Exploring global natural product databases for NLRP3 inhibition: Unveiling novel combinatorial therapeutic strategy for hidradenitis suppurativa

IF 4.7 3区 医学 Q1 INFECTIOUS DISEASES
Muhammad Suleman , Abduh Murshed , Abrar Mohammad Sayaf , Abbas Khan , Salman Ali Khan , Paola Maura Tricarico , Chiara Moltrasio , Abdelali Agouni , Kar Kheng Yeoh , Angelo Valerio Marzano , Sergio Crovella
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引用次数: 0

Abstract

Background

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition of the terminal hair follicle, which can present in sporadic, familial, or syndromic forms. The exact pathogenesis of HS remains elusive, posing a challenge for the development of effective treatments. Among the various immunological mechanisms, the NLRP3 inflammasome is thought to contribute to the pathogenesis of HS, releasing cytokines such as IL-1β and IL-18 which initiates and exacerbates inflammation. Consequently, targeting NLRP3 offers a potential strategy for mitigating inflammation in HS-affected skin.

Methods

In this study we used the docking, molecular dynamics simulation and binding free energy approaches to identify the potent inhibitor of NLRP3 by screening the African phytocompounds and traditional Chinese medicine databases.

Results

Our virtual drug screening analysis identified two lead compounds from each database, characterized by high docking scores such as SA-21676268 (-8.135 kcal/mol), SA-167673 (-10.251 kcal/mol), EA-45360194 (-10.376 kcal/mol), EA-46881231 (-10.011 kcal/mol), NEA-44258150 (-9.856 kcal/mol), NEA-135926572 (-7.662 kcal/mol), NA-163089376 (-9.237 kcal/mol), NA-440735 (-8.826 kcal/mol), TCM-392442 (-10.438 kcal/mol), and TCM-10043097 (-9.046 kcal/mol) which highlighted the strong binding affinity as compared to the control NP3–146 drug (-5.09 kcal/mol). Moreover, the values of dissociation constant further validated the strong binding affinity between the identified lead compounds and NLRP3. The dynamic stability and strong bonding energies of the lead compounds-NLRP3 complexes were confirmed by the molecular dynamic simulation and binding free energy calculation. The analysis of ADMET properties for all compounds indicated high intestinal absorption, water solubility, absence of hepatotoxicity, and skin sensitivity.

Conclusion

In conclusion, our molecular simulations and binding free energy calculations confirmed the strong affinity of these lead compounds for NLRP3 as compared to the control drug, highlighting their potential as part of a combinatorial therapeutic strategy for HS to effectively reduce disease-related inflammation.
探索NLRP3抑制的全球天然产物数据库:揭示化脓性汗腺炎的新组合治疗策略
化脓性毛囊炎(HS)是一种终末毛囊的慢性炎症性皮肤病,可表现为散发性、家族性或综合征形式。HS的确切发病机制仍然难以捉摸,这对开发有效的治疗方法提出了挑战。在多种免疫机制中,NLRP3炎性小体被认为与HS的发病有关,它释放IL-1β和IL-18等细胞因子,引发和加剧炎症。因此,靶向NLRP3提供了减轻hs影响皮肤炎症的潜在策略。方法通过对接、分子动力学模拟和结合自由能等方法,筛选非洲植物化合物和中药数据库,鉴定有效的NLRP3抑制剂。ResultsOur虚拟药物筛选从每个数据库,分析确定了两个铅化合物的特点是高对接分数如sa - 21676268(-8.135 千卡每摩尔),sa - 167673(-10.251 千卡每摩尔),ea - 45360194(-10.376 千卡每摩尔),ea - 46881231(-10.011 千卡每摩尔),恩颐投资- 44258150(-9.856 千卡每摩尔),恩颐投资- 135926572(-7.662 千卡每摩尔),na - 163089376(-9.237 千卡每摩尔),na - 440735(-8.826 千卡每摩尔),中医- 392442(-10.438 千卡每摩尔),与对照药物NP3-146(-5.09 kcal/mol)相比,中药-10043097(-9.046 kcal/mol)具有较强的结合亲和力。此外,解离常数的值进一步验证了所鉴定的先导化合物与NLRP3之间的强结合亲和力。通过分子动力学模拟和结合自由能计算证实了先导化合物- nlrp3配合物的动态稳定性和强大的键能。所有化合物的ADMET特性分析表明,它们具有较高的肠道吸收、水溶性、无肝毒性和皮肤敏感性。总之,我们的分子模拟和结合自由能计算证实,与对照药物相比,这些先导化合物对NLRP3具有很强的亲和力,突出了它们作为HS联合治疗策略的一部分的潜力,可以有效减少疾病相关炎症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Infection and Public Health
Journal of Infection and Public Health PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH -INFECTIOUS DISEASES
CiteScore
13.10
自引率
1.50%
发文量
203
审稿时长
96 days
期刊介绍: The Journal of Infection and Public Health, first official journal of the Saudi Arabian Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences and the Saudi Association for Public Health, aims to be the foremost scientific, peer-reviewed journal encompassing infection prevention and control, microbiology, infectious diseases, public health and the application of healthcare epidemiology to the evaluation of health outcomes. The point of view of the journal is that infection and public health are closely intertwined and that advances in one area will have positive consequences on the other. The journal will be useful to all health professionals who are partners in the management of patients with communicable diseases, keeping them up to date. The journal is proud to have an international and diverse editorial board that will assist and facilitate the publication of articles that reflect a global view on infection control and public health, as well as emphasizing our focus on supporting the needs of public health practitioners. It is our aim to improve healthcare by reducing risk of infection and related adverse outcomes by critical review, selection, and dissemination of new and relevant information in the field of infection control, public health and infectious diseases in all healthcare settings and the community.
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