Design of serine protease inhibitors with conformation restricted by amino acid side-chain-side-chain CH/? interaction

Shimohigashi, Yasuyuki; Nose, Takeru; Yamauchi, Yasuko; Maeda, Isamu

doi:10.1002/(sici)1097-0282(1999)51:1<9::aid-bip3>3.0.co;2-5

Cited by 25 publications

(19 citation statements)

References 26 publications

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“…The importance of this interaction has also been recognized in the design of serine protease inhibitors [10,11]. There are also recent reviews [12][13][14] and monographs [3] where the role of CH/π interactions in the structure of chemical and biological macromolecules are described.…”

Section: Introductionsupporting

confidence: 79%

Exploring the Role of C–H….π Interactions on the Structural Stability of Single Chain “All-Alpha” Proteins

Shanthi

Ramanathan

Sethumadhavan

2009

Appl Biochem Biotechnol

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C-H....pi interactions are known to be important contributors to protein stability. In this study, we have analyzed the influence of C-H....pi interactions in single chain "all-alpha" proteins. In the data set, a total of 181 C-H....pi interactions were observed. The most prominent representatives are the interactions between aromatic C-H donor groups and aromatic pi acceptors. Eighty-one percent of the C-H....pi interactions between side chain to side chain and remaining19% of the C-H....pi interactions were observed between side-chain to side-chain five-member aromatic ring. The donor atom contribution to C-H....pi interactions was mainly from Phe, Tyr, and Trp residues. The acceptor atom contribution to C-H....pi interactions was mainly from Phe, Tyr, Trp, and His. The highest percentage of C-H....pi interactions were observed form Phe residue. The secondary structure preference analysis of all C-H....pi interacting residues showed that Phe, Tyr, Trp, and His preferred to be in helix. Long-range C-H....pi interactions are the predominant type of interactions in single chain all-alpha proteins data set. All the C-H....pi interactions forming residues in the data set preferred to be in the buried region. Seventy-three percent of the donor residues and 65% of the acceptor residues are highly conserved.

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Section: Introductionsupporting

confidence: 79%

Exploring the Role of C–H….π Interactions on the Structural Stability of Single Chain “All-Alpha” Proteins

Shanthi

Ramanathan

Sethumadhavan

2009

Appl Biochem Biotechnol

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“…Aromatic–aromatic interaction26 was defined when the distance between aromatic ring centroid was <7 Å and the angle between the planes of the two rings between 60° and 120°. CH‐π interaction27 between an aromatic ring and the side chain of a Pro was assigned when the ring shift, calculated by the Total program, of a hydrogen bonded to a carbon was < −0.25 ppm 28–30…”

Section: Methodsmentioning

confidence: 99%

“…Weakly polar interactions in short peptides are able to constrain side‐chain conformation and stabilize local structures 6–8, 12. This is the case in the deltorfin 2 analogue, Hat‐ D ‐Ala‐Phe‐Glu‐Ile‐Ile‐Gly‐NH 2 , in which an Ar( i )–HN( i + 2) interaction is between the aromatic ring of Phe3 and the backbone amide of Ile5 (Geza Toth, personal communication).…”

Section: Introductionmentioning

confidence: 99%

Significance of aromatic‐backbone amide interactions in protein structure

et al. 2001

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Weakly polar interactions between aromatic rings of amino acids and hydrogens of backbone amides (Ar-HN) have been shown to support local structures in proteins. Their role in secondary structures, however, has not been elucidated. To investigate the relationship between Ar-HN interaction and the stability of local and secondary structures of polypeptides and to improve the prediction of this interaction based on amino acid sequence, the structures of 560 nonhomologous proteins, from the Protein Data Bank, were searched for Ar-HN interactions between the aromatic ring of each Phe, Tyr, and Trp residue at position i and the backbone amide group of any residue, except Pro, at the positions i, i - 1, i - 2, i - 3, i + 1, i + 2, and i + 3. Ar-HN interactions were identified by calculating the chemical shift of the amide hydrogen caused by the proximal aromatic ring. Ar(i)-HN(i + 1, i + 2 and i + 3) interactions were more common (7.10%, 2.08%, and 0.54%, respectively) than were Ar(i)-HN(i - 1, i - 2, and i - 3) interactions (0.66%, <0.1%, and 0.18%, respectively). The value of the chi(1) torsion angle of the aromatic residue in position i depended on the direction of the Ar-HN interaction. The position of the aromatic ring in Ar(i)-HN(i + 1, i + 2, and i + 3) interactions was mostly trans, in Ar(i)-HN(i - 1, i - 2, and i - 3) interactions mainly gauche(-), and in Ar(i)-HN(i) interactions mostly gauche(+). The analyses of the secondary structures of the protein fragments containing Ar-HN interactions showed that Ar-HN interactions were in all types of secondary structures. Search results suggest that Ar-HN interactions have a stabilizing effect on all types of secondary structures.

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“…46,47 Shimohigashi e colaboradores mostraram que as interações CH-π são importantes no desenho e no reconhecimento de alguns inibidores de serina proteases. 48 As interações alquila-arila entre o ligante e a proteina são importantes para estabilidade da conformação do composto α-cetooxazólico (12). Na estrutura cristalográfica da enzima hidrolase de amida de ácido graxo (código 3K83 no PDB), observaram-se interações CH-π entre os resíduos Val491 e Thr488 com grupos fenila do inibidor (12) (Figura 15), 49 além de interações de empilhamento T (ver item a seguir) com os resíduos Phe192 e Phe381.…”

Section: Interação Alquila-arilaunclassified

Há Algo Novo No Reconhecimento Molecular Aplicado À Química Medicinal?

et al. 2020

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In Medicinal Chemistry, the knowledge, the study and the understanding of the intermolecular interactions inherent to the molecular recognition of a ligand by its target bioreceptor are essential. This is because understanding these interactions, which define the molecular complementarity between the two, is the key to analyze critically structure-activity relationship studies, allowing the optimization of the modulation of a target bioreceptor by a ligand. Thus, it is necessary the constant study and analysis of intermolecular interactions related to the ligand-bioreceptor complexes. In general, these interactions are all electrostatic in nature, being traditionally classified into two large groups, the electrostatic forces themselves (such as those present in ion-dipole or ion-ion interactions) and van der Waals forces. Despite being well known, theoretical and experimental studies have revealed an increasing number of interactions mediated by these forces. This work presents and discusses intermolecular interactions considering "classical interactions" and "new interactions" in the context of Medicinal Chemistry, taking into account their current definitions, some theoretical principles of each interaction and addressing examples in which these interactions were important for complementarity between a ligand and a biorreceptor.

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Design of serine protease inhibitors with conformation restricted by amino acid side-chain-side-chain CH/? interaction

Cited by 25 publications

References 26 publications

Exploring the Role of C–H….π Interactions on the Structural Stability of Single Chain “All-Alpha” Proteins

Exploring the Role of C–H….π Interactions on the Structural Stability of Single Chain “All-Alpha” Proteins

Significance of aromatic‐backbone amide interactions in protein structure

Há Algo Novo No Reconhecimento Molecular Aplicado À Química Medicinal?

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