Peptide Inhibitors of Kv1.5: An Option for the Treatment of Atrial Fibrillation

The human voltage gated potassium channel Kv1.5 that conducts the IKur current is a key determinant of the atrial action potential. Its mutations have been linked to hereditary forms of atrial fibrillation (AF), and the channel is an attractive target for the management of AF. The development of IKur blockers to treat AF resulted in small molecule Kv1.5 inhibitors. The selectivity of the blocker for the target channel plays an important role in the potential therapeutic application of the drug candidate: the higher the selectivity, the lower the risk of side effects. In this respect, small molecule inhibitors of Kv1.5 are compromised due to their limited selectivity. A wide range of peptide toxins from venomous animals are targeting ion channels, including mammalian channels. These peptides usually have a much larger interacting surface with the ion channel compared to small molecule inhibitors and thus, generally confer higher selectivity to the peptide blockers. We found two peptides in the literature, which inhibited IKur: Ts6 and Osu1. Their affinity and selectivity for Kv1.5 can be improved by rational drug design in which their amino acid sequences could be modified in a targeted way guided by in silico docking experiments.

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Elucidating Protein-protein Interactions Through Computational Approaches and Designing Small Molecule Inhibitors Against them for Various Diseases

Current Topics in Medicinal Chemistry ◽

10.2174/1568026618666181025114903 ◽

2018 ◽

Vol 18 (20) ◽

pp. 1719-1736 ◽

Cited By ~ 3

Author(s):

Sharanya Sarkar ◽

Khushboo Gulati ◽

Manikyaprabhu Kairamkonda ◽

Amit Mishra ◽

Krishna Mohan Poluri

Keyword(s):

Small Molecule ◽

Protein Interactions ◽

Small Molecule Inhibitors ◽

Computational Techniques ◽

Protein Protein Interactions ◽

Computational Tools ◽

Computational Approaches ◽

Protein Protein Interaction ◽

Wide Range ◽

Therapeutic Measures

Background: To carry out wide range of cellular functionalities, proteins often associate with one or more proteins in a phenomenon known as Protein-Protein Interaction (PPI). Experimental and computational approaches were applied on PPIs in order to determine the interacting partners, and also to understand how an abnormality in such interactions can become the principle cause of a disease. Objective: This review aims to elucidate the case studies where PPIs involved in various human diseases have been proven or validated with computational techniques, and also to elucidate how small molecule inhibitors of PPIs have been designed computationally to act as effective therapeutic measures against certain diseases. Results: Computational techniques to predict PPIs are emerging rapidly in the modern day. They not only help in predicting new PPIs, but also generate outputs that substantiate the experimentally determined results. Moreover, computation has aided in the designing of novel inhibitor molecules disrupting the PPIs. Some of them are already being tested in the clinical trials. Conclusion: This review delineated the classification of computational tools that are essential to investigate PPIs. Furthermore, the review shed light on how indispensable computational tools have become in the field of medicine to analyze the interaction networks and to design novel inhibitors efficiently against dreadful diseases in a shorter time span.

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Small Molecule Inhibitors in the Treatment of Rheumatoid Arthritis and Beyond: Latest Updates and Potential Strategy for Fighting COVID-19

Cells ◽

10.3390/cells9081876 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1876

Author(s):

Magdalena Massalska ◽

Wlodzimierz Maslinski ◽

Marzena Ciechomska

Keyword(s):

Rheumatoid Arthritis ◽

Small Molecule ◽

Viral Entry ◽

Small Molecule Inhibitors ◽

Large Family ◽

Downstream Signaling ◽

Wide Range ◽

Synthetic Dmards ◽

Potential Strategy ◽

Inflammatory Molecules

The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19.

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Molecular Recognition of the Hybrid-Type G-Quadruplexes in Human Telomeres

Molecules ◽

10.3390/molecules24081578 ◽

2019 ◽

Vol 24 (8) ◽

pp. 1578 ◽

Cited By ~ 6

Author(s):

Guanhui Wu ◽

Luying Chen ◽

Wenting Liu ◽

Danzhou Yang

Keyword(s):

Small Molecule ◽

Solution Structure ◽

Structural Information ◽

Rational Drug Design ◽

Hybrid Type ◽

G4 Dna ◽

Rational Drug ◽

G Quadruplex ◽

Molecule Recognition ◽

Dna Secondary Structures

G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes.

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Enzyme regulation by biological disulfides

Bioscience Reports ◽

10.1007/bf01119803 ◽

1989 ◽

Vol 9 (5) ◽

pp. 593-604 ◽

Cited By ~ 17

Author(s):

Raul N. Ondarza

Keyword(s):

Drug Design ◽

Small Molecule ◽

Regulatory Mechanism ◽

Enzyme Regulation ◽

Rational Drug Design ◽

Host Cells ◽

Disulfide Exchange ◽

Rational Drug

More than a dozen enzymes have been found to be activated or inhibited in vitro by disulfide-exchange between the protein and small-molecule disulfides. Accordingly, thiol/disulfide ratio changes in vivo may be of great importance in the regulation of cellular metabolism. An awareness of this regulatory mechanism in both host cells and parasites, coupled with information on the presence or absence of key enzymes, may lead to rational drug design against certain diseases involving thiol intermediates, including trypanosomiasis.

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Grid-Based Technologies for In Silico Screening and Drug Design

Current Medicinal Chemistry ◽

10.2174/0929867325666180309112454 ◽

2018 ◽

Vol 25 (29) ◽

pp. 3526-3537 ◽

Cited By ~ 10

Author(s):

Vladimir Potemkin ◽

Maria Grishina

Keyword(s):

Drug Design ◽

Design Methodology ◽

Rational Drug Design ◽

Training Dataset ◽

Drug Candidate ◽

In Silico Screening ◽

Docking Method ◽

Rational Drug ◽

Sar Study ◽

Grid Based

Various techniques for rational drug design are presented in the paper. The methods are based on a substitution of antipharmacophore atoms of the molecules of training dataset by new atoms and/or group of atoms increasing the atomic bioactivity increments obtained from an SAR study. Furthermore, a design methodology based on the genetic algorithm DesPot for discrete optimization and generation of new drug candidate structures is described. Additionally, wide spectra of SAR approaches (3D/4D QSAR interior and exterior-based methods – BiS, CiS, ConGO, CoMIn, high-quality docking method - ReDock) using MERA force field and/or AlteQ quantum chemical method for correct prognosis of bioactivity and the bioactive probability have been described. The design methods are implemented at www.chemosophia.com web-site for online computational services.

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Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

International Journal of Molecular Sciences ◽

10.3390/ijms21155262 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5262 ◽

Cited By ~ 1

Author(s):

Qingxin Li ◽

CongBao Kang

Keyword(s):

Drug Discovery ◽

Small Molecules ◽

Structural Biology ◽

Small Molecule ◽

Molecular Interactions ◽

Mechanisms Of Action ◽

Rational Drug Design ◽

Binding Modes ◽

Small Molecule Drugs ◽

Rational Drug

Small-molecule drugs are organic compounds affecting molecular pathways by targeting important proteins. These compounds have a low molecular weight, making them penetrate cells easily. Small-molecule drugs can be developed from leads derived from rational drug design or isolated from natural resources. A target-based drug discovery project usually includes target identification, target validation, hit identification, hit to lead and lead optimization. Understanding molecular interactions between small molecules and their targets is critical in drug discovery. Although many biophysical and biochemical methods are able to elucidate molecular interactions of small molecules with their targets, structural biology is the most powerful tool to determine the mechanisms of action for both targets and the developed compounds. Herein, we reviewed the application of structural biology to investigate binding modes of orthosteric and allosteric inhibitors. It is exemplified that structural biology provides a clear view of the binding modes of protease inhibitors and phosphatase inhibitors. We also demonstrate that structural biology provides insights into the function of a target and identifies a druggable site for rational drug design.

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The mislabelling of deoxycorticosterone: making sense of corticosteroid structure and function

Journal of Endocrinology ◽

10.1530/joe-11-0178 ◽

2011 ◽

Vol 211 (1) ◽

pp. 3-16 ◽

Cited By ~ 26

Author(s):

Gavin P Vinson

Keyword(s):

Receptor Activation ◽

Structure And Function ◽

Rational Drug Design ◽

Hydroxyl Group ◽

Making Sense ◽

Rational Drug ◽

Wide Range ◽

Clear Insight ◽

Systematic Understanding ◽

And Function

Over the 70 or so years since their discovery, there has been continuous interest and activity in the field of corticosteroid functions. However, despite major advances in the characterisation of receptors and coregulators, in some ways we still lack clear insight into the mechanism of receptor activation, and, in particular, the relationship between steroid hormone structure and function remains obscure. Thus, why should deoxycorticosterone (DOC) reportedly be a weak mineralocorticoid, while the addition of an 11β-hydroxyl group produces glucocorticoid activity, yet further hydroxylation at C18 leads to the most potent mineralocorticoid, aldosterone? This review aims to show that the field has been confused by the misreading of the earlier literature and that DOC, far from being relatively inactive, in fact has a wide range of activities not shared by the other corticoids. In contrast to the accepted view, the presence of an 11β-hydroxyl group yields, in corticosterone or cortisol, hormones with more limited functions, and also more readily regulated, by 11β-hydroxysteroid dehydrogenase. This interpretation leads to a more systematic understanding of structure–function relationships in the corticosteroids and may assist more rational drug design.

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Exploring the Human Cytomegalovirus Core Nuclear Egress Complex as a Novel Antiviral Target: A New Type of Small Molecule Inhibitors

Viruses ◽

10.3390/v13030471 ◽

2021 ◽

Vol 13 (3) ◽

pp. 471 ◽

Cited By ~ 1

Author(s):

Sewar Alkhashrom ◽

Jintawee Kicuntod ◽

Sigrun Häge ◽

Johannes Schweininger ◽

Yves A. Muller ◽

...

Keyword(s):

Small Molecule ◽

Human Cytomegalovirus ◽

Hcmv Infection ◽

Small Molecule Inhibitors ◽

Inhibitory Effect ◽

Drug Candidate ◽

Chemical Library ◽

Nuclear Egress ◽

Complex Core ◽

New Type

Nuclear egress is an essential process in the replication of human cytomegalovirus (HCMV), as it enables the migration of newly formed viral capsids from the nucleus into the cytoplasm. Inhibition of the HCMV core nuclear egress complex (core NEC), composed of viral proteins pUL50 and pUL53, has been proposed as a potential new target for the treatment of HCMV infection and disease. Here, we present a new type of small molecule inhibitors of HCMV core NEC formation, which inhibit the pUL50-pUL53 interaction at nanomolar concentrations. These inhibitors, i.e., verteporfin and merbromin, were identified through the screening of the Prestwick Chemical Library® of approved drug compounds. The inhibitory effect of merbromin is both compound- and target-specific, as no inhibition was seen for other mercury-organic compounds. Furthermore, merbromin does not inhibit an unrelated protein–protein interaction either. More importantly, merbromin was found to inhibit HCMV infection of cells in three different assays, as well as to disrupt HCMV NEC nuclear rim formation. Thus, while not being an ideal drug candidate by itself, merbromin may serve as a blueprint for small molecules with high HCMV core NEC inhibitory potential, as candidates for novel anti-herpesviral drugs.

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Identification of Novel Potential VEGFR-2 Inhibitors Using a Combination of Computational Methods for Drug Discovery

Life ◽

10.3390/life11101070 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1070

Author(s):

Mohammad M. Al-Sanea ◽

Garri Chilingaryan ◽

Narek Abelyan ◽

Arsen Sargsyan ◽

Sargis Hovhannisyan ◽

...

Keyword(s):

Drug Discovery ◽

Computational Methods ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Clinical Effects ◽

Wide Range ◽

Critical Issues ◽

Endothelial Growth Factor

The vascular endothelial growth factor receptor 2 (VEGFR-2) is largely recognized as a potent therapeutic molecular target for the development of angiogenesis-related tumor treatment. Tumor growth, metastasis and multidrug resistance highly depends on the angiogenesis and drug discovery of the potential small molecules targeting VEGFR-2, with the potential anti-angiogenic activity being of high interest to anti-cancer research. Multiple small molecule inhibitors of the VEGFR-2 are approved for the treatment of different type of cancers, with one of the most recent, tivozanib, being approved by the FDA for the treatment of relapsed or refractory advanced renal cell carcinoma (RCC). However, the endogenous and acquired resistance of the protein, toxicity of compounds and wide range of side effects still remain critical issues, which lead to the short-term clinical effects and failure of antiangiogenic drugs. We applied a combination of computational methods and approaches for drug design and discovery with the goal of finding novel, potential and small molecule inhibitors of VEGFR2, as alternatives to the known inhibitors’ chemical scaffolds and components. From studying several of these compounds, the derivatives of pyrido[1,2-a]pyrimidin-4-one and isoindoline-1,3-dione in particular were identified.

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