Computational Approach to Identifying New Chemical Entities as Elastase Inhibitors with Potential Antiaging Effects

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22310%2F24%3A43931113" target="_blank" >RIV/60461373:22310/24:43931113 - isvavai.cz</a>

Result on the web

<a href="https://www.mdpi.com/1422-0067/25/20/11174" target="_blank" >https://www.mdpi.com/1422-0067/25/20/11174</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/ijms252011174" target="_blank" >10.3390/ijms252011174</a>

Result language

angličtina

Original language name

Computational Approach to Identifying New Chemical Entities as Elastase Inhibitors with Potential Antiaging Effects

Original language description

In the aging process, skin morphology might be affected by wrinkle formation due to the loss of elasticity and resilience of connective tissues linked to the cleavage of elastin by the enzymatic activity of elastase. Little information is available about the structural requirements to efficiently inhibit elastase 1 (EC 3.4.21.36) expressed in skin keratinocytes. In this study, a structure-based approach led to the identification to the pharmacophoric hypotheses that described the main structural requirements for binding to porcine pancreatic elastase as a valuable tool for the development of skin therapeutic agents due to its similarity with human elastase 1. The obtained models were subsequently refined through the application of computational alanine-scanning mutagenesis to evaluate the effect of single residues on the binding affinity and protein stability; in turn, molecular dynamic simulations were carried out; these procedures led to a simplified model bearing few essential features, enabling a reliable collection of chemical features for their interactions with elastase. Then, a virtual screening campaign on the in-house library of synthetic compounds led to the identification of a nonpeptide-based inhibitor (IC50 = 60.4 mu M) belonging to the class of N-substituted-1H-benzimidazol-2-yl]thio]acetamides, which might be further exploited to obtain more efficient ligands of elastase for therapeutic applications.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10201 - Computer sciences, information science, bioinformathics (hardware development to be 2.2, social aspect to be 5.8)

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

ISSN

1661-6596

e-ISSN

1422-0067

Volume of the periodical

25

Issue of the periodical within the volume

20

Country of publishing house

LT - LITHUANIA

Number of pages

16

Pages from-to

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UT code for WoS article

001341329100001

EID of the result in the Scopus database

2-s2.0-85207425036