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PyconsFold: a fast and easy tool for modelling and docking using distance predictions.

ABSTRACT: Contact predictions within a protein has recently become a viable method for accurate prediction of protein structure. Using predicted distance distributions has been shown in many cases to be superior to only using a binary contact annotation. Using predicted inter-protein distances has also been shown to be able to dock some protein dimers. Here, we present pyconsFold. Using CNS as its underlying folding mechanism and predicted contact distance it outperforms regular contact prediction based modelling on our dataset of 210 proteins. It performs marginally worse than the state of the art pyRosetta folding pipeline but is on average about 20 times faster per model. More importantly pyconsFold can also be used as a fold-and-dock protocol by using predicted inter-protein contacts/distances to simultaneously fold and dock two protein chains. pyconsFold is implemented in Python 3 with a strong focus on using as few dependencies as possible for longevity. It is available both as a pip package in Python 3 and as source code on GitHub and is published under the GPLv3 license. Install instructions, examples and parameters can be found in the supplemental notes. The data underlying this article together with source code are available on github, at https://github.com/johnlamb/pyconsfold.

SUBMITTER: Lamb J

PROVIDER: S-EPMC8570809 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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pyconsFold: a fast and easy tool for modeling and docking using distance predictions.

Lamb J J Elofsson A A

Bioinformatics (Oxford, England) 20211101 21

<h4>Motivation</h4>Contact predictions within a protein have recently become a viable method for accurate prediction of protein structure. Using predicted distance distributions has been shown in many cases to be superior to only using a binary contact annotation. Using predicted interprotein distances has also been shown to be able to dock some protein dimers.<h4>Results</h4>Here, we present pyconsFold. Using CNS as its underlying folding mechanism and predicted contact distance it outperforms ...[more]

PMID: 34240102

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Project description:UnlabelledMammalian target of rapamycin (mTOR) is a key regulator of cell growth, proliferation and angiogenesis. mTOR signaling is frequently hyper activated in a broad spectrum of human cancers thereby making it a potential drug target. The current drugs available have been successful in inhibiting the mTOR signaling, nevertheless, show low oral bioavailability and suboptimal solubility. Considering the narrow therapeutic window of the available inhibitors, through computational approaches, the present study pursues to identify a compound with optimal oral bioavailability and better solubility properties in addition ensuing high affinity between FKBP12 and FRB domain of mTOR. Current mTOR inhibitors; Everolimus, Temsirolimus Deforolimus and Echinomycin served as parent molecules for similarity search with a threshold of 95%. The query molecules and respective similar molecules were docked at the binding cleft of FKBP12 protein. Aided by MolDock algorithm, high affinity compounds against FKBP12 were retrieved. Patch Dock supervised protein-protein interactions were established between FRB domain of mTOR and ligand (query and similar) bound and free states of FKBP12. All the similar compounds thus retrieved showed better solubility properties and enabled better complex formation of mTOR and FKBP12. In particular Everolimus similar compound PubChem ID: 57284959 showed appreciable drugs like properties bestowed with better solubility higher oral bioavailability. In addition this compound brought about enhanced interaction between FKBP12 and FRB domain of mTOR. In the study, we report Everolimus similar compound PubChem ID: 57284959 to be potential inhibitor for mTOR pathway which can overcome the affinity and solubility concerns of current mTOR drugs.AbbreviationsmTOR - Mammalian Target of Rapamycin, FRB domain - FKBP12-rapamycin associated protein, FKBP12 - FK506-binding protein 12, OPLS - Optimized Potentials for Liquid Simulations, Akt - RAC-alpha serine/threonine-protein kinase, PI3K - phosphatidylinositide 3-kinases.

Dataset Information

PyconsFold: a fast and easy tool for modelling and docking using distance predictions.

Publications

pyconsFold: a fast and easy tool for modeling and docking using distance predictions.

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