Evaluation of Virtual Screening Strategies for the Identification of γ-Secretase Inhibitors and Modulators

γ-Secretase is an intramembrane aspartyl protease that is important in regulating normal cell physiology via cleavage of over 100 transmembrane proteins, including Amyloid Precursor Protein (APP) and Notch family receptors. However, aberrant proteolysis of substrates has implications in the progression of disease pathologies, including Alzheimer’s disease (AD), cancers, and skin disorders. While several γ-secretase inhibitors have been identified, there has been toxicity observed in clinical trials associated with non-selective enzyme inhibition. To address this, γ-secretase modulators have been identified and pursued as more selective agents. Recent structural evidence has provided an insight into how γ-secretase inhibitors and modulators are recognized by γ-secretase, providing a platform for rational drug design targeting this protease. In this study, docking- and pharmacophore-based screening approaches were evaluated for their ability to identify, from libraries of known inhibitors and modulators with decoys with similar physicochemical properties, γ-secretase inhibitors and modulators. Using these libraries, we defined strategies for identifying both γ-secretase inhibitors and modulators incorporating an initial pharmacophore-based screen followed by a docking-based screen, with each strategy employing distinct γ-secretase structures. Furthermore, known γ-secretase inhibitors and modulators were able to be identified from an external set of bioactive molecules following application of the derived screening strategies. The approaches described herein will inform the discovery of novel small molecules targeting γ-secretase.

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NICEdrug.ch, a workflow for rational drug design and systems-level analysis of drug metabolism

eLife ◽

10.7554/elife.65543 ◽

2021 ◽

Vol 10 ◽

Author(s):

Homa MohammadiPeyhani ◽

Anush Chiappino-Pepe ◽

Kiandokht Haddadi ◽

Jasmin Hafner ◽

Noushin Hadadi ◽

...

Keyword(s):

Drug Targets ◽

Drug Repurposing ◽

Rational Drug Design ◽

Bioactive Molecules ◽

Lead Discovery ◽

Minimal Impact ◽

Practical Applications ◽

Rational Drug ◽

Golden Standard ◽

And Performance

The discovery of a drug requires over a decade of intensive research and financial investments – and still has a high risk of failure. To reduce this burden, we developed the NICEdrug.ch resource, which incorporates 250,000 bioactive molecules, and studied their enzymatic metabolic targets, fate, and toxicity. NICEdrug.ch includes a unique fingerprint that identifies reactive similarities between drug–drug and drug–metabolite pairs. We validated the application, scope, and performance of NICEdrug.ch over similar methods in the field on golden standard datasets describing drugs and metabolites sharing reactivity, drug toxicities, and drug targets. We use NICEdrug.ch to evaluate inhibition and toxicity by the anticancer drug 5-fluorouracil, and suggest avenues to alleviate its side effects. We propose shikimate 3-phosphate for targeting liver-stage malaria with minimal impact on the human host cell. Finally, NICEdrug.ch suggests over 1300 candidate drugs and food molecules to target COVID-19 and explains their inhibitory mechanism for further experimental screening. The NICEdrug.ch database is accessible online to systematically identify the reactivity of small molecules and druggable enzymes with practical applications in lead discovery and drug repurposing.

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Binding site matching in rational drug design: algorithms and applications

Briefings in Bioinformatics ◽

10.1093/bib/bby078 ◽

2018 ◽

Vol 20 (6) ◽

pp. 2167-2184 ◽

Cited By ~ 3

Author(s):

Misagh Naderi ◽

Jeffrey Mitchell Lemoine ◽

Rajiv Gandhi Govindaraj ◽

Omar Zade Kana ◽

Wei Pan Feinstein ◽

...

Keyword(s):

Small Molecules ◽

Binding Site ◽

Protein Structures ◽

Chemical Properties ◽

Drug Repurposing ◽

Rational Drug Design ◽

Basic Knowledge ◽

Rational Drug ◽

Binding Pockets ◽

Local Protein

Abstract Interactions between proteins and small molecules are critical for biological functions. These interactions often occur in small cavities within protein structures, known as ligand-binding pockets. Understanding the physicochemical qualities of binding pockets is essential to improve not only our basic knowledge of biological systems, but also drug development procedures. In order to quantify similarities among pockets in terms of their geometries and chemical properties, either bound ligands can be compared to one another or binding sites can be matched directly. Both perspectives routinely take advantage of computational methods including various techniques to represent and compare small molecules as well as local protein structures. In this review, we survey 12 tools widely used to match pockets. These methods are divided into five categories based on the algorithm implemented to construct binding-site alignments. In addition to the comprehensive analysis of their algorithms, test sets and the performance of each method are described. We also discuss general pharmacological applications of computational pocket matching in drug repurposing, polypharmacology and side effects. Reflecting on the importance of these techniques in drug discovery, in the end, we elaborate on the development of more accurate meta-predictors, the incorporation of protein flexibility and the integration of powerful artificial intelligence technologies such as deep learning.

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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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Binding of small molecules at interface of protein–protein complex – A newer approach to rational drug design

Saudi Journal of Biological Sciences ◽

10.1016/j.sjbs.2016.01.008 ◽

2017 ◽

Vol 24 (2) ◽

pp. 379-388 ◽

Cited By ~ 11

Author(s):

A.B. Gurung ◽

A. Bhattacharjee ◽

M. Ajmal Ali ◽

F. Al-Hemaid ◽

Joongku Lee

Keyword(s):

Drug Design ◽

Small Molecules ◽

Protein Complex ◽

Rational Drug Design ◽

Rational Drug

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Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy

Journal of Personalized Medicine ◽

10.3390/jpm11111185 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1185

Author(s):

Matteo Costacurta ◽

Jackson He ◽

Philip E. Thompson ◽

Jake Shortt

Keyword(s):

Multiple Myeloma ◽

Small Molecules ◽

Molecular Mechanisms ◽

Rational Drug Design ◽

Genome Wide ◽

Rational Drug ◽

Anti Cancer ◽

Cellular Machinery ◽

Endogenous Substrates ◽

New Generation

Thalidomide analogues (or immunomodulatory imide drugs, IMiDs) are cornerstones in the treatment of multiple myeloma (MM). These drugs bind Cereblon (CRBN), a receptor for the Cullin-ring 4 ubiquitin-ligase (CRL4) complex, to modify its substrate specificity. IMiDs mediate CRBN-dependent engagement and proteasomal degradation of ‘neosubstrates’, Ikaros (IKZF1) and Aiolos (IKZF3), conveying concurrent antimyeloma activity and T-cell costimulation. There is now a greater understanding of physiological CRBN functions, including endogenous substrates and chaperone activity. CRISPR Cas9-based genome-wide screening has further elucidated the complex cellular machinery implicated in IMiD sensitivity, including IKZF1/3-independent mechanisms. New-generation IMiD derivatives with more potent anti-cancer properties—the CELMoDs (Cereblon E3 ligase modulators)—are now being evaluated. Rational drug design also allows ‘hijacking’ of CRL4CRBN utilising proteolysis targeting chimeras (PROTACs) to convey entirely distinct substrate repertoires. As all these chemotypes—thalidomide, IMiDs, CELMoDs and PROTACs—engage CRBN and modify its functions, we describe them here in aggregate as ‘CRBN-interacting small molecules’ (CISMs). In this review, we provide a contemporary summary of the biological consequences of CRBN modulation by CISMs. Detailed molecular insight into CRBN–CISM interactions now provides an opportunity to more effectively target previously elusive cancer dependencies, representing a new and powerful tool for the implementation of precision medicine.

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Rational Drug Design of Antineoplastic Agents Using 3D-QSAR, Cheminformatic, and Virtual Screening Approaches

Current Medicinal Chemistry ◽

10.2174/0929867324666170712115411 ◽

2019 ◽

Vol 26 (21) ◽

pp. 3874-3889 ◽

Cited By ~ 3

Author(s):

Jelica Vucicevic ◽

Katarina Nikolic ◽

John B.O. Mitchell

Keyword(s):

Virtual Screening ◽

Drug Design ◽

Antineoplastic Agents ◽

Drug Targets ◽

3D Qsar ◽

Pharmacophore Modeling ◽

Rational Drug Design ◽

Bioactive Molecules ◽

Computational Approaches ◽

Rational Drug

Background: Computer-Aided Drug Design has strongly accelerated the development of novel antineoplastic agents by helping in the hit identification, optimization, and evaluation. Results: Computational approaches such as cheminformatic search, virtual screening, pharmacophore modeling, molecular docking and dynamics have been developed and applied to explain the activity of bioactive molecules, design novel agents, increase the success rate of drug research, and decrease the total costs of drug discovery. Similarity, searches and virtual screening are used to identify molecules with an increased probability to interact with drug targets of interest, while the other computational approaches are applied for the design and evaluation of molecules with enhanced activity and improved safety profile. Conclusion: In this review are described the main in silico techniques used in rational drug design of antineoplastic agents and presented optimal combinations of computational methods for design of more efficient antineoplastic drugs.

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Mechanistic Insight into SARS-CoV-2 Mpro Inhibition by Organoselenides: The Ebselen Case Study

Applied Sciences ◽

10.3390/app11146291 ◽

2021 ◽

Vol 11 (14) ◽

pp. 6291

Author(s):

Andrea Madabeni ◽

Pablo Andrei Nogara ◽

Folorunsho Bright Omage ◽

João Batista Teixeira Rocha ◽

Laura Orian

Keyword(s):

Density Functional ◽

Rational Drug Design ◽

Functional Theory ◽

Main Protease ◽

Rational Drug ◽

Mechanistic Investigation ◽

Pharmacologically Active ◽

First Time ◽

Insight Into

The main protease (Mpro) of SARS-CoV-2 is a current target for the inhibition of viral replication. Through a combined Docking and Density Functional Theory (DFT) approach, we investigated in-silico the molecular mechanism by which ebselen (IUPAC: 2-phenyl-1,2-benzoselenazol-3-one), the most famous and pharmacologically active organoselenide, inhibits Mpro. For the first time, we report on a mechanistic investigation in an enzyme for the formation of the covalent -S-Se- bond between ebselen and a key enzymatic cysteine. The results highlight the strengths and weaknesses of ebselen and provide hints for a rational drug design of bioorganic selenium-based inhibitors.

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The Who, Why, and How of Small-Molecule Production in Invertebrate Microbiomes: Basic Insights Fueling Drug Discovery

mSystems ◽

10.1128/msystems.00186-17 ◽

2018 ◽

Vol 3 (2) ◽

Cited By ~ 2

Author(s):

Jason C. Kwan

Keyword(s):

Systems Biology ◽

Small Molecules ◽

Small Molecule ◽

Bioactive Molecules ◽

Ecological Niches ◽

Biosynthetic Pathways ◽

Selective Forces ◽

Insight Into ◽

Molecule Production ◽

Selection Of

ABSTRACT Bacteria have supplied us with many bioactive molecules for use in medicine and agriculture. However, rates of discovery have decreased as the biosynthetic capacity of the culturable biosphere has been continuously mined for many decades. The as-yet-uncultured biosphere is likely to hold far greater biosynthetic potential, especially where ecological niches favor the selection of therapeutically useful bioactivities. I outline here how metagenomics and other systems biology approaches can be used to gain insight into small-molecule biosynthesis and the selective forces which shape it. I also argue that we need a greater understanding of the function of small molecules in complex microbiomes and rational synthetic biology methods to functionally reconstruct large biosynthetic pathways in heterologous hosts.

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Computational Methods Applied to Rational Drug Design

The Open Medicinal Chemistry Journal ◽

10.2174/1874104501610010007 ◽

2016 ◽

Vol 10 (1) ◽

pp. 7-20 ◽

Cited By ~ 20

Author(s):

David Ramírez

Keyword(s):

Drug Design ◽

Small Molecules ◽

De Novo ◽

Relevant Information ◽

Binding Mode ◽

Rational Drug Design ◽

Computational Techniques ◽

Computational Tools ◽

Rational Drug ◽

Number Of Publications

Due to the synergic relationship between medical chemistry, bioinformatics and molecular simulation, the development of new accurate computational tools for small molecules drug design has been rising over the last years. The main result is the increased number of publications where computational techniques such as molecular docking,de novodesign as well as virtual screening have been used to estimate the binding mode, site and energy of novel small molecules. In this work I review some tools, which enable the study of biological systems at the atomistic level, providing relevant information and thereby, enhancing the process of rational drug design.

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Recognition of Potential COVID-19 Drug Treatments through the Study of Existing Protein–Drug and Protein–Protein Structures: An Analysis of Kinetically Active Residues

Biomolecules ◽

10.3390/biom10091346 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1346

Author(s):

Ognjen Perišić

Keyword(s):

Small Molecules ◽

Active Sites ◽

Protein Structures ◽

Normal Modes ◽

Rational Drug Design ◽

Rational Drug ◽

In Silico Study ◽

Drug Treatments ◽

Protein Pockets ◽

Approved Drugs

We report the results of our in silico study of approved drugs as potential treatments for COVID-19. The study is based on the analysis of normal modes of proteins. The drugs studied include chloroquine, ivermectin, remdesivir, sofosbuvir, boceprevir, and α-difluoromethylornithine (DMFO). We applied the tools we developed and standard tools used in the structural biology community. Our results indicate that small molecules selectively bind to stable, kinetically active residues and residues adjoining them on the surface of proteins and inside protein pockets, and that some prefer hydrophobic sites over other active sites. Our approach is not restricted to viruses and can facilitate rational drug design, as well as improve our understanding of molecular interactions, in general.

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