Novel Anti-plasmodial Hits Identified by Virtual Screening of the ZINC Database

Overview

Journal J Comput Aided Mol Des

Publisher Springer

Specialties Biomedical Engineering
Molecular Biology

Date 2013 Oct 26

PMID 24158745

Citations 6

Authors

Grace Mugumbate

Ana S Newton

Philip J Rosenthal

Jiri Gut

Rui Moreira

Kelly Chibale

Rita C Guedes

Affiliations

Soon will be listed here.

Abstract

Increased resistance of Plasmodium falciparum to most available drugs challenges the control of malaria. Studies with protease inhibitors have suggested important roles for the falcipain family of cysteine proteases. These enzymes act in concert with other proteases to hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. In order to find potential new antimalarial drugs, we screened in silico the ZINC database using two different protocols involving structure- and ligand-based methodologies. Our search identified 19 novel low micromolar inhibitors of cultured chloroquine resistant P. falciparum. The most active compound presented an IC50 value of 0.5 μM against cultured parasites and it also inhibited the cysteine protease falcipain-2 (IC50 = 25.5 μM). These results identify novel classes of antimalarials that are structurally different from those currently in use and which can be further derivatized to deliver leads suitable for optimisation.

Citing Articles

Three Decades of Targeting Falcipains to Develop Antiplasmodial Agents: What have we Learned and What can be Done Next?.

Gonzalez J, Salas-Sarduy E, Alvarez L, Valiente P, Arni R, Pascutti P Curr Med Chem. 2023; 31(16):2234-2263.

PMID: 37711130 DOI: 10.2174/0929867331666230913165219.

Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity.

Uddin A, Gupta S, Mohammad T, Shahi D, Hussain A, Alajmi M Front Pharmacol. 2022; 13:850176.

PMID: 35462917 PMC: 9020225. DOI: 10.3389/fphar.2022.850176.

Establishing Computational Approaches Towards Identifying Malarial Allosteric Modulators: A Case Study of Hsp70s.

Amusengeri A, Astl L, Lobb K, Verkhivker G, Tastan Bishop O Int J Mol Sci. 2019; 20(22).

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South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches.

Musyoka T, Tastan Bishop O Molecules. 2019; 24(22).

PMID: 31703388 PMC: 6891524. DOI: 10.3390/molecules24224036.

Guided Drug Repurposing: Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2.

Alberca L, Chuguransky S, Alvarez C, Talevi A, Salas-Sarduy E Front Chem. 2019; 7:534.

PMID: 31448257 PMC: 6691349. DOI: 10.3389/fchem.2019.00534.

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