In Silico Prediction of Mutant HIV-1 Proteases Cleaving a Target Sequence

Jensen, Jan H.; Willemoës, Martin; Winther, Jakob R.; Vico, Luca De

doi:10.1371/journal.pone.0095833

Cited by 15 publications

(17 citation statements)

References 57 publications

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“…PIEs can be used to identify the residue fragments, which are important factors in the catalytic activity. [71][72][73] It should be noted that here, as in other FMO publications, fragments are defined by detaching Cα-C bonds at Cα, so that fragment residues in FMO are shifted compared to conventional residues by a carboxyl group.…”

Section: An Application Of Fmo/fdd To An Enzymatic Reactionmentioning

confidence: 99%

“…69,70 FMO has also been used to refine enzymatic reaction energetics for structures obtained with other methods. [71][72][73] In this work, previously 65 neglected terms in the analytic gradient are derived and implemented for the frozen domain with dimers (FDD) formulation of FMO (FMO/FDD), achieving fully analytic gradient. Secondly, analytic second derivatives are developed for FMO/FDD.…”

Section: Introductionmentioning

confidence: 99%

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Simulations of Chemical Reactions with the Frozen Domain Formulation of the Fragment Molecular Orbital Method

Nakata

Fedorov

Nagata

et al. 2015

J. Chem. Theory Comput.

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The fully analytic first and second derivatives of the energy in the frozen domain formulation of the fragment molecular orbital (FMO) were developed and applied to locate transition states and determine vibrational contributions to free energies. The development is focused on the frozen domain with dimers (FDD) model. The intrinsic reaction coordinate method was interfaced with FMO. Simulations of IR and Raman spectra were enabled using FMO/FDD by developing the calculation of intensities. The accuracy is evaluated for S(N)2 reactions in explicit solvent, and for the free binding energies of a protein-ligand complex of the Trp cage protein (PDB: 1L2Y ). FMO/FDD is applied to study the keto-enol tautomeric reaction of phosphoglycolohydroxamic acid and the triosephosphate isomerase (PDB: 7TIM ), and the role of amino acid residue fragments in the reaction is discussed.

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Section: An Application Of Fmo/fdd To An Enzymatic Reactionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Simulations of Chemical Reactions with the Frozen Domain Formulation of the Fragment Molecular Orbital Method

Nakata

Fedorov

Nagata

et al. 2015

J. Chem. Theory Comput.

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“…4, is based on the flexible peptide docking algorithm used by Chaudhury & Gray (2009), but, with respect to that, there are some differences: a larger number of cycles (8 × 4 × 6 = 192 compared to 8 × 12 = 96) and more “small” and “shear” moves for the perturbation of both side chain and backbone atoms are performed (Jensen et al, 2014). The side chain conformations are further optimized through a repacking algorithm (Kuhlman & Baker, 2000) and using the extended Dunbrack library (Dunbrack & Cohen, 1997; Wang, Schueler-Furman & Baker, 2005).…”

Section: Methodsmentioning

confidence: 99%

Hypothesis onSerenoa repens(Bartram) small extract inhibition of prostatic 5α-reductase through anin silicoapproach on 5β-reductase x-ray structure

Governa

Giachetti

Biagi

et al. 2016

PeerJ

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Benign prostatic hyperplasia is a common disease in men aged over 50 years old, with an incidence increasing to more than 80% over the age of 70, that is increasingly going to attract pharmaceutical interest. Within conventional therapies, such as α-adrenoreceptor antagonists and 5α-reductase inhibitor, there is a large requirement for treatments with less adverse events on, e.g., blood pressure and sexual function: phytotherapy may be the right way to fill this need. Serenoa repens standardized extract has been widely studied and its ability to reduce lower urinary tract symptoms related to benign prostatic hyperplasia is comprehensively described in literature. An innovative investigation on the mechanism of inhibition of 5α-reductase by Serenoa repens extract active principles is proposed in this work through computational methods, performing molecular docking simulations on the crystal structure of human liver 5β-reductase. The results confirm that both sterols and fatty acids can play a role in the inhibition of the enzyme, thus, suggesting a competitive mechanism of inhibition. This work proposes a further confirmation for the rational use of herbal products in the management of benign prostatic hyperplasia, and suggests computational methods as an innovative, low cost, and non-invasive process for the study of phytocomplex activity toward proteic targets.

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“…For the elastase‐2 study, we selected the structure 1PPF from the Protein Data Bank . Here we adopted a procedure similar in spirit to that used by Chaudhury and Gray and Jensen et al to understand the effects of mutants in determining the specificity of the HIV‐1 protease. Briefly, a binding model for the backbone interactions of a potential substrate was derived from the protein turkey ovomucoid inhibitor bound to elastase‐2 in the 1PPF structure.…”

Section: Methodsmentioning

confidence: 99%

A combined cheminformatic and bioinformatic approach to address the proteolytic stability challenge in peptide‐based drug discovery

et al. 2015

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We have created models to predict cleavage sites for several human proteases including caspase-1, caspase-3, caspase-6, caspase-7, cathepsin B, cathepsin D, cathepsin G, cathepsin K, cathepsin L, elastase-2, granzyme A, granzyme B, matrix metallopeptidase-2 (MMP2), MMP7, MMP9, thrombin, and trypsin-1. Rather than representing the sequence pattern around the potential cleavage site through a series of flags with each flag representing one of the 20 standard amino acids, we first represent each amino acid by its calculated properties. For these calculated properties, we use validated cheminformatic descriptors, such as molecular weight, logP, and polar surface area, of the individual amino acids. Finally, the cleavage site-specific descriptors are calculated through various combinations of the individual amino acid descriptors for the residues surrounding the cleavage site. Some of these combinations do not take into account the location of the residue, as long as it is in a prescribed neighborhood of the potential cleavage site, whereas others are sensitive to the precise order of the residues in the sequence. The key advantage of this approach is that it allows one to perform meaningful calculations with nonstandard amino acids for which little or no data exists. Finally, using both docking and molecular dynamics simulations, we examine the potential for and limitations of protease crystal structures to impact the design of proteolytically stable peptides.

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In Silico Prediction of Mutant HIV-1 Proteases Cleaving a Target Sequence

Cited by 15 publications

References 57 publications

Simulations of Chemical Reactions with the Frozen Domain Formulation of the Fragment Molecular Orbital Method

Simulations of Chemical Reactions with the Frozen Domain Formulation of the Fragment Molecular Orbital Method

Hypothesis onSerenoa repens(Bartram) small extract inhibition of prostatic 5α-reductase through anin silicoapproach on 5β-reductase x-ray structure

A combined cheminformatic and bioinformatic approach to address the proteolytic stability challenge in peptide‐based drug discovery

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