Dataset Information

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

ABSTRACT: Malaria is among the leading causes of death worldwide. The emergence of Plasmodium falciparum resistant strains with reduced sensitivity to the first line combination therapy and suboptimal responses to insecticides used for Anopheles vector management have led to renewed interest in novel therapeutic options. Here, we report the development and validation of an ensemble of ligand-based computational models capable of identifying falcipain-2 inhibitors, and their subsequent application in the virtual screening of DrugBank and Sweetlead libraries. Among four hits submitted to enzymatic assays, two (odanacatib, an abandoned investigational treatment for osteoporosis and bone metastasis, and the antibiotic methacycline) confirmed inhibitory effects on falcipain-2, with Ki of 98.2 nM and 84.4 ?M. Interestingly, Methacycline proved to be a non-competitive inhibitor (? = 1.42) of falcipain-2. The effects of both hits on falcipain-2 hemoglobinase activity and on the development of P. falciparum were also studied.

SUBMITTER: Alberca LN

PROVIDER: S-EPMC6691349 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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<i>In silico</i> Guided Drug Repurposing: Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2.

Alberca Lucas N LN Chuguransky Sara R SR Álvarez Cora L CL Talevi Alan A Salas-Sarduy Emir E

Frontiers in chemistry 20190806

Malaria is among the leading causes of death worldwide. The emergence of <i>Plasmodium falciparum</i> resistant strains with reduced sensitivity to the first line combination therapy and suboptimal responses to insecticides used for Anopheles vector management have led to renewed interest in novel therapeutic options. Here, we report the development and validation of an ensemble of ligand-based computational models capable of identifying falcipain-2 inhibitors, and their subsequent application i ...[more]

PMID: 31448257

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Project description:MotivationThe outbreak of coronavirus health issues caused by COVID-19(SARS-CoV-2) creates a global threat to public health. Therefore, there is a need for effective remedial measures using existing and approved therapies with proven safety measures has several advantages. Dexamethasone (Pubchem ID: CID0000005743), baricitinib(Pubchem ID: CID44205240), remdesivir (PubchemID: CID121304016) are three generic drugs that have demonstrated in-vitro high antiviral activity against SARS-CoV-2. The present study aims to widen the search and explore the anti-SARS-CoV-2 properties of these potential drugs while looking for new drug indications with optimised benefits via in-silico research.MethodHere, we designed a unique drug-similarity model to repurpose existing drugs against SARS-CoV-2, using the anti-Covid properties of dexamethasone, baricitinib, and remdesivir as references. Known chemical-chemical interactions of reference drugs help extract interactive compounds withimprovedanti-SARS-CoV-2 properties. Here, we calculated the likelihood of these drug compounds treating SARS-CoV-2 related symptoms using chemical-protein interactions between the interactive compounds of the reference drugs and SARS-CoV-2 target genes. In particular, we adopted a two-tier clustering approach to generate a drug similarity model for the final selection of potential anti-SARS-CoV-2 drug molecules. Tier-1 clustering was based on t-Distributed Stochastic Neighbor Embedding (t-SNE) and aimed to filter and discard outlier drugs. The tier-2 analysis incorporated two cluster analyses performed in parallel using Ordering Points To Identify the Clustering Structure (OPTICS) and Hierarchical Agglomerative Clustering (HAC). As a result, itidentified clusters of drugs with similar actions. In addition, we carried out a docking study for in-silico validation of top candidate drugs.ResultOur drug similarity model highlighted ten drugs, including reference drugs that can act as potential therapeutics against SARS-CoV-2. The docking results suggested that doxorubicin showed the least binding energy compared to reference drugs. Their practical utility as anti-SARS-CoV-2 drugs, either individually or in combination, warrants further investigation.

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Dataset Information

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

Publications

<i>In silico</i> Guided Drug Repurposing: Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2.

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