Combining Machine Learning and Pharmacophore-Based Interaction Fingerprint for in Silico Screening

Sato, Tomohiro; Honma, Teruki; Yokoyama, Shigeyuki

doi:10.1021/ci900382e

Cited by 111 publications

(124 citation statements)

References 60 publications

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“…PLIFs are effectively a barcode for a particular protein:ligand complex, classifying interactions according to whether the interaction is mediated through the main chain or side chain, whether it is polar, non-polar or a hydrogen bond and whether the interaction is strong or weak (57). The frequency with which an interaction was predicted between citrate and a particular amino acid in the docking experiments was calculated from the PLIFs and is summarised in the heat maps presented in Figure 4.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of homologous phosphorolytic ribonucleases by citrate may represent an evolutionarily conserved communicative link between RNA degradation and central metabolism

Stone

Butt

Bufton

et al. 2017

Nucleic Acids Research

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Ribonucleases play essential roles in all aspects of RNA metabolism, including the coordination of post-transcriptional gene regulation that allows organisms to respond to internal changes and environmental stimuli. However, as inherently destructive enzymes, their activity must be carefully controlled. Recent research exemplifies the repertoire of regulatory strategies employed by ribonucleases. The activity of the phosphorolytic exoribonuclease, polynucleotide phosphorylase (PNPase), has previously been shown to be modulated by the Krebs cycle metabolite citrate in Escherichia coli. Here, we provide evidence for the existence of citrate-mediated inhibition of ribonucleases in all three domains of life. In silico molecular docking studies predict that citrate will bind not only to bacterial PNPases from E. coli and Streptomyces antibioticus, but also PNPase from human mitochondria and the structurally and functionally related archaeal exosome complex from Sulfolobus solfataricus. Critically, we show experimentally that citrate also inhibits the exoribonuclease activity of bacterial, eukaryotic and archaeal PNPase homologues in vitro. Furthermore, bioinformatics data, showing key citrate-binding motifs conserved across a broad range of PNPase homologues, suggests that this regulatory mechanism may be widespread. Overall, our data highlight a communicative link between ribonuclease activity and central metabolism that may have been conserved through the course of evolution.

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Section: Resultsmentioning

confidence: 99%

Inhibition of homologous phosphorolytic ribonucleases by citrate may represent an evolutionarily conserved communicative link between RNA degradation and central metabolism

Stone

Butt

Bufton

et al. 2017

Nucleic Acids Research

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“…The method was successfully applied to study the SAR (Structure Activity Relationship) of 35 PDE-4 inhibitors. In another similar approach, atom based Interaction Fingerprint (IF) were applied to describe the patterns of ligand pharmacophores that interacted with proteins in complex [97]. These fingerprints are calculated from the distance of pairs of ligand pharmacophore features that interact with protein atoms delineating important geometrical patterns of ligand pharmacophores.…”

Section: Combination Lock and Keymentioning

confidence: 99%

Molecular Docking: From Lock and Key to Combination Lock

Tripathi

Bankaitis

2018

J Mol Med Clin Appl

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Accurate modeling of protein ligand binding is an important step in structure-based drug design, is a useful starting point for finding new lead compounds or drug candidates. The ‘Lock and Key’ concept of protein-ligand binding has dominated descriptions of these interactions, and has been effectively translated to computational molecular docking approaches. In turn, molecular docking can reveal key elements in protein-ligand interactions-thereby enabling design of potent small molecule inhibitors directed against specific targets. However, accurate predictions of binding pose and energetic remain challenging problems. The last decade has witnessed more sophisticated molecular docking approaches to modeling protein-ligand binding and energetics. However, the complexities that confront accurate modeling of binding phenomena remain formidable. Subtle recognition and discrimination patterns governed by three-dimensional features and microenvironments of the active site play vital roles in consolidating the key intermolecular interactions that mediates ligand binding. Herein, we briefly review contemporary approaches and suggest that future approaches treat protein-ligand docking problems in the context of a ‘combination lock’ system.

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“…MetaSite [161], as well. The advantages of using pharmacophoric models over conventional docking scoring functions are that pharmacophore provides versatility for any type of protein of interest and options to accentuate target-specific interactions, such as -orbital interactions and entropy effects [162].…”

Section: Structure-based Pharmacophore Modelingmentioning

confidence: 99%

“…Furthermore, Sato et al reported a new interaction fingerprint (IF) based on ligand pharmacophore (Pharm-IF) (Fig. 1c) [162]. Similar to residue-based PLIF developed by MOE, Pharm-IF is calculated from the distances of pairs of pharmacophore features which form interactions with protein [162].…”

Section: Structure-based Pharmacophore Modelingmentioning

confidence: 99%

From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

Chen¹,

Morrow²,

Tran³

et al. 2012

curr drug metab

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As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting protein-ligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issues, may also cause failures. In this review, state-of-the-art techniques for protein modeling (e.g. structure prediction, modeling protein flexibility, etc.), hit identification/optimization (e.g. molecular docking, focused library design, fragment-based design, molecular dynamic, etc.), and polypharmacology design will be discussed. We will explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches. KeywordsStructure-based drug design; protein modeling; focused library design; pharmacophore; flexible docking; high-throughput virtual screening; de novo design; protein-protein interaction; polypharmacology Modern computational-aided drug design established a novel platform by which researchers perform in-depth in silico simulation prior to labor-extensive wet-lab validation [1]. It comprises of two major parts corresponding to the information of molecular source it utilizes: structure-based (or receptor-based) drug design and ligand-based drug design. Structure-based drug design, which relies on the knowledge of biological target structures, aims to discover small molecules/peptides leads with desired chemistry properties, and orchestrate the following experimental validation and lead optimization. Structure-based approach provides mechanism-based basis, where potential ligands are excavated using receptor-dependent parameters, while ligand-based approaches bypass the consideration of complex biomolecular "black box" in a living cell. This in silico method permeates all aspects of drug discovery today [2], and we expect it will draw more attentions with the unprecedented advances of computational power and modeling accuracy in this decade.* Corresponding author: Shuxing Zhang, Ph.D., The University of Texas M. D. Anderson Cancer Center, Department of Experimental Therapeutics, Unit 1950, 1901 East Rd., Houston, TX 77054, Telephone: (713)-745-2958 794-5577, shuzhang@mdanderson.org. Conflict of interestThe authors declare that they do not have competing interests. NIH Public Access Author ManuscriptCurr Pharm Des. Author manuscript; available in PMC 2013 November 07.Published in final edited form as:Curr Pharm Des. 2012 ; 18(9): 1217-1239. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn this review, we will overview the state-of-the-art structure-based drug discovery techniques ranging from receptor modeling to lead identification and optimization. In each topic, we will also highlight the fruitful successes as well as ch...

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Combining Machine Learning and Pharmacophore-Based Interaction Fingerprint for in Silico Screening

Cited by 111 publications

References 60 publications

Inhibition of homologous phosphorolytic ribonucleases by citrate may represent an evolutionarily conserved communicative link between RNA degradation and central metabolism

Inhibition of homologous phosphorolytic ribonucleases by citrate may represent an evolutionarily conserved communicative link between RNA degradation and central metabolism

Molecular Docking: From Lock and Key to Combination Lock

From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

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