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Drug Discovery Today Jan 2023The time taken and the cost of producing novel therapeutic drugs presents a significant burden - a typical target-based drug discovery process involves computational... (Review)
Review
The time taken and the cost of producing novel therapeutic drugs presents a significant burden - a typical target-based drug discovery process involves computational screening of drug libraries, compound assays and expensive clinical trials. This review summarises the value of dynamic conformational information obtained by optical tweezers and how this information can target 'undruggable' proteins. Optical tweezers provide insights into the link between biological mechanisms and structural conformations, which can be used in drug discovery. Developing workflows including software and sample preparation will improve throughput, enabling adoption of optical tweezers in biopharma. As a complementary tool, optical tweezers increase the number of drug candidates, improve the understanding of a target's complex structural dynamics and elucidate interactions between compounds and their targets.
Topics: Optical Tweezers; Proteins; Drug Discovery; Molecular Conformation
PubMed: 36396117
DOI: 10.1016/j.drudis.2022.103443 -
Current Opinion in Structural Biology Jun 2020Carbohydrate molecules are essential actors in key biological events, being involved as recognition points for cell-cell and cell-matrix interactions related to health... (Review)
Review
Carbohydrate molecules are essential actors in key biological events, being involved as recognition points for cell-cell and cell-matrix interactions related to health and disease. Despite outstanding advances in cryoEM, X-ray crystallography and NMR still remain the most employed techniques to unravel their conformational features and to describe the structural details of their interactions with biomolecular receptors. Given the intrinsic flexibility of saccharides, NMR methods are of paramount importance to deduce the extent of motion around their glycosidic linkages and to explore their receptor-bound conformations. We herein present our particular view on the latest advances in NMR methodologies that are permitting to magnify their applications for deducing glycan conformation and dynamics and understanding the recognition events in which there are involved.
Topics: Models, Molecular; Molecular Conformation; Nuclear Magnetic Resonance, Biomolecular; Polysaccharides; Protein Binding; Proteins
PubMed: 31835069
DOI: 10.1016/j.sbi.2019.11.004 -
Acta Crystallographica. Section C,... Oct 20104-Deoxy-4-fluoro-β-D-glucopyranose, C(6)H(11)FO(5), (I), crystallizes from water at room temperature in a slightly distorted (4)C(1) chair conformation. The observed...
4-Deoxy-4-fluoro-β-D-glucopyranose, C(6)H(11)FO(5), (I), crystallizes from water at room temperature in a slightly distorted (4)C(1) chair conformation. The observed chair distortion differs from that observed in β-D-glucopyranose [Kouwijzer, van Eijck, Kooijman & Kroon (1995). Acta Cryst. B51, 209-220], (II), with the former skewed toward a B(C3,O5) (boat) conformer and the latter toward an (O5)TB(C2) (twist-boat) conformer, based on Cremer-Pople analysis. The exocyclic hydroxymethyl group conformations in (I) and (II) are similar; in both cases, the O-C-C-O torsion angle is ∼-60° (gg conformer). Intermolecular hydrogen bonding in the crystal structures of (I) and (II) is conserved in that identical patterns of donors and acceptors are observed for the exocyclic substituents and the ring O atom of each monosaccharide. Inspection of the crystal packing structures of (I) and (II) reveals an essentially identical packing configuration.
Topics: Crystallography, X-Ray; Glucose; Hydrogen Bonding; Models, Molecular; Molecular Conformation
PubMed: 20921614
DOI: 10.1107/S0108270110034001 -
Journal of Chemical Information and... Nov 2021The chameleonic behavior of cyclosporin A (CsA) was investigated through conformational ensembles employing multicanonical molecular dynamics simulations that could...
The chameleonic behavior of cyclosporin A (CsA) was investigated through conformational ensembles employing multicanonical molecular dynamics simulations that could sample the cis and trans isomers of N-methylated amino acids; these assessments were conducted in explicit water, dimethyl sulfoxide, acetonitrile, methanol, chloroform, cyclohexane (CHX), and -hexane (HEX) using AMBER ff03, AMBER10:EHT, AMBER12:EHT, and AMBER14:EHT force fields. The conformational details were discussed employing the free-energy landscapes (FELs) at = 300 K; it was observed that the experimentally determined structures of CsA were only a part of the conformational space. Comparing the ROESY measurements in CHX-d12 and HEX-d14, the major conformations in those apolar solvents were essentially the same as that in CDCl except for the observation of some sidechain rotamers. The effects of the metal ions on the conformations, including the cis/trans isomerization, were also investigated. Based on the analysis of FELs, it was concluded that the AMBER ff03 force field best described the experimentally derived conformations, indicating that CsA intrinsically formed membrane-permeable conformations and that the metal ions might be the key to the cis/trans isomerization of N-methylated amino acids before binding a partner protein.
Topics: Cyclosporine; Molecular Conformation; Molecular Dynamics Simulation; Protein Conformation; Solvents; Water
PubMed: 34672629
DOI: 10.1021/acs.jcim.1c00771 -
Molecules (Basel, Switzerland) Sep 2021Ribitol (CHO), an acyclic sugar alcohol, is present on mammalian α-dystroglycan as a component of -mannose glycan. In this study, we examine the conformation and...
Ribitol (CHO), an acyclic sugar alcohol, is present on mammalian α-dystroglycan as a component of -mannose glycan. In this study, we examine the conformation and dynamics of ribitol by database analysis, experiments, and computational methods. Database analysis reveals that the anti-conformation (180°) is populated at the C3-C4 dihedral angle, while the gauche conformation (±60°) is seen at the C2-C3 dihedral angle. Such conformational asymmetry was born out in a solid-state C-NMR spectrum of crystalline ribitol, where C1 and C5 signals are unequal. On the other hand, solution C-NMR has identical chemical shifts for C1 and C5. NMR coupling constants and OH exchange rates suggest that ribitol is an equilibrium of conformations, under the influence of hydrogen bonds and/or steric hinderance. Molecular dynamics (MD) simulations allowed us to discuss such a chemically symmetric molecule, pinpointing the presence of asymmetric conformations evidenced by the presence of correlations between C2-C3 and C3-C4 dihedral angles. These findings provide a basis for understanding the dynamic structure of ribitol and the function of ribitol-binding enzymes.
Topics: Hydrogen Bonding; Magnetic Resonance Spectroscopy; Molecular Conformation; Molecular Dynamics Simulation; Ribitol; Solutions
PubMed: 34576942
DOI: 10.3390/molecules26185471 -
Journal of Chemical Information and... Dec 2020Macrocycles target proteins that are otherwise considered undruggable because of a lack of hydrophobic cavities and the presence of extended featureless surfaces....
Macrocycles target proteins that are otherwise considered undruggable because of a lack of hydrophobic cavities and the presence of extended featureless surfaces. Increasing efforts by computational chemists have developed effective software to overcome the restrictions of torsional and conformational freedom that arise as a consequence of macrocyclization. Moloc is an efficient algorithm, with an emphasis on high interactivity, and has been constantly updated since 1986 by drug designers and crystallographers of the Roche biostructural community. In this work, we have benchmarked the shape-guided algorithm using a dataset of 208 macrocycles, carefully selected on the basis of structural complexity. We have quantified the accuracy, diversity, speed, exhaustiveness, and sampling efficiency in an automated fashion and we compared them with four commercial (Prime, MacroModel, molecular operating environment, and molecular dynamics) and four open-access (experimental-torsion distance geometry with additional "basic knowledge" alone and with Merck molecular force field minimization or universal force field minimization, Cambridge Crystallographic Data Centre conformer generator, and conformator) packages. With three-quarters of the database processed below the threshold of high ring accuracy, Moloc was identified as having the highest sampling efficiency and exhaustiveness without producing thousands of conformations, random ring splitting into two half-loops, and possibility to interactively produce globular or flat conformations with diversity similar to Prime, MacroModel, and molecular dynamics. The algorithm and the Python scripts for full automatization of these parameters are freely available for academic use.
Topics: Benchmarking; Macrocyclic Compounds; Molecular Conformation; Molecular Dynamics Simulation; Software
PubMed: 33270455
DOI: 10.1021/acs.jcim.0c01038 -
International Journal of Molecular... Dec 2022Integration host factor (IHF) is a nucleoid-associated protein involved in DNA packaging, integration of viral DNA and recombination. IHF binds with nanomolar affinity...
Integration host factor (IHF) is a nucleoid-associated protein involved in DNA packaging, integration of viral DNA and recombination. IHF binds with nanomolar affinity to duplex DNA containing a 13 bp consensus sequence, inducing a bend of ~160° upon binding. We determined that IHF binds to DNA Four-way or Holliday junctions (HJ) with high affinity regardless of the presence of the consensus sequence, signifying a structure-based mechanism of recognition. Junctions, important intermediates in DNA repair and homologous recombination, are dynamic and can adopt either an open or stacked conformation, where the open conformation facilitates branch migration and strand exchange. Using ensemble and single molecule Förster resonance energy transfer (FRET) methods, we investigated IHF-induced changes in the population distribution of junction conformations and determined that IHF binding shifts the population to the open conformation. Further analysis of smFRET dynamics revealed that even in the presence of protein, the junctions remain dynamic as fast transitions are observed for the protein-bound open state. Protein binding alters junction conformational dynamics, as cross correlation analyses reveal the protein slows the transition rate at 1 mM Mg but accelerates the transition rate at 10 mM Mg. Stopped flow kinetic experiments provide evidence for two binding steps, a rapid, initial binding step followed by a slower step potentially associated with a conformational change. These measurements also confirm that the protein remains bound to the junction during the conformer transitions and further suggest that the protein forms a partially dissociated state that allows junction arms to be dynamic. These findings, which demonstrate that IHF binds HJs with high affinity and stabilizes junctions in the open conformation, suggest that IHF may play multiple roles in the processes of integration and recombination in addition to stabilizing bacterial biofilms.
Topics: DNA, Cruciform; Integration Host Factors; Nucleic Acid Conformation; Fluorescence Resonance Energy Transfer; DNA, Viral
PubMed: 36614023
DOI: 10.3390/ijms24010580 -
Bioinformatics (Oxford, England) Jul 2023Identifying the probable positions of the protein side-chains is one of the protein modelling steps that can improve the prediction of protein-ligand and protein-protein...
MOTIVATION
Identifying the probable positions of the protein side-chains is one of the protein modelling steps that can improve the prediction of protein-ligand and protein-protein interactions. Most of the strategies predicting the side-chain conformations use predetermined dihedral angle lists, also called rotamer libraries, that are usually generated from a subset of high-quality protein structures. Although these methods are fast to apply, they tend to average out geometries instead of taking into account the surrounding atoms and molecules and ignore structures not included in the selected subset. Such simplifications can result in inaccuracies when predicting possible side-chain atom positions.
RESULTS
We propose an approach that takes into account both of these circumstances by scanning through sterically accessible side-chain conformations and generating dihedral angle libraries specific to the target proteins. The method avoids the drawbacks of lacking conformations due to unusual or rare protein structures and successfully suggests potential rotamers with average RMSD closer to the experimentally determined side-chain atom positions than other widely used rotamer libraries.
AVAILABILITY AND IMPLEMENTATION
The technique is implemented in open-source software package rotag and available at GitHub: https://www.github.com/agrybauskas/rotag, under GNU Lesser General Public License.
Topics: Models, Molecular; Proteins; Molecular Conformation; Software; Ligands; Protein Conformation
PubMed: 37439702
DOI: 10.1093/bioinformatics/btad429 -
International Journal of Molecular... Jun 2023An accurate description of the conformational behavior of drug-like molecules is often a prerequisite for a comprehensive understanding of their behavior, in particular...
An accurate description of the conformational behavior of drug-like molecules is often a prerequisite for a comprehensive understanding of their behavior, in particular in the targeted receptor surroundings [...].
Topics: Ligands; Molecular Conformation; Protein Conformation
PubMed: 37298581
DOI: 10.3390/ijms24119630 -
Molecules (Basel, Switzerland) Mar 2022High level DLPNO−CCSD(T) electronic structure calculations with extended basis sets over B3LYP−D3 optimized geometries indicate that the three methyl groups in...
High level DLPNO−CCSD(T) electronic structure calculations with extended basis sets over B3LYP−D3 optimized geometries indicate that the three methyl groups in caffeine overcome steric hindrance to adopt uncommon conformations, each one placing a C−H bond on the same plane of the aromatic system, leading to the C−H bonds eclipsing one carbonyl group, one heavily delocalized C−N bond constituent of the fused double ring aromatic system, and one C−H bond from the imidazole ring. Deletion of indiscriminate and selective non-Lewis orbitals unequivocally show that hyperconjugation in the form of a bidirectional −CH3 ⇆ aromatic system charge transfer is responsible for these puzzling conformations. The structural preferences in caffeine are exclusively determined by orbital interactions, ruling out electrostatics, induction, bond critical points, and density redistribution because the steric effect, the allylic effect, the Quantum Theory of Atoms in Molecules (QTAIM), and the non-covalent interactions (NCI), all predict wrong energetic orderings. Tiny rotational barriers, not exceeding 1.3 kcal/mol suggest that at room conditions, each methyl group either acts as a free rotor or adopts fluxional behavior, thus preventing accurate determination of their conformations. In this context, our results supersede current experimental ambiguity in the assignation of methyl conformation in caffeine and, more generally, in methylated xanthines and their derivatives.
Topics: Caffeine; Molecular Conformation; Quantum Theory; Static Electricity
PubMed: 35335301
DOI: 10.3390/molecules27061937