors of PfHsp90 using pharmacophore modeling, virtual screening protocols, induced fit docking (IFD), and cell-based and biochemical assays. The pharmacophore model (DHHRR), composed of one hydrogen bond donor, two hydrophobic groups, and two aromatic rings, was used to mine commercial databases for initial hits, which were rescored to 20 potential hits using IFD. Eight of these compounds displayed moderate to high activity toward P. falciparum NF54 (i.e., IC 50 s ranging from 6.0 to 0.14 μM) and averaged >10 in terms of selectivity indices toward CHO and HepG2 cells. Additionally, four compounds inhibited PfHsp90 with greater selectivity than a known inhibitor, harmine, and bound to PfHsp90 with weak to moderate affinity. Our findings support the use of a pharmacophore model to discover diverse chemical scaffolds such as FM2, FM6, F10, and F11 exhibiting anti-Plasmodium activities and serving as valuable new PfHsp90 inhibitors. Optimization of these hits may enable their development into potent leads for future antimalarial drugs.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacophore Model-Based Virtual Screening Workflow for Discovery of Inhibitors Targeting Plasmodium falciparum Hsp90

Mafethe,

Ntseane,

Dongola

et al. 2023

ACS Omega

View full text Add to dashboard Cite

show abstract

“…In a recent study, virtual screening of compounds on the ZINC15 database [ 145 ] identified three potent novel compounds, CP-6, CP-7, and CP-10, that target the ATP binding pocket of PfHsp90 [ 146 ]. These three compounds selectively inhibited the growth of chloroquine-sensitive P. falciparum 3D7 strain without toxicity to human fibroblast BJ cell line [ 146 ]. This highlights the ability of these antimalarials to specifically target PfHsp90 without inducing cytotoxicity in the human host.…”

Section: P Falciparum Hsp90 As Drug Targetsmentioning

confidence: 99%

“…This highlights the ability of these antimalarials to specifically target PfHsp90 without inducing cytotoxicity in the human host. Of these three hits, CP-7 was the most potent due to strong binding through the 1,3-benzodioxole ring of CP-7forming hydrogen bonds with Thr101 near the phosphate-binding site of the ATP pocket which is further strengthened by non-polar interactions with Tyr125 [ 146 ]. The central amide of CP-7 also forms an H-bond with the Asn37 primary amide, which makes stronger interactions resulting in higher potency against P. falciparum parasites [ 146 ].…”

Section: P Falciparum Hsp90 As Drug Targetsmentioning

confidence: 99%

“…Of these three hits, CP-7 was the most potent due to strong binding through the 1,3-benzodioxole ring of CP-7forming hydrogen bonds with Thr101 near the phosphate-binding site of the ATP pocket which is further strengthened by non-polar interactions with Tyr125 [ 146 ]. The central amide of CP-7 also forms an H-bond with the Asn37 primary amide, which makes stronger interactions resulting in higher potency against P. falciparum parasites [ 146 ]. This suggests that these three compounds provide a scaffolding platform for promising antimalarial drug candidates.…”

Section: P Falciparum Hsp90 As Drug Targetsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future

Stofberg

Caillet

Villiers

et al. 2021

Cells

View full text Add to dashboard Cite

Malaria is still one of the major killer parasitic diseases in tropical settings, posing a public health threat. The development of antimalarial drug resistance is reversing the gains made in attempts to control the disease. The parasite leads a complex life cycle that has adapted to outwit almost all known antimalarial drugs to date, including the first line of treatment, artesunate. There is a high unmet need to develop new strategies and identify novel therapeutics to reverse antimalarial drug resistance development. Among the strategies, here we focus and discuss the merits of the development of antimalarials targeting the Heat shock protein 90 (Hsp90) due to the central role it plays in protein quality control.

show abstract

Auto QSAR-based Active learning docking for hit identification of potential inhibitors ofPlasmodium falciparumHsp90 as antimalarial agents

Matlhodi,

Makatsela,

Dongola

et al. 2024

Preprint

View full text Add to dashboard Cite

Malaria which is mainly caused by Plasmodium falciparum parasite remains a devastating public health concern, necessitating the need to develop new antimalarial agents. P. falciparum heat shock protein 90 (Hsp90), is indispensable for parasite survival and a promising drug target. Inhibitors targeting the ATP-binding pocket of the N-terminal domain have anti-Plasmodium effects. We proposed a de novo active learning (AL) driven method in tandem with docking to predict inhibitors with unique scaffolds and preferential selectivity towards PfHsp90. Reference compounds, predicted to bind PfHsp90 at the ATP-binding pocket and possessing anti-Plasmodium activities, were used to generate 10,000 unique derivatives and to build the Auto-quantitative structures activity relationships (QSAR) models. Glide docking was performed to predict the docking scores of the derivatives and > 15,000 compounds obtained from the ChEMBL database. Re-iterative training and testing of the models was performed until the optimum Kennel-based Partial Least Square (KPLS) regression model with a regression coefficient R2 = 0.75 for the training set and squared correlation prediction Q2 = 0.62 for the test set reached convergence. Rescoring using induced fit docking and molecular dynamics simulations enabled us to prioritize 15 ATP/ADP-like design ideas for purchase. The compounds exerted moderate activity towards P. falciparum NF54 strain with IC50 values of ≤ 6μM and displayed moderate to weak affinity towards PfHsp90 (KD range: 13.5-19.9μM) comparable to the reported affinity of ADP. The most potent compound was FTN-T5 (PfN54 IC50:1.44μM; HepG2/CHO cells SI≥ 29) which bound to PfHsp90 with moderate affinity (KD:7.7μM), providing a starting point for optimization efforts. Our work demonstrates the great utility of AL for the rapid identification of novel molecules for drug discovery (i.e., hit identification). The potency of FTN-T5 will be critical for designing species-selective inhibitors towards developing more efficient agents against malaria.

show abstract

Identification of Plasmodium falciparum heat shock 90 inhibitors via molecular docking

Cited by 6 publications

References 32 publications

Pharmacophore Model-Based Virtual Screening Workflow for Discovery of Inhibitors Targeting Plasmodium falciparum Hsp90

Pharmacophore Model-Based Virtual Screening Workflow for Discovery of Inhibitors Targeting Plasmodium falciparum Hsp90

Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future

Auto QSAR-based Active learning docking for hit identification of potential inhibitors ofPlasmodium falciparumHsp90 as antimalarial agents

Contact Info

Product

Resources

About