Molecular Diversity最新文献

{"title":"\"Several birds with one stone\": exploring the potential of AI methods for multi-target drug design.","authors":"Muhetaer Mukaidaisi, Madiha Ahmed, Karl Grantham, Aws Al-Jumaily, Shoukat Dedhar, Michael Organ, Alain Tchagang, Jinqiang Hou, Syed Ejaz Ahmed, Renata Dividino, Yifeng Li","doi":"10.1007/s11030-024-11042-0","DOIUrl":"https://doi.org/10.1007/s11030-024-11042-0","url":null,"abstract":"<p><p>Drug discovery is a time-consuming and expensive process. Artificial intelligence (AI) methodologies have been adopted to cut costs and speed up the drug development process, serving as promising in silico approaches to efficiently design novel drug candidates targeting various health conditions. Most existing AI-driven drug discovery studies follow a single-target approach which focuses on identifying compounds that bind a target (i.e., one-drug-one-target approach). Polypharmacology is a relatively new concept that takes a systematic approach to search for a compound (or a combination of compounds) that can bind two or more carefully selected protein biomarkers simultaneously to synergistically treat the disease. Recent studies have demonstrated that multi-target drugs offer superior therapeutic potentials compared to single-target drugs. However, it is intuitively thought that searching for multi-target drugs is more challenging than finding single-target drugs. At present, it is unclear how AI approaches perform in designing multi-target drugs. In this paper, we comprehensively investigated the performance of multi-objective AI approaches for multi-target drug design. Our findings are quite counter-intuitive demonstrating that, in fact, AI approaches for multi-target drug design are able to efficiently generate more high-quality novel compounds than the single-target approaches while satisfying a number of constraints.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Late-stage-functionalization of anti-depressant molecule buspirone.","authors":"Yalin Guo, Debin Yang, Bo Hu, Yongtao Duan, Yibing Cheng, Yu Tang, Caili Guo, Yuanzhe Li, Bing Yu","doi":"10.1007/s11030-024-11029-x","DOIUrl":"https://doi.org/10.1007/s11030-024-11029-x","url":null,"abstract":"<p><p>Buspirone, a well-established anxiolytic agent, has gained attention for its potential role as an antidepressant, primarily due to its unique pharmacological profile and the ability to modulate serotonin receptors effectively. Late-stage functionalization is considered as a pivotal strategy in drug synthesis that enhances the therapeutic efficacy of existing molecules. This review summarizes various late-stage functionalization techniques applicable to Buspirone, including photocatalyzed, metal-catalyzed, and enzyme-catalyzed reactions.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HFIP-driven Schmidt-type reaction enables chromone-3-carbonitriles and its applications.","authors":"Jia Xu, Jie Lei, Li-Xin Zhang, Shan Yu, Cheng-He Zhou, Zhi-Gang Xu, Hong-Wei Du, Zhong-Zhu Chen","doi":"10.1007/s11030-024-11027-z","DOIUrl":"https://doi.org/10.1007/s11030-024-11027-z","url":null,"abstract":"<p><p>Chromone-3-carbonitrile has been extensively studied in a panel of high-value transformations. However, existing protocols for the synthesis of this scaffold are often constrained by the structure of the starting materials and harsh conditions. To address these issues, we present a novel strategy that HFIP (hexafluoroisopropanol)-driven strategy, enables chromone-3-carbonitriles synthesis without undesirable side reactions. This protocol features readily available feedstocks, mild conditions, catalytic amount of acid and good to excellent yields. The utility of this chemistry is further demonstrated by amenable modifications of chromone-pyrimidines and imidazoles. Moreover, the analogous transformation of aldehydes is successfully constructed to achieve useful compounds such as 2-hydroxybenzonitriles, heterocyclic nitriles, and α, β-unsaturated nitriles. The HFIP-driven strategy offers an interesting access to different types of nitriles in a sustainably manner.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and biological evaluation of novel molecules as potent inhibitors of indoleamine 2,3-dioxygenase 1.","authors":"Shujuan Wei, Fuao Zhang, Wenyan Wang, Guangying Du, Pengfei Yu, Liang Ye, Hongbo Wang, Yifei Yang, Jingwei Tian","doi":"10.1007/s11030-024-11043-z","DOIUrl":"https://doi.org/10.1007/s11030-024-11043-z","url":null,"abstract":"<p><p>Tumoral immune escape is an obstacle to successful cancer therapy. Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an active area of drug development. Several classes of small molecule-based IDO1 inhibitors have already been reported. Still, only a few compounds are currently being evaluated in various stages of clinical trials as adjuvants or in combination with chemo- and radiotherapies. In this study, a novel series of 1,2,5-oxadiazole-3-carboximidamide derivatives were designed, synthesized, and evaluated for inhibitory activities against IDO1, and their structure-activity relationship was investigated. Notably, several compounds (11c, 11j, 11o, and 11u) showed powerful anti-tumor effects in the low micromolar range. Among them, compound 11u exhibited excellent inhibitory potency against hIDO1 (IC₅₀ = 42.2 ± 2.23 nM) and in Hela cells expressing hIDO1 (IC₅₀ = 4.35 ± 0.13 nM). Combined with favorable in vitro potency, pharmacokinetic profile, and in vivo efficacy, the promising antitumor drug candidate 11u has subsequently advanced into preclinical research. These compounds provide valuable ideas and information for developing new cancer immunotherapy.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and interaction mechanism of novel small molecule antagonists targeting CC chemokine receptor 1/3/5 for treatment of non-small cell lung cancer.","authors":"Xiaomeng Wang, Juan Wang, Qiao Fu, Jing Luo, Mao Shu, Zhihua Lin","doi":"10.1007/s11030-024-11025-1","DOIUrl":"https://doi.org/10.1007/s11030-024-11025-1","url":null,"abstract":"<p><p>Non-Small Cell Lung Cancer (NSCLC) was one of the most prevalent forms of lung cancer. Due to its ease of invasion and migration, the five-year survival rate was relatively low. Therefore, new strategies for NSCLC treatment were needed. CC chemokine receptor 1/3/5 (CCR1/CCR3/CCR5), a member of the G-protein coupled receptor family, could promote the migration and invasion of NSCLC cells by binding to related chemokines. Consequently, targeting CCR1, CCR3 and CCR5 might prevent the progression of the disease. So far, no compound had been reported as a common antagonist for CCR1, CCR3, and CCR5. In this research, we utilized virtual screening and structural optimization to obtain compound 5, which effectively inhibited the migration and invasion of NSCLC cells. Meanwhile, Western Blot and Enzyme linked immunosorbent assay (ELISA) manifested that compound 5 suppressed migration and invasion of NSCLC cells by suppressing the nuclear factor κB (NF-κB) and the consequently decreased Matrix Metalloproteinase-9(MMP-9) secretion. Moreover, drug affinity responsive target stability (DARTS) experiment and molecular simulations confirmed that compound 5 was capable of binding with CCR1/CCR3/CCR5, and Van der Waals forces were instrumental in the binding process. Ile91, Tyr113, Gln284, and Ser184(CCR1-ligand5), Ile189, Met213, and Leu209(CCR3-ligand5), Phe109, Gln194, and Thr195(CCR5-ligand5) had Van der Waals interactions with ligand 5. Dynamic cross-correlation matrix (DCCM) and free energy landscape (FEL) showed that compound 5 could stably bind to CCR1/CCR3/CCR5 to change conformation of the protein and the tendency of residue movements, leading to a persistent inhibitory effect. This study aimed to provide assistance in the rational design of common antagonists for CCR1, CCR3, and CCR5.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated computational approaches for identification of potent pyrazole-based glycogen synthase kinase-3β (GSK-3β) inhibitors: 3D-QSAR, virtual screening, docking, MM/GBSA, EC, MD simulation studies.","authors":"Desu Gayathri Niharika, Punam Salaria, M Amarendar Reddy","doi":"10.1007/s11030-024-11026-0","DOIUrl":"10.1007/s11030-024-11026-0","url":null,"abstract":"<p><p>Glycogen synthase kinase-3β (GSK-3β) has emerged as a crucial target due to its substantial contribution in various cellular processes. Dysfunctional GSK-3β activity can lead to ion channel disturbances, sustain abnormal excitability, and contribute to the pathogenesis of epilepsy and other GSK-3β-related disorders. A set of 82 pyrazole analogs was utilized to study its structural features using a three-dimensional quantitative structure-activity relationship (3D-QSAR), virtual screening, molecular docking, and molecular dynamics. The QSAR model, validated using internal and external methods, demonstrated robustness with a high correlation coefficient r²_training = 0.99, cross-validation coefficient q² = 0.79, r²_test = 0.69, and r²_external = 0.74. The \"Average of Actives\" in the Activity Atlas model identified 17 molecules as active. Subsequent pharmacophore-based virtual screening of 17 actives yielded 70 compounds, which were selected as the prediction set to determine the potential GSK-3β inhibitors. Docking studies pinpointed compound P66 as the promising lead compound, with a docking score of - 10.555 kcal/mol. These findings were further supported by electrostatic potential (ESP), electrostatic complementarity (EC), and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analyses. Furthermore, a 500 ns molecular dynamics (MD) simulation confirmed the structural and conformational stability of the lead complex throughout the simulation period. As a result, this study suggests that compound P66 holds the potential to be a potent lead candidate for the inhibition of GSK-3β, offering a novel therapeutic approach for GSK-3β related disorders, including epilepsy.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptome and interactome-based analyses to unravel crucial proteins and pathways involved in Acinetobacter baumannii pathogenesis.","authors":"Aishwarya Swain, Smruti Sikha Senapati, Archana Pan","doi":"10.1007/s11030-024-11041-1","DOIUrl":"10.1007/s11030-024-11041-1","url":null,"abstract":"<p><p>The present study employed an integrated transcriptome and interactome-based analyses to identify key proteins and pathways associated with Acinetobacter baumannii infection towards the development of novel therapeutics against this pathogen. Transcriptome analysis of A.baumannii strains (ATCC 17978 and AbH12O-A2) identified 253 and 619 differentially expressed genes (DEGs), respectively. These genes were involved in essential molecular functions, including DNA binding, metal ion binding, and oxidoreductase activity. The centrality and module analyses of these identified DEGs had shortlisted 27 and 41 hub proteins, which were central to the ATCC 17978 and AbH12O-A2 networks, and essential for bacterial survival. Significantly, three proteins (SecA, glutathione synthase, and aromatic-amino-acid transaminase) from the ATCC 17978 strain and seven proteins (ATP synthase subunit alpha, translation initiation factor IF-2, SecY, elongation factors G, Tu, and Ts, and tRNA guanine-N1-methyltransferase) from the AbH12O-A2 strain showed interactions with human proteins, identified through host-pathogen interaction (HPI) analysis of hub proteins (referred as hub-HPI proteins). These proteins were observed to participate in vital pathways, including glutathione metabolism, secondary metabolite biosynthesis and quorum sensing. Targeting these hub-HPI proteins through novel therapeutic strategies holds the potential to disrupt the critical bacterial pathways, thereby controlling A. baumannii infections. Furthermore, their localization analysis indicated that nine proteins were cytoplasmic and one was membrane protein. Among them, six were druggable and four were novel proteins. Overall, this comprehensive study provides valuable insights into the crucial proteins and pathways involved during A. baumannii infection, and offers potential therapeutic targets for designing novel antimicrobial agents to tackle the pathogen.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of potential antigenic proteins and epitopes for the development of a monkeypox virus vaccine: an in silico approach.","authors":"Emre Aktaş, Osman Uğur Sezerman, Murat Özer, Kevser Kübra Kırboğa, Ahmet Efe Köseoğlu, Nehir Özdemir Özgentürk","doi":"10.1007/s11030-024-11033-1","DOIUrl":"https://doi.org/10.1007/s11030-024-11033-1","url":null,"abstract":"<p><p>Virus assembly, budding, or surface proteins play important roles such as viral attachment to cells, fusion, and entry into cells. The present study aimed to identify potential antigenic proteins and epitopes that could be used to develop a vaccine or diagnostic assay against the Monkeypox virus (MPXV) which may cause a potential epidemic. To do this, 39 MPXV proteins (including assembly, budding, and surface proteins) were analyzed using an in silico approach. Of these 39 proteins, the F5L virus protein was found to be the best vaccine candidate due to its signal peptide properties, negative GRAVY value, low transmembrane helix content, moderate aliphatic index, large molecular weight, long-estimated half-life, beta wrap motifs, and being stable, soluble, and containing non-allergic features. Moreover, the F5L protein exhibited alpha-helical secondary structures, making it a potential \"structural antigen\" recognized by antibodies. The other viral protein candidates were A9 and A43, but A9 lacked beta wrap motifs, while A43 had a positive GRAVY value and was insoluble. These two proteins were not as suitable candidates as the F5L protein. The KRVNISLTCL epitope from the F5L protein demonstrated the highest antigen score (2.4684) for MHC-I, while the GRFGYVPYVGYKCI epitope from the A9 protein exhibited the highest antigenicity (1.754) for MHC-II. Both epitopes met the criteria for high antigenicity, non-toxicity, solubility, non-allergenicity, and the presence of cleavage sites. Molecular docking and dynamics (MD) simulations further validated their potential, revealing stable and energetically favorable interactions with MHC molecules. The immunogenicity assessment showed that GRFGYVPYVGYKCI could strongly induce immune responses through both IFN-γ and IL-4 pathways, suggesting its capacity to provoke a balanced Th1 and Th2 response. In contrast, KRVNISLTCL exhibited limited immunostimulatory potential. Overall, these findings lay the groundwork for future vaccine development, indicating that F5L, particularly the GRFGYVPYVGYKCI epitope, may serve as an effective candidate for peptide-based vaccine design against MPXV.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fe₃O₄@SiO₂@[Aminoglycol][Formate] as a new superparamagnetic nanocatalyst and [Aminoglycol][Formate] as a novel ionic liquid catalyst for preparation of new dimethyldihydropyrimido[4,5-b]quinolone derivatives.","authors":"Fatemeh Bani Asadi, Farhad Shirzaei, Hamid Reza Shaterian","doi":"10.1007/s11030-024-11013-5","DOIUrl":"https://doi.org/10.1007/s11030-024-11013-5","url":null,"abstract":"<p><p>Efficient synthesis of novel dimethyldihydropyrimido[4,5-b]quinolones via three-component condensation of barbituric acid, arylaldehydes, and 3,4-dimethylaniline catalyzed by Fe₃O₄@SiO₂@[Aminoglycol][Formate] as a new superparamagnetic nanocatalyst and [Aminoglycol][Formate] as a novel ionic liquid catalyst was described. The new heterogeneous nanocatalyst was characterized by FE-SEM, XRD, FT-IR, TGA-DTG, and VSM techniques. The new ionic liquid was characterized by ¹³CNMR, ¹HNMR, and FT-IR techniques. The present work has advantages, such as excellent yields, short reaction times, environmentally friendly protocol, easy separation, and purification of products. The catalysts kept its catalytic properties after even five recoverability and reusability.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico studies on nicotinamide analogs as competitive inhibitors of nicotinamidase in methicillin-resistant Staphylococcus aureus.","authors":"Jaikee Kumar Singh, Jai Singh, Ishita Jha, Tarini Rajput, Saurabh Srivastava, Sandeep Kumar Srivastava","doi":"10.1007/s11030-024-11036-y","DOIUrl":"https://doi.org/10.1007/s11030-024-11036-y","url":null,"abstract":"<p><p>Nicotinamidase/PncA is a member of the hydrolase enzyme family, catalyzing the de-amidation of nicotinamide (NM) to nicotinic acid (NA) via salvage pathway. Products are fed into Preiss-Handler pathway for NAD⁺ biosynthesis which is an important enzyme cofactor and crucial for redox balance in microorganisms. Pathogens like methicillin-resistant Staphylococcus aureus (MRSA) are NAD⁺ auxotroph and rely on their host environment for NAD⁺ precursors to synthesize NAD⁺. Mutations in nicotinamidase/PncA have been reported to be associated with resistance to pyrazinamide (PZA), a front-line anti-tubercular drug, underlying its importance as an important link in NAD⁺ biosynthesis network in pathogenic organisms such as MRSA. The conserved features of PncA and essentiality of salvage route in MRSA and the absence of this enzyme in humans and other eukaryotes are attractive options to explore therapeutics against this target. In this work, we have screened novel substrate analogs from the PubChem database using virtual screening approaches employing fingerprint tanimoto-based 2D similarity search against Staphylococcus aureus PncA (SaPncA). Identified compounds were further assessed using molecular dynamics simulations to investigate conformational stability and structural integrity. We propose two analogs, namely L28 and L33 with greater stability, favorable binding and strong binding free energies in MM-PBSA calculations. The strategy could provide an important clue in developing similar compound scaffolds as potent drug-like molecules against MRSA and other pathogenic species harboring this enzyme. Smaller scaffolds of these molecules could be attractive options for fragment-based derivatization for inhibitor discovery.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}