Reverse Docking: A Powerful Tool for Drug Repositioning and Drug Rescue

Kharkar, Prashant S.; Warrier, Sona; Gaud, Ram

doi:10.4155/fmc.13.207

Cited by 125 publications

(86 citation statements)

References 47 publications

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“…Graph/network theory sees the biological network of proteins and their regulators as graphs in which nodes are interconnected via vertices [49]. Reverse or inverse docking modifies the original concept of docking a series of ligands against a single-target protein to the docking of a series of proteins to a target compound [50]. Owing to the availability of huge volumes of data in medicinal chemistry, there is growing interest to harness the knowledge from these data via large-scale structure--activity relationships.…”

Section: Systems-based Drug Discoverymentioning

confidence: 99%

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Maximizing computational tools for successful drug discovery

Nantasenamat

Prachayasittikul

2015

Expert Opinion on Drug Discovery

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Section: Systems-based Drug Discoverymentioning

confidence: 99%

“…Along this line is a semantic web explorer PharmaTrek [53] that allows users to perform complex query on multi-target polypharmacology in an intuitive manner. Thus, proteochemometrics as well as reverse docking could readily be used in drug repositioning FDA-approved drugs against a multitude of new diseases [50,54].…”

Section: Systems-based Drug Discoverymentioning

confidence: 99%

Maximizing computational tools for successful drug discovery

Nantasenamat

Prachayasittikul

2015

Expert Opinion on Drug Discovery

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“…In silico approaches such as molecular docking provide rapid ways to assess likely binding compounds with target macromolecules, and is therefore being widely practiced in pharmacology (Stark and Powers, 2012). Inverse docking has proved to be an important computational tool in the identification of novel macromolecular targets for a drug or ligand pertaining to its mechanism of action and/ or side effects (Grinter et al, 2011;Chen and Ren, 2014), and involves the docking of a small ligand or drug in potential binding sites of a set of clinically relevant macromolecular targets (Kharkar et al, 2014). The second approach of target fishing is the reverse pharmacophore mapping approach, which is based on the fitting and mapping of small query molecules against predetermined pharmacophore features of targets (Liu et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Target fishing of glycopentalone using integrated inverse docking and reverse pharmacophore mapping approach

et al. 2016

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ABSTRACT. Glycopentalone isolated from Glycosmis pentaphylla (family Rutaceae) has cytotoxic and apoptosis inducing effects in various human cancer cell lines; however, its mode of action is not 2 A.B. gurung et al. Genetics and Molecular Research 15 (3): gmr.15038544 known. Therefore, target fishing of glycopentalone using a combined approach of inverse docking and reverse pharmacophore mapping approach was used to identify potential targets of glycopentalone, and gain insight into its binding modes against the selected molecular targets, viz., CDK-2, CDK-6, Topoisomerase I, Bcl-2, VEGFR-2, Telomere:Gquadruplex and Topoisomerase II. These targets were chosen based on their key roles in the progression of cancer via regulation of cell cycle and DNA replication. Molecular docking analysis revealed that glycopentalone displayed binding energies ranging from -6.38 to -8.35 kcal/mol and inhibition constants ranging from 0.758 to 20.90 µM. Further, the binding affinities of glycopentalone to the targets were in the order: Telomere:G-quadruplex > VEGFR-2 > CDK-6 > CDK-2 > Topoisomerase II > Topoisomerase I > Bcl-2. Binding mode analysis revealed critical hydrogen bonds as well as hydrophobic interactions with the targets. The targets were validated by reverse pharmacophore mapping of glycopentalone against a set of 2241 known human target proteins which revealed CDK-2 and VEGFR-2 as the most favorable targets. The glycopentalone was well mapped to CDK-2 and VEGFR-2 which involve six pharmacophore features (two hydrophobic centers and four hydrogen bond acceptors) and nine pharmacophore features (five hydrophobic, two hydrogen bond acceptors and two hydrogen bond donors), respectively. The present computational approach may aid in rational identification of targets for small molecules against large set of candidate macromolecules before bioassays validation.

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“…Therefore, the pharmaceutical scientists are in search of alternate drug development strategies. Of the several such lateral approaches, investigations involving approved/ existing small-molecule drugs (drug repositioning or repurposing) or shelved compounds (drug rescue) seem to be attractive on time and money scale [3]. Repositioning of already existing drugs lead to substantial reduction in development cost and time compared to the traditional discovery efforts, due to availability of previously collected pharmacokinetic, toxicology, and safety data [4].…”

Section: Introductionmentioning

confidence: 99%

Inverse Virtual Screening in Drug Repositioning: Detailed Investigation and Case Studies

Warrier

Kharkar

2016

Crystallizing Ideas – The Role of Chemistry

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Inverse virtual screening is a useful tool for drug repositioning or repurposing. The utility of this tool lies in the identification of potential targets for small-molecule ligands. With reference to drug repositioning, approved/existing small-molecule drugs can be processed by inverse virtual screening for the discovery of potential new molecular targets for such drugs. Both the ligand-and structure-based approaches can be used for the in silico screening. PharmMapper is a web-based tool for ligand-based inverse screening that employs pharmacophore mapping approach and identifies potential target candidates for small molecules. The present study demonstrates the usefulness of this approach for computational repositioning of approved/existing drugs. Here, query molecules belonging to protein kinase inhibitors, monoamine transporter inhibitors and G protein-coupled receptor antagonists were used. The results revealed potential novel molecular targets for the query molecules. Detailed literature search involving the query molecule-novel target pair led to interesting findings. The book chapter summarizes the interesting outcomes of the ligand-based inverse virtual screening.

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Reverse Docking: A Powerful Tool for Drug Repositioning and Drug Rescue

Cited by 125 publications

References 47 publications

Maximizing computational tools for successful drug discovery

Maximizing computational tools for successful drug discovery

Target fishing of glycopentalone using integrated inverse docking and reverse pharmacophore mapping approach

Inverse Virtual Screening in Drug Repositioning: Detailed Investigation and Case Studies

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