Rational design of an orthogonal noncovalent interaction system at the MUPP1 PDZ11 complex interface with CaMKIIα-derived peptides in human fertilization

2017 ◽  
Vol 13 (10) ◽  
pp. 2145-2151 ◽  
Author(s):  
Yi-Le Zhang ◽  
Zhao-Feng Han
Keyword(s):  
Hydrogen Bond ◽  
Rational Design ◽  
Halogen Bond ◽  
Noncovalent Interaction ◽  
Rational Approach ◽  
Interaction System ◽  
Human Fertilization

An orthogonal noncovalent interaction (ONI) system between a native hydrogen bond and a designed halogen bond across the complex interface of the MUPP1 PDZ11 domain with the CaMKIIαsia[Asn-1Phe] peptide mutant is introduced using a structure-based rational approach.

Rational Design of an Orthogonal Molecular Interaction System at the Complex Interface of Lung Cancer-Related MDM2 Protein with p53 Peptide

2016 ◽  
Vol 69 (10) ◽  
pp. 1167 ◽  
Author(s):  
Yanwen Li ◽  
Xiyan Yu ◽  
Ying Lou ◽  
Tong Wang
Keyword(s):  
Lung Cancer ◽  
Molecular Interaction ◽  
Rational Design ◽  
Halogen Atom ◽  
Halogen Bond ◽  
Negative Control ◽  
Negative Regulator ◽  
Transactivation Domain ◽  
Interaction System ◽  
Oncogenic Protein

The oncogenic protein MDM2 is an important negative regulator of p53 tumour suppressor. Overexpression of this protein is closely related to the pathological progression and metastasis of lung cancer and other tumours. Previously, a 12-mer peptide segment 17ETFSDLWKLLPE28 (p5317–28) corresponding to residues 17–28 of the human p53 transactivation domain was identified to interact moderately with MDM2. Here, we successfully created an orthogonal molecular interaction system between a native hydrogen bond (H-bond) and a designed halogen bond (X-bond) across the protein–peptide complex interface, where the X-bond was introduced by substituting the 3-hydrogen atom of the benzene ring of the p5317–28 Phe19 residue with a halogen atom X, resulting in a series of 3X-peptides (X = F, Cl, Br or I). Theoretical analysis found that chlorine is a good compromise between X-bonding strength and steric hindrance due to introducing a bulkier halogen atom to the tightly packed complex interface. Consequently, the 3Cl-peptide (Kd = 105 nM) was determined to exhibit ~5-fold affinity improvement relative to p5317–28 (Kd = 570 nM). In contrast, the binding affinity of the 2Cl-peptide (Kd = 492 nM), a negative control that cannot form the X-bond according to computational analysis, did not change considerably on the halogenation.

scholarly journals Next Step in Gene Delivery: Modern Approaches and Further Perspectives of AAV Tropism Modification

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 750
Author(s):  
Maxim A. Korneyenkov ◽  
Andrey A. Zamyatnin
Keyword(s):  
Gene Therapy ◽  
Genome Organization ◽  
Rational Design ◽  
Structural Data ◽  
Rational Approach ◽  
Tissue Tropism ◽  
Adeno Associated Virus ◽  
Chemical Conjugation ◽  
The Usa ◽  
Therapy Delivery

Today, adeno-associated virus (AAV) is an extremely popular choice for gene therapy delivery. The safety profile and simplicity of the genome organization are the decisive advantages which allow us to claim that AAV is currently among the most promising vectors. Several drugs based on AAV have been approved in the USA and Europe, but AAV serotypes’ unspecific tissue tropism is still a serious limitation. In recent decades, several techniques have been developed to overcome this barrier, such as the rational design, directed evolution and chemical conjugation of targeting molecules with a capsid. Today, all of the abovementioned approaches confer the possibility to produce AAV capsids with tailored tropism, but recent data indicate that a better understanding of AAV biology and the growth of structural data may theoretically constitute a rational approach to most effectively produce highly selective and targeted AAV capsids. However, while we are still far from this goal, other approaches are still in play, despite their drawbacks and limitations.

scholarly journals Linking Ligand-Induced Alterations in Androgen Receptor Structure to Differential Gene Expression: A First Step in the Rational Design of Selective Androgen Receptor Modulators

2006 ◽  
Vol 20 (6) ◽  
pp. 1201-1217 ◽  
Author(s):  
Dmitri Kazmin ◽  
Tatiana Prytkova ◽  
C. Edgar Cook ◽  
Russell Wolfinger ◽  
Tzu-Ming Chu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Androgen Receptor ◽  
Rational Design ◽  
Dynamic Structure ◽  
Rational Approach ◽  
Peptide Phage Display ◽  
Differential Gene ◽  
Receptor Modulators ◽  
Kinetics Of

Abstract We have previously identified a family of novel androgen receptor (AR) ligands that, upon binding, enable AR to adopt structures distinct from that observed in the presence of canonical agonists. In this report, we describe the use of these compounds to establish a relationship between AR structure and biological activity with a view to defining a rational approach with which to identify useful selective AR modulators. To this end, we used combinatorial peptide phage display coupled with molecular dynamic structure analysis to identify the surfaces on AR that are exposed specifically in the presence of selected AR ligands. Subsequently, we used a DNA microarray analysis to demonstrate that differently conformed receptors facilitate distinct patterns of gene expression in LNCaP cells. Interestingly, we observed a complete overlap in the identity of genes expressed after treatment with mechanistically distinct AR ligands. However, it was differences in the kinetics of gene regulation that distinguished these compounds. Follow-up studies, in cell-based assays of AR action, confirmed the importance of these alterations in gene expression. Together, these studies demonstrate an important link between AR structure, gene expression, and biological outcome. This relationship provides a firm underpinning for mechanism-based screens aimed at identifying SARMs with useful clinical profiles.

scholarly journals (Z)-3-[2-(2,4-Dinitrophenyl)hydrazin-1-ylidene]isobenzofuran-1(3H)-one dichloromethane hemisolvate

2014 ◽  
Vol 70 (4) ◽  
pp. o418-o418
Author(s):  
Palak Agarwal ◽  
Pragati Mishra ◽  
Nikita Gupta ◽  
Neelam ◽  
Priyaranjan Sahoo ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Benzene Ring ◽  
Dihedral Angle ◽  
Title Compound ◽  
Crystal Packing ◽  
Halogen Bond ◽  
Solvent Molecule ◽  
Twofold Axis ◽  
Bond Interaction ◽  
The Mean

In the title compound, 2C14H8N4O6·CH2Cl2, the dichloromethane solvent molecule resides on a crystallographic twofold axis. The mean plane of the phthalisoimide ring is oriented at a dihedral angle of 32.93 (12)° with respect to the nitro-substituted benzene ring. An intramolecular N—H...O hydrogen bond occurs. The crystal packing features a short Cl...O halogen-bond interaction [3.093 (3) Å].

Rational Design of 2,4-Disubstituted Quinazoline Small Molecules to Inhibit the Inflammatory Cytokine Oncostatin M

2020 ◽  
Author(s):  
Riley Olsen
Keyword(s):  
Amino Acids ◽  
Hydrogen Bond ◽  
Chemical Shift ◽  
Fluorescence Quenching ◽  
Rational Design ◽  
Specific Binding ◽  
Oncostatin M ◽  
Drug Candidate ◽  
Chemical Shift Perturbation ◽  
Computational Docking

Inflammation is one of the body's most important natural defense mechanisms involved in wound healing. It is usually triggered by a harmful event, such as physical trauma or exposure to external stimuli including bacteria, fungi, viruses, harmful chemicals, or environmental particulates. The inflammatory process brings blood containing inflammatory mediators consisting of leukocytes, hormones, and cytokines to the site of trauma to begin healing. However, the lack of a proper inflammatory response or an overactive response can lead to further progressive tissue damage resulting in chronic inflammatory conditions or death. The cytokine oncostatin M (OSM) is of particular interest due to the pivotal role it plays in chronic inflammatory diseases like rheumatoid arthritis, inflammatory bowel disease, and various forms of cancer. These diseases have a detrimental impact on a person’s quality of life and life expectancy, as well as the economy and health care system. There is currently no clinically approved treatment targeting OSM. Thus, we propose the development of a small molecule inhibitor (SMI) targeting OSM. Using the known crystal structure of OSM combined with computational methods, a sample of 10,000 randomly selected molecules from online databases were docked in the OSM binding site 3, the site presumably responsible for binding to its receptor. The most energetically favorable binding poses were used to create a weighted density map (WDM) that shows the probability of aromatic carbons, hydrogen bond acceptors, and hydrogen bond donors to bind to OSM at particular locations in site 3. A 2,4-disubstituted quinazoline SMI was rationally designed that constructively overlaid with the WDM and was predicted to bind with high affinity based on computational docking studies. The SMI and analogs thereof, termed the SMI-27 series, were synthesized using a 4-step reaction sequence to create a small library to be tested against OSM. In order to evaluate the ability of the SMIs to inhibit OSM activity and to determine cytokine binding specificity, enzyme-linked immunosorbent assays (ELISAs) and western blot assays were performed. Fluorescence quenching experiments were used to determine the binding affinity of SMI analogs toward OSM. Finally, chemical shift perturbation NMR experiments were used to identify the important amino acids required for binding of the SMI to OSM. All of the SMI-27 analogs tested by ELISA inhibited OSM induced pSTAT3 expression below the level of the control. Additionally, SMIs 27B3 and 27B5 showed specific binding to OSM, and not to leukemia inhibitory factor (LIF) or interleukin-6 (IL-6), structurally related cytokines. The fluorescence quenching assays indicate that all SMIs exhibited direct binding to OSM, with 27B12 having a Kd of 5.1 ± 2.7 uM. Finally, the chemical shift perturbation assay identified several amino acids that appear to be involved in SMI binding. Importantly, three of these, tentatively assigned as Arg91, Leu92, and Gly166, are all located in OSM site 3. These experiments support our hypothesis that an SMI can be used to inhibit OSM activity and lay a solid foundation for the development of an SMI drug candidate that would provide a significant advancement in clinical treatments of OSM-related diseases.

Halogen Bonding Organocatalysis Enhanced through Intramolecular Hydrogen Bonds

2022 ◽  
Author(s):  
Asia Marie S Riel ◽  
Daniel Adam Decato ◽  
Jiyu Sun ◽  
Orion Berryman
Keyword(s):  
Hydrogen Bond ◽  
Hydrogen Bonds ◽  
Halogen Bond ◽  
Direct Interaction ◽  
Halogen Bonding ◽  
Intramolecular Hydrogen Bonds ◽  
Intramolecular Hydrogen

Recent results indicate a halogen bond donor is strengthened through direct interaction with a hydrogen bond to the electron-rich belt of the halogen. Here, this Hydrogen Bond enhanced Halogen Bond...

Designer drugs: pipe-dreams or realities?

Parasitology ◽  
1997 ◽  
Vol 114 (7) ◽  
pp. 145-151 ◽  
Author(s):  
W. E. GUTTERIDGE
Keyword(s):  
Chemical Synthesis ◽  
Rational Design ◽  
Molecular Design ◽  
Designer Drugs ◽  
Rational Approach ◽  
Parasitic Infections ◽  
Tropical Diseases ◽  
Track Record ◽  
Discovery Research ◽  
Long Run

New chemotherapies are urgently needed for the parasitic infections of animals and for the tropical diseases of man. Rational molecular design approaches to attempt to discover such products require a massive investment of resources up-front of actual chemical synthesis. However, such investment is justified, since chemical synthesis itself is highly resource-consuming. The fact that few targets have yet been validated to justify a rational approach is an argument only to get on and validate more. Not all the components of molecular design can yet be done totally rationally, but this is not an argument against applying this approach where it is possible. Absence of a successful track record is inevitable for any newly emerging technology. It is too early to draw conclusions about the relative costs of rational design versus empirical synthesis, since the former is only now beginning to become reality and the latter is in the middle of a (combinatorial) revolution. Similarly, it is too soon to predict with certainty which of these two approaches will prevail in the long run. However, they lend themselves to parallel tracks, so both may well continue for the foreseeable future. Current concerns about who would develop successful discoveries are not reasons for stopping discovery research. Indeed, a string of putative products held at the discovery/development interface would be useful ammunition to those trying to develop partnerships such as a Tropical Diseases R&D Alliance aimed at carrying out such work and sharing costs.

Cooperative interaction between hydrogen bond and N···Y interactions (Y = H, Li, F, Cl, and Br): a comparative study

2015 ◽  
Vol 93 (6) ◽  
pp. 626-631
Author(s):  
Zahra Fallah Ebrahimi ◽  
Mehdi D. Esrafili ◽  
Esmail Vessally
Keyword(s):  
Hydrogen Bond ◽  
Comparative Study ◽  
Ab Initio ◽  
Halogen Bond ◽  
Cooperative Interaction ◽  
Ab Initio Study ◽  
Absolute Value ◽  
Lithium Bond ◽  
Cooperative Energy

A comparative ab initio study is performed to investigate the cooperativity between the N···H hydrogen bond and the N···Y interactions in XCN···HCN···YCN complexes, where X = H, F, and Y = H, Li, F, Cl, and Br. To understand the properties of the systems better, the corresponding dimers are also studied. It is found that the lithium bond has a larger influence on the hydrogen bond than vice versa. The shortening of the N···H distances in the trimers is dependent on the strength of the H···Y interactions and they become larger in the order lithium bond > hydrogen bond > halogen bond. The estimated values of cooperative energy Ecoop are all negative with much larger Ecoop in absolute value for the systems including lithium.

Linear Neutral Receptors for Anions: Synthesis, Structure and Applications

Synthesis ◽  
2018 ◽  
Vol 50 (23) ◽  
pp. 4555-4568 ◽  
Author(s):  
Janusz Jurczak ◽  
Agnieszka Cholewiak ◽  
Pawel Stepniak
Keyword(s):  
Hydrogen Bond ◽  
Steric Hindrance ◽  
Rational Design ◽  
Anion Receptors ◽  
Benzene Derivatives ◽  
Pyridine Derivatives ◽  
Naphthalene Derivatives ◽  
Pyrrole Derivatives ◽  
Anthracene Derivatives ◽  
Shed Light

A selective digest of linear anion receptors based on different aromatic skeletons is presented. Since the structures of anions vary from one to another, different strategies have been developed over recent years in order to bind anions efficiently and selectively. Rigidity, number of hydrogen bond donors, steric hindrance, and special preorganization of linear receptors are analyzed to shed light on the rational design of anion receptors.1 Introduction2 1,3- and 1,2-Benzene Derivatives3 1,3- and 5,7-Azulene Derivatives4 1,8-Naphthalene Derivatives5 1,8-Anthracene Derivatives6 2,6-Pyridine Derivatives7 2,5-Pyrrole Derivatives8 Diamidoarenodipyrrole Derivatives9 Carbazole Derivatives10 DITIPIRAM Derivatives11 Conclusion

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