A pedagogical view about the design of isoxazolyl-penicillins of the ampc betalactamase receptor 1fcm using the docking molecular technique

Co-crystals are one of the most popular ways to modify the physicochemical properties of active pharmaceutical ingredients (API) without changing pharmacological activity through non-covalent interactions with one or more co-formers. A “green method” has recently prompted many researchers to develop solvent-free techniques or minimize solvents for arranging the eco-friendlier process of co-crystallization. Researchers have also been looking for less-risk co-formers that produce the desired API’s physicochemical properties. This review purposed to collect the report studies of amino acids as the safe co-former and explored their advantages. Structurally, amino acids are promising co-former candidates as they have functional groups that can form hydrogen bonds and increase stability through zwitterionic moieties, which support strong interactions. The co-crystals and deep eutectic solvent yielded from this natural compound have been proven to improve pharmaceutical performance. For example, l-glutamine could reduce the side effects of mesalamine through an acid-base stabilizing effect in the gastrointestinal fluid. In addition, some amino acids, especially l-proline, enhances API’s solubility and absorption in its natural deep eutectic solvent and co-crystals systems. Moreover, some ionic co-crystals of amino acids have also been designed to increase chiral resolution. Therefore, amino acids are safe potential co-formers, which are suitable for improving the physicochemical properties of API and prospective to be developed further in the dosage formula and solid-state syntheses.

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The relation between intrinsic protein conformational changes and ligand binding

10.1101/2020.03.03.974634 ◽

2020 ◽

Cited By ~ 1

Author(s):

Marijn de Boer

Keyword(s):

Conformational Changes ◽

Structural Changes ◽

Conformational Equilibrium ◽

Biological Function ◽

Free Protein ◽

Classical Statistical Mechanics ◽

Protein Conformational Changes ◽

Ligand Free ◽

Non Covalent Interactions ◽

Covalent Interactions

1ABSTRACTStructural changes in proteins allow them to exist in several conformations. Non-covalent interactions with ligands drive the structural changes, thereby allowing the protein to perform its biological function. Recent findings suggest that many proteins are always in an equilibrium of different conformations and that each of these conformations can be formed by both the ligand-free and ligand-bound protein. By using classical statistical mechanics, we derived the equilibrium probabilities of forming a conformation with and without ligand. We found, under certain conditions, that increasing the probability of forming a conformation by the ligand-free protein also increases the probability of forming the same conformation when the protein has a ligand bound. Further, we found that changes in the conformational equilibrium of the ligand-free protein can increase or decrease the affinity for the ligand.

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Labeling Preferences of Diazirines with Protein Biomolecules

10.26434/chemrxiv.13373249 ◽

2020 ◽

Author(s):

Alexander West ◽

Giovanni Muncipinto ◽

Hung-Yi Wu ◽

Andrew Huang ◽

Matthew T. Labenski ◽

...

Keyword(s):

Amino Acids ◽

Systematic Evaluation ◽

Probe Design ◽

Dependent Manner ◽

Membrane Proteome ◽

Non Covalent Interactions ◽

Acidic Proteins ◽

Cell Proteome ◽

Covalent Interactions ◽

Net Positive Charge

<p>Diazirines are widely used in photoaffinity labeling (PAL) to trap non-covalent interactions with biomolecules. However, design and interpretation of PAL experiments is challenging without a molecular understanding of the reactivity of diazirines with protein biomolecules. Here, we report a systematic evaluation of the labeling preferences of alkyl and aryl diazirines with individual amino acids, single proteins, and in the whole cell proteome. We find that aryl-fluorodiazirines react primarily through a carbene intermediate, while alkyl diazirines generate a reactive alkyl diazo intermediate on route to the carbene. The generation of a reactive diazo intermediate leads to preferential labeling of acidic amino acids in a pH-dependent manner. From a survey of 32 alkyl diazirine probes, we use this reactivity profile to rationalize why these probes preferentially enrich highly acidic proteins or those embedded in membranes and why probes with a net positive-charge tend to produce higher labeling yields. These results indicate that alkyl diazirines are an especially effective chemistry for surveying the membrane proteome, and will facilitate probe design and interpretation of biomolecular labeling experiments with diazirines.<b></b></p>

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Catalytic Enantioselective Synthesis of Heterocyclic Vicinal Fluoroamines Using Asymmetric Protonation: A Method Development and Mechanistic Study

10.26434/chemrxiv.11920947 ◽

2020 ◽

Author(s):

Matthew Ashford ◽

Chao Xu ◽

john molloy ◽

Cameron Carpenter-Warren ◽

Alexandra Slawin ◽

...

Keyword(s):

Method Development ◽

Data Bank ◽

Enantioselective Synthesis ◽

Mechanistic Study ◽

Type Analysis ◽

Conformational Landscape ◽

Non Covalent Interactions ◽

Chiral Bronsted Acid ◽

Covalent Interactions ◽

Insight Into

<div> <div> <div> <p>A catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines is reported. A chiral Brønsted acid promotes aza-Michael addition to fluoroalkenyl heterocycles to give a prochiral enamine intermediate, which undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C–F stereocenter in high enantioselectivity, and is also amenable to stereogenic C–CF3 bonds. Extensive DFT calculations have provided insight into the reaction mechanism and the origin of catalyst selectivity. Crystal structure data shows the dominance of non-covalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran-type analysis of conformer distribution and protein data bank mining has indicated benzylic fluorination using this approach has potential for improved potency in several marketed drugs. </p> </div> </div> </div>

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Non-covalent interactions in thermodynamic stereoselectivity of mixed-ligand copper(II)-D- or L-histidine complexes with L-amino acids. A possible model of metal ion-assisted molecular recognition

Journal of the Chemical Society Dalton Transactions ◽

10.1039/dt9900002095 ◽

1990 ◽

pp. 2095 ◽

Cited By ~ 31

Author(s):

Gianna Borghesani ◽

Ferdinando Pulidori ◽

Maurizio Remelli ◽

Roberto Purrello ◽

Enrico Rizzarelli

Keyword(s):

Amino Acids ◽

Molecular Recognition ◽

Metal Ion ◽

Mixed Ligand ◽

Non Covalent Interactions ◽

Covalent Interactions

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Labeling Preferences of Diazirines with Protein Biomolecules

10.26434/chemrxiv.13373249.v1 ◽

2020 ◽

Author(s):

Alexander West ◽

Giovanni Muncipinto ◽

Hung-Yi Wu ◽

Andrew Huang ◽

Matthew T. Labenski ◽

...

Keyword(s):

Amino Acids ◽

Systematic Evaluation ◽

Probe Design ◽

Dependent Manner ◽

Membrane Proteome ◽

Non Covalent Interactions ◽

Acidic Proteins ◽

Cell Proteome ◽

Covalent Interactions ◽

Net Positive Charge

<p>Diazirines are widely used in photoaffinity labeling (PAL) to trap non-covalent interactions with biomolecules. However, design and interpretation of PAL experiments is challenging without a molecular understanding of the reactivity of diazirines with protein biomolecules. Here, we report a systematic evaluation of the labeling preferences of alkyl and aryl diazirines with individual amino acids, single proteins, and in the whole cell proteome. We find that aryl-fluorodiazirines react primarily through a carbene intermediate, while alkyl diazirines generate a reactive alkyl diazo intermediate on route to the carbene. The generation of a reactive diazo intermediate leads to preferential labeling of acidic amino acids in a pH-dependent manner. From a survey of 32 alkyl diazirine probes, we use this reactivity profile to rationalize why these probes preferentially enrich highly acidic proteins or those embedded in membranes and why probes with a net positive-charge tend to produce higher labeling yields. These results indicate that alkyl diazirines are an especially effective chemistry for surveying the membrane proteome, and will facilitate probe design and interpretation of biomolecular labeling experiments with diazirines.<b></b></p>

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Structural and functional impact of non- synonymous SNPs in the CST complex subunit TEN1: Structural genomics approach

10.1101/507046 ◽

2018 ◽

Author(s):

Mohd. Amir ◽

Vijay Kumar ◽

Taj Mohammad ◽

Ravins Dohare ◽

Md. Tabish Rehman ◽

...

Keyword(s):

Structural Changes ◽

Computational Prediction ◽

Structure Stability ◽

Helix 12 ◽

Functional Consequences ◽

Non Covalent Interactions ◽

Telomere Homeostasis ◽

And Function ◽

Blue Print ◽

Covalent Interactions

TEN1 protein is a key component of CST complex, implicated in maintaining the telomere homeostasis, and provide stability to the eukaryotic genome. Mutations in TEN1 gene have higher chances of deleterious impact; thus, interpreting the number of mutations and their consequential impact on the structure, stability and function is essentially important. Here, we have investigated the structural and functional consequences of nsSNPs in the TEN1 gene. A wide array of sequence- and structure-based computational prediction tools were employed to identify the effects of 78 nsSNPs on the structure and function of TEN1 protein and deleterious nsSNPs were identified. These deleterious or destabilizing nsSNPs are scattered throughout the structure of TEN1. However, major mutations were observed in the α1-helix (12-16) and β5-strand (88-96). We further observed that mutations at C-terminal region were have higher tendency to form aggregate. In-depth structural analysis of these mutations reveals that the pathogenecity of these mutations are driven mainly through larger structural changes because of alterations in non-covalent interactions. This work provides a blue print to pinpoint the possible consequences of pathogenic mutations in the CST complex subunit TEN1.

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Structural and functional impact of non-synonymous SNPs in the CST complex subunit TEN1: structural genomics approach

Bioscience Reports ◽

10.1042/bsr20190312 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 6

Author(s):

Mohd. Amir ◽

Vijay Kumar ◽

Taj Mohammad ◽

Ravins Dohare ◽

Md. Tabish Rehman ◽

...

Keyword(s):

Structural Changes ◽

Computational Prediction ◽

Structure Stability ◽

Prediction Tools ◽

Helix 12 ◽

Functional Consequences ◽

Non Covalent Interactions ◽

Telomere Homeostasis ◽

And Function ◽

Covalent Interactions

Abstract TEN1 protein is a key component of CST complex, implicated in maintaining the telomere homeostasis, and provides stability to the eukaryotic genome. Mutations in TEN1 gene have higher chances of deleterious impact; thus, interpreting the number of mutations and their consequential impact on the structure, stability, and function is essentially important. Here, we have investigated the structural and functional consequences of nsSNPs in the TEN1 gene. A wide array of sequence- and structure-based computational prediction tools were employed to identify the effects of 78 nsSNPs on the structure and function of TEN1 protein and to identify the deleterious nsSNPs. These deleterious or destabilizing nsSNPs are scattered throughout the structure of TEN1. However, major mutations were observed in the α1-helix (12–16 residues) and β5-strand (88–96 residues). We further observed that mutations at the C-terminal region were having higher tendency to form aggregate. In-depth structural analysis of these mutations reveals that the pathogenicity of these mutations are driven mainly through larger structural changes because of alterations in non-covalent interactions. This work provides a blueprint to pinpoint the possible consequences of pathogenic mutations in the CST complex subunit TEN1.

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