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Covalent Inhibitors as Selective Drug Candidates

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (31 August 2021)

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Special Issue Editors

Dr. Robert Vianello

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Guest Editor

Institute Ruder Boskovic, Zagreb, Croatia
Interests: computational chemistry; protein-ligand interactions; reaction mechanisms; structure-based drug design; electronic structure calculations; molecular dynamics simulation

Dr. Hrvoje Rimac

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Guest Editor

Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
Interests: QSAR; molecular dynamics; pharmacokinetic interactions; drug metabolism

Special Issue Information

Dear Colleagues,

This Special Issue is addressed to authors who are engaged in designing and testing of covalent enzyme inhibitors or receptor antagonists. Even though ligands that covalently bind to their targets have been present for more than a century (e.g., acetylsalicylic acid from 1899 and penicillin V from 1928), intentionally designing molecules that make such bonds is relatively new for fear of their reactivity and potential adverse effects. However, successfully developed drugs, such as ibrutinib, dacomitinib, and voxelotor, demonstrate that it is possible to optimize selectivity of covalent drug candidates.

Therefore, we invite all authors whose research interests deal with any part of development of covalent ligands, from designing, synthesizing, screening, and QSAR model development for potential drug candidates, to their in vitro and in vivo testing. Paper on finding and exploring new, unidentified binding sites, especially on orphan proteins are highly encouraged.

Dr. Robert Vianello
Dr. Hrvoje Rimac
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Dr. Robert Vianello
Dr. Hrvoje Rimac
Guest Editors

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Keywords

covalent ligands
molecular modeling
synthesis
in vitro studies
in vivo studies
orphan proteins

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Research

28 pages, 5322 KiB

Open AccessArticle

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

by Yuran Qiu, Xiaolan Yin, Xinyi Li, Yuanhao Wang, Qiang Fu, Renhua Huang and Shaoyong Lu

Pharmaceutics 2021, 13(5), 747; https://doi.org/10.3390/pharmaceutics13050747 - 18 May 2021

Cited by 44 | Viewed by 3611

Abstract

Dual-targeting therapeutics by coadministration of allosteric and orthosteric drugs is drawing increased attention as a revolutionary strategy for overcoming the drug-resistance problems. It was further observed that the occupation of orthosteric sites by therapeutics agents has the potential to enhance allosteric ligand binding, which leads to improved potency of allosteric drugs. Epidermal growth factor receptor (EGFR), as one of the most critical anti-cancer targets belonging to the receptor tyrosine kinase family, represents a quintessential example. It was revealed that osimertinib, an ATP-competitive covalent EGFR inhibitor, remarkably enhanced the affinity of a recently developed allosteric inhibitor JBJ-04-125-02 for EGFR^L858R/T790M. Here, we utilized extensive large-scale molecular dynamics simulations and the reversed allosteric communication to untangle the detailed molecular underpinning, in which occupation of osimertinib at the orthosteric site altered the overall conformational ensemble of EGFR mutant and reshaped the allosteric site via long-distance signaling. A unique intermediate state resembling the active conformation was identified, which was further stabilized by osimertinib loading. Based on the allosteric communication pathway, we predicted a novel allosteric site positioned around K867, E868, H893, and K960 within the intermediate state. Its correlation with the orthosteric site was validated by both structural and energetic analysis, and its low sequence conservation indicated the potential for selective targeting across the human kinome. Together, these findings not only provided a mechanistic basis for future clinical application of the dual-targeting therapeutics, but also explored an innovative perception of allosteric inhibition of tyrosine kinase signaling. Full article

(This article belongs to the Special Issue Covalent Inhibitors as Selective Drug Candidates)

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22 pages, 8504 KiB

Open AccessArticle

Structural Analysis of the Simultaneous Activation and Inhibition of γ-Secretase Activity in the Development of Drugs for Alzheimer’s Disease

by Željko M. Svedružić, Katarina Vrbnjak, Manuel Martinović and Vedran Miletić

Pharmaceutics 2021, 13(4), 514; https://doi.org/10.3390/pharmaceutics13040514 - 8 Apr 2021

Cited by 12 | Viewed by 3736

Abstract

Significance: The majority of the drugs which target membrane-embedded protease γ-secretase show an unusual biphasic activation–inhibition dose-response in cells, model animals, and humans. Semagacestat and avagacestat are two biphasic drugs that can facilitate cognitive decline in patients with Alzheimer’s disease. Initial mechanistic studies showed that the biphasic drugs, and pathogenic mutations, can produce the same type of changes in γ-secretase activity. Results: DAPT, semagacestat LY-411,575, and avagacestat are four drugs that show different binding constants, and a biphasic activation–inhibition dose-response for amyloid-β-40 products in SH-SY5 cells. Multiscale molecular dynamics studies have shown that all four drugs bind to the most mobile parts in the presenilin structure, at different ends of the 29 Å long active site tunnel. The biphasic dose-response assays are a result of the modulation of γ-secretase activity by the concurrent binding of multiple drug molecules at each end of the active site tunnel. The drugs activate γ-secretase by facilitating the opening of the active site tunnel, when the rate-limiting step is the tunnel opening, and the formation of the enzyme–substrate complex. The drugs inhibit γ-secretase as uncompetitive inhibitors by binding next to the substrate, to dynamic enzyme structures which regulate processive catalysis. The drugs can modulate the production of different amyloid-β catalytic intermediates by penetration into the active site tunnel, to different depths, with different flexibility and different binding affinity. Conclusions: Biphasic drugs and pathogenic mutations can affect the same dynamic protein structures that control processive catalysis. Successful drug-design strategies must incorporate transient changes in the γ-secretase structure in the development of specific modulators of its catalytic activity. Full article

(This article belongs to the Special Issue Covalent Inhibitors as Selective Drug Candidates)

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15 pages, 3417 KiB

Open AccessArticle

Quinuclidine-Based Carbamates as Potential CNS Active Compounds

by Ana Matošević, Andreja Radman Kastelic, Ana Mikelić, Antonio Zandona, Maja Katalinić, Ines Primožič, Anita Bosak and Tomica Hrenar

Pharmaceutics 2021, 13(3), 420; https://doi.org/10.3390/pharmaceutics13030420 - 20 Mar 2021

Cited by 7 | Viewed by 2867

Abstract

The treatment of central nervous system (CNS) diseases related to the decrease of neurotransmitter acetylcholine in neurons is based on compounds that prevent or disrupt the action of acetylcholinesterase and butyrylcholinesterase. A series of thirteen quinuclidine carbamates were designed using quinuclidine as the structural base and a carbamate group to ensure the covalent binding to the cholinesterase, which were synthesized and tested as potential human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The synthesized compounds differed in the substituents on the amino and carbamoyl parts of the molecule. All of the prepared carbamates displayed a time-dependent inhibition with overall inhibition rate constants in the 10³ M⁻¹ min⁻¹ range. None of the compounds showed pronounced selectivity for any of the cholinesterases. The in silico determined ability of compounds to cross the blood–brain barrier (BBB) revealed that six compounds should be able to pass the BBB by passive transport. In addition, the compounds did not show toxicity toward cells that represented the main models of individual organs. By machine learning, the most optimal regression models for the prediction of bioactivity were established and validated. Models for AChE and BChE described 89 and 90% of the total variations among the data, respectively. These models facilitated the prediction and design of new and more potent inhibitors. Altogether, our study confirmed that quinuclidinium carbamates are promising candidates for further development as CNS-active drugs, particularly for Alzheimer’s disease treatment. Full article

(This article belongs to the Special Issue Covalent Inhibitors as Selective Drug Candidates)

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