Computational methods, especially molecular docking-based calculations, have become indispensable in the modern drug discovery workflow. The constantly increasing chemical space requires fast, robust ...but most of all highly predictive methods to search for new bioactive agents. Thus, the scoring function (SF) is a useful and broadly applied energy-based element of docking software, allowing quick and effective evaluation of a ligand's propensity to bind to selected protein targets. Despite many spectacular successes of molecular docking applications in virtual screening (VS), the obtained results are often far from ideal, leading to incorrect selection of hit molecules and poor pose prediction. In our study we focused on docking calculation for the selected class A G-protein coupled receptors (GPCRs), with experimentally determined 3D structures and a sufficient set of known ligands with affinity values reported in the ChEMBL database. Our goal is to investigate how much the energy-based scoring function for this particular target class changes when changing from the default to the re-estimated weighting scheme on the specified energy terms in the SF definition. Additionally, we want to verify if indeed more accurate results are obtained when considering different levels of the biological hierarchy, namely: the whole class A GPCRs, sub-subfamilies, or just the individual proteins while applying default or specifically designed weighting coefficients. The performed calculation and evaluation factor values suggest a significant improvement of docking results for the designed SF definition. This individual approach improves the accuracy of binding affinity prediction and active compound recognition. The designed scoring function for classes, sub-subfamilies, or proteins leads to a significant improvement of molecular docking performance, especially at the level of individual proteins. Our results show that to increase the efficiency and predictive power of molecular docking calculations applied in classical VS, the strategy based on the individual approach for scoring function definition for selected proteins should be considered.
Targeted scoring function for different levels of biological hierarchy of selected GPCRs, leads to improvement in molecular docking predictive power.
Carotenoids are very effectively delivered by albumin to adipocytes. The uptake of carotenoids to the cells occurs in the form of self-aggregates that localize in the vicinity of the adipocyte ...membrane, as shown by high spatial resolution Raman spectroscopy. The binding of carotenoids to albumin and the mechanism of their transport were elucidated with the help of chiroptical spectroscopies, in tandem with molecular docking and molecular dynamics simulations. In particular, apart from the recognized high affinity pocket of albumin that binds a carotenoid monomer in domain I, we have identified a hydrophobic periphery area in domain IIIB that loosely bounds the self-aggregated carotenoid in aqueous media and enables its easy detachment in hydrophobic environments. This explains the effectiveness of albumins as nanocarriers of carotenoids to adipocytes
in vitro
.
A hydrophobic periphery area of albumin loosely bounds the self-aggregated astaxanthin in water and enables its easy detachment in hydrophobic environment. This explains the effectiveness of albumins as nanocarriers of carotenoids to adipocytes.
Titanium(
iv
) enolates of cyclododecanone (CDD) were investigated as convenient CH-acidic units for stereoselective aldol additions to various benzaldehydes leading to β-hydroxy carbonyl compounds. ...Aldol reactions were carried out at low temperatures, below −40 °C, which allowed minimizing the processes of dehydration and formation of enones. In contrast to alkali metal enolates that produced mainly
anti
-aldols, titanium(
iv
) enolates of CDD tend to favor
syn
-stereoselectivity. Studies showed that the stereoselectivity of aldolization depended on the size and location of substituents in the aromatic ring of benzaldehydes used. The strongest effect was exerted by substituents in
ortho
and
meta
positions, while
para
-substituted benzaldehydes were characterized by stereoselectivity comparable to that of unsubstituted benzaldehydes. The presented work is so far the only method of synthesizing
syn
aldols from cyclododecanone in a one-step reaction.
The application of the "soft enolization technique" led to the first synthesis of
syn
aldols from cyclododecanone titanium(
iv
) enolates and aromatic aldehydes.
'Atypical Ugi' tetrazoles Abdelraheem, Eman M. M; Goodwin, Imogen; Shaabani, Shabnam ...
Chemical communications (Cambridge, England),
02/2020, Volume:
56, Issue:
12
Journal Article
Peer reviewed
Open access
Amino acid-derived isocyano amides together with TMSN
3
, oxocomponents and 1° or 2° amines are common substrates in the Ugi tetrazole reaction. We surprisingly found that combining these substrates ...gives two different constitutional isomeric Ugi products A and B. A is the expected classical Ugi product whereas B is an isomeric product ('atypical Ugi') of the same molecular weight with the tetrazole heterocycle migrated to a different position. We synthesized, separated and characterized 22 different isomorphic examples of the two constitutional isomers of the Ugi reaction to unambiguously prove the formation of A and B. Mechanistic studies resulted in a proposed mechanism for the concomitant formation of A and B.
We surprisingly found that combining the substrates of Ugi tetrazole reaction gives two different constitutional isomeric Ugi products A and B. A is the expected classical Ugi products whereas B is an isomeric product ('atypical Ugi').
A new class of semiconducting materials has been prepared based on bismuth(
iii
) iodide in reaction with ternary amine
N
-oxides, sulfoxides, and phosphinoxides. Depending on the nature of the ...ligand, various structures originating from fragments of the BiI
3
lattice are formed. The band structure of these materials, optical spectroscopy, and work function measurements indicate the importance of metal-ligand and intraligand interactions in the electronic properties of these complexes. These materials are usually p-type semiconductors, but bidentate benzo(
c
)cinnoline-
N
,
N
′-dioxide results in an n-type semiconducting complex. They can be used for fabrication of MIM (metal-insulator-metal) type devices, which show interesting memristive properties, including modulation of the memristive properties simply due to the change of the type of metallic contact. The operation of the presented devices is based solely on the interface effects and the modulation of the Schottky barrier height. The change of only one of the two electrodes leads to a change from the clockwise to the anticlockwise direction of propagation of the hysteresis loop as well as from the Hebbian to the anti-Hebbian learning mode.
A clockwise and anticlockwise
I
-
V
pattern observed for memristive devices based on bismuth(
iii
) iodide organic-inorganic complexes and different metal electrodes.
A series of new potential intramolecular charge transfer ICT fluorescent receptors of Zn
2+
, Cd
2+
, Hg
2+
, Ga
3+
, In
3+
, and Tl
3+
ions based on
N
-aryl or
N
-alkyl variously fused ...pyridopyrrolopyrazine or pyrrolo2,3-
b
quinoxaline with an integrated donor group, such as 3-aminopropanol, were synthesized and verified. Among
N
,
N
,
O
tridentate donors
4a
,
6a-d
,
10a
,
12e
, and
14e
, only the integrated fluorophore-receptors with the nitrogen atom at the N-5 position of heterocyclic systems, pyrido2,3-
b
pyrrolo2,3-
e
pyrazine
6a
, selectively respond to zinc and indium with significant fluorescent enhancement and different mechanisms of binding. The first example of
Z
to
E
interconversion of enaminone forms of a ligand responsible for Zn
2+
complex fluorescence enhancement was documented.
1
H NMR titration showed different mechanisms of binding of zinc and indium to
E
- and
Z
-diastereoisomers of pyrido2,3-
b
pyrrolo2,3-
e
pyrazine
6a
.
A diastereoselective one pot five-component reaction toward the synthesis of 4-(tetrazole)-1,3-oxazinanes has been reported. The sonication-accelerated, catalyst-free, simple, general and highly time ...efficient, Asinger-Ugi-tetrazole reaction was used for the synthesis of diverse 4-(tetrazole)-1,3-oxazinanes. The reaction exhibit excellent diastereoselectivity and broad substrate scope.
A diastereoselective one pot five-component reaction toward the synthesis of 4-(tetrazole)-1,3-oxazinanes has been reported.
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Oligoisocyanides are attractive synthetic targets, however, only a few are known. Here, we describe the smallest stable tetraisocyanide possible, the 1,3-diisocyano-2,2-bis(isocyano-methyl)propane (
...1
) with
S
4
symmetry. Its four-step synthesis, structure, and reactivity in unprecedented symmetric fourfold Ugi 4CR and fourfold Passerini 3CR are described. Exhibiting high functional group tolerance and moderate to high yields, we foresee multiple applications of 1,3-diisocyano-2,2-bis(isocyanomethyl)propane, for example in MOFs, COFs, dendrimers, or artificial organs.
We developed a gram-scale synthesis of the novel tetraisocyanide 1,3-diisocyano-2,2-bis(isocyanomethyl)propane and applied this in unprecedented fourfold Ugi four-component and Passerini three-component reaction achieving unique symmetric structures.
The development of compounds with enhanced activity and selectivity by a conserved spatial orientation of the pharmacophore elements has a long history in medicinal chemistry. Rigidified compounds ...are an example of this concept. However, the intramolecular interactions were seldom used as a basis for conformational restraints. Here, we show the weak intramolecular interactions that contribute to the relatively well-conserved geometry of N1-arylsulfonyl indole derivatives. The structure analysis along with quantum mechanics calculations revealed a crucial impact of the sulfonyl group on the compound geometry. The weak intramolecular C-H O interaction stabilizes the mutual "facing" orientation of two aromatic fragments. These findings extend the pharmacological interpretation of the sulfonyl group role from the double hydrogen bond acceptor to the conformational scaffold based on intramolecular forces. This feature has, to date, been omitted in
in silico
drug discovery. Our results should increase the awareness of researchers to consider the conformational preference when designing new compounds or improving computational methods.
The impact of weak intramolecular C-H O interactions on the conformational stability of bis-arylsulfones is discussed, suggesting different role of sulfonyl group in the ligand - 5HT
6
receptor interaction.
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A bioisosteric strategy was successfully implemented with a screening protocol for new, potent 5-HT
6
R ligands. Initially, 2-5-(4-methylpiperazin-1-yl)-2-nitrophenyl-1,2,3,4-tetrahydroisoquinoline (
...9
) was found in commercial databases using a bioisosteric query (screening 5-HT
6
R
K
i
= 128 nM). Then, the hit compound was bioisosterically modified (ring alteration) leading to a novel, high affinity (
K
i
= 6 nM) 5-HT
6
R ligand (
10
). Extensive docking studies followed by structural interaction fingerprint analysis supported by single-crystal X-ray structures of the investigated ligands suggest different binding modes with 5-HT
6
R models for compounds with varying activity. An alternative anchoring point for protonated amine (D7.36) that has not been previously reported was identified.
A bioisosteric strategy was successfully implemented with a screening protocol for new, potent 5-HT
6
R ligands.
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