Structure-Based Virtual Screening and De Novo Design to Identify Submicromolar Inhibitors of G2019S Mutant of Leucine-Rich Repeat Kinase 2

Park, Hwangseo; Kim, Sang Woo; Kim, Kewon; Jang, Ahyoung; Hong, Sungwoo

doi:10.3390/ijms232112825

Cited by 10 publications

(3 citation statements)

References 61 publications

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“…Where computational methods have been implemented, MD simulations may help to ensure the validity of these models. Park et al [ 90 ] employed MD simulations to investigate the binding properties of an optimised lead compound with predicted antagonistic effects against the G2019S mutant leucine-rich repeat kinase 2 (LRRK2) receptor. The mutated LRRK2 receptor is known to contribute to Parkinson’s disease pathophysiology through increased activity.…”

Section: Structure-based Methodsmentioning

confidence: 99%

Computer-Aided Drug Design towards New Psychotropic and Neurological Drugs

2023

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Central nervous system (CNS) disorders are a therapeutic area in drug discovery where demand for new treatments greatly exceeds approved treatment options. This is complicated by the high failure rate in late-stage clinical trials, resulting in exorbitant costs associated with bringing new CNS drugs to market. Computer-aided drug design (CADD) techniques minimise the time and cost burdens associated with drug research and development by ensuring an advantageous starting point for pre-clinical and clinical assessments. The key elements of CADD are divided into ligand-based and structure-based methods. Ligand-based methods encompass techniques including pharmacophore modelling and quantitative structure activity relationships (QSARs), which use the relationship between biological activity and chemical structure to ascertain suitable lead molecules. In contrast, structure-based methods use information about the binding site architecture from an established protein structure to select suitable molecules for further investigation. In recent years, deep learning techniques have been applied in drug design and present an exciting addition to CADD workflows. Despite the difficulties associated with CNS drug discovery, advances towards new pharmaceutical treatments continue to be made, and CADD has supported these findings. This review explores various CADD techniques and discusses applications in CNS drug discovery from 2018 to November 2022.

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Section: Structure-based Methodsmentioning

confidence: 99%

Computer-Aided Drug Design towards New Psychotropic and Neurological Drugs

2023

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“…In the past decade, LRRK2 inhibitors have yielded excellent outcomes and successfully entered the clinic. Although the majority of reported LRRK2 kinase inhibitors were identified by HTS, LRRK2 inhibitors with some other scaffolds, generally identified from virtual screening or high throughput screening, are also reported recently, which may inspire the design of a new LRRK2 inhibitor. − However, since these compounds are currently lacking medicinal chemistry optimization and elucidation of SAR, they are not further discussed in this paper. Also, kinase inhibitors that selectively target G2019S LRRK2 were developed because a precision medicine approach of selectively targeting only the pathogenic mutations while sparing the physiological LRRK2 may offer efficacy and safety benefits for a specific patient population.…”

Section: Perspectivementioning

confidence: 99%

The Development and Design Strategy of Leucine-Rich Repeat Kinase 2 Inhibitors: Promising Therapeutic Agents for Parkinson’s Disease

Xing

et al. 2023

J. Med. Chem.

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Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions of people worldwide. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for PD. Elevated LRRK2 kinase activity is found in idiopathic and familial PD cases. LRRK2 mutations are involved in multiple PD pathogeneses, including dysregulation of mitochondrial homeostasis, ciliogenesis, etc. Here, we provide a comprehensive overview of the biological function, structure, and mutations of LRRK2. We also examine recent advances and challenges in developing LRRK2 inhibitors and address prospective protein-based targeting strategies. The binding mechanisms, structure−activity relationships, and pharmacokinetic features of inhibitors are emphasized to provide a comprehensive compendium on the rational design of LRRK2 inhibitors. We hope that this publication can serve as a guide for designing novel LRRK2 inhibitors based on the summarized facts and perspectives.

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“…Additionally, ligand-based screening may only identify hits with more similar chemical scaffolds compared to the query. Thus, structure-based screening is a popular approach to identifying novel ligands for biological targets and can help to identify novel chemical scaffolds [21][22][23][24][25][26][27][28]. Recently, we identified a novel allosteric binding site of MB327 (MB327-PAM-1) and described a potential binding mode of UNC0646 in MB327-PAM-1 [13,29], providing necessary input for three-dimensional ligandbased screening and structure-based screening.…”

Section: Introductionmentioning

confidence: 99%

Identification of ligands binding to MB327-PAM-1, a binding pocket relevant for resensitization of nAChRs

Kaiser,

Gertzen,

Bernauer

et al. 2023

Preprint

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Desensitization of nicotinic acetylcholine receptors (nAChRs) can be induced by overstimulation with acetylcholine (ACh) caused by an insufficient degradation of ACh after poisoning with organophosphorus compounds (OPCs). Currently, there is no generally applicable treatment for OPC poisoning that directly targets the desensitized nAChR. The bispyridinium compound MB327, an allosteric modulator of nAChR, has been shown to act as a resensitizer of nAChRs, indicating that drugs binding directly to nAChRs can have beneficial effects after OPC poisoning. However, MB327 also acts as an inhibitor of nAChRs at higher concentrations and can thus not be used for OPC poisoning treatment. Consequently, novel, more potent resensitizers are required. To successfully design novel ligands, the knowledge of the binding site is of utmost importance. Recently, we performedin silicostudies to identify a new potential binding site of MB327, MB327-PAM-1, for which a more affine ligand, UNC0646, has been described. In this work, we performed ligand-based screening approaches to identify novel analogs of UNC0646 to help further understand the structure-affinity relationship of this compound class. Furthermore, we used structure-based screenings and identified compounds representing four new chemotypes binding to MB327-PAM-1. One of these compounds, cycloguanil, is the active metabolite of the antimalaria drug proguanil and shows a higher affinity towards MB327-PAM-1 than MB327. Furthermore, cycloguanil can reestablish the muscle force in soman-inhibited rat muscles. These results can act as a starting point to develop more potent resensitizers of nAChR and to close the gap in the treatment after OPC poisoning.

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Structure-Based Virtual Screening and De Novo Design to Identify Submicromolar Inhibitors of G2019S Mutant of Leucine-Rich Repeat Kinase 2

Cited by 10 publications

References 61 publications

Computer-Aided Drug Design towards New Psychotropic and Neurological Drugs

Computer-Aided Drug Design towards New Psychotropic and Neurological Drugs

The Development and Design Strategy of Leucine-Rich Repeat Kinase 2 Inhibitors: Promising Therapeutic Agents for Parkinson’s Disease

Identification of ligands binding to MB327-PAM-1, a binding pocket relevant for resensitization of nAChRs

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