Journal of Biomolecular Structure & Dynamics最新文献

The multifaceted interplay between neurodegenerative pathologies, including Alzheimer's disease (AD), and the highly virulent severe acute respiratory syndrome coronavirus (SARS-CoV), is implicated in various conditions. AD and SARS-CoV pathogenesis involve the APOE4 allele, NLRP3 inflammasome, and ACE2-SPIKE complex. APOE4, a genetic polymorphism of the APOE gene, is associated with an increased susceptibility to AD. NLRP3, an inflammatory protein of the innate immune system, plays a pivotal role in immune response cascades. In SARS-CoV, the ACE2 receptor serves as the principal portal for cellular entry, while APOE4 intricately interacts with the ACE2-spike protein complex, enhancing viral internalization process. The interaction of NLRP3 with the ACE2-spike protein complex leads to increased inflammatory signaling. The convergence of APOE4/NLRP3 and ACE2-spike protein complex interactions suggests a possible link between SARS and AD. Therefore, the current research centralizes the association between by utilizing SARS-CoV datasets to explore possible mechanisms that account for the pathogenesis of SARS-CoV and AD. The work is further extended to unveil the molecular interactions of APOE4 and NLRP3 with the ACE2-Spike protein complex at the molecular level by employing molecular dynamics simulation techniques. The therapeutic efficacy of Chyawanprash nutraceuticals is evaluated as their inhibitory potential towards APOE4-ACE2-Spike protein and NLRP3-ACE2-Spike protein complexes. Notably, our simulations unequivocally demonstrate the robust and enduring binding capability of the compound Phyllantidine with the target complexes throughout the simulation period. The findings of the studies further corroborate the primary hypothesis of APOE4 and NLRP3 as driver factors in the pathogenesis of both SARS-CoV and AD. Therefore, this research establishes a paradigm for comprehending the complex interaction between AD and SARS-CoV and lays the groundwork for further study in this domain.Communicated by Ramaswamy H. Sarma.

Lung cancer is a complex and heterogeneous disease, which has been associated with various molecular alterations, including the overexpression and mutations of the epidermal growth factor receptor (EGFR). In this study, designed a library of 1843 benzimidazole-1,2,3-triazole hybrids and carried out pharmacophore-based screening to identify potential EGFR inhibitors. The 164 compounds were further evaluated using molecular docking and molecular dynamics simulations to understand the binding interactions between the compounds and the receptor. In-si-lico ADME and toxicity studies were also conducted to assess the drug-likeness and safety of the identified compounds. The results of this study indicate that benzimidazole-1,2,3-triazole hybrids BENZI-0660, BENZI-0125, BENZI-0279, BENZI-0415, BENZI-0437, and BENZI-1110 exhibit dock scores of -9.7, -9.6, -9.6, -9.6, -9.6, -9.6 while referencing molecule -7.9 kcal/mol for EGFR (PDB ID: 4HJO), respectively. The molecular docking and molecular dynamics simulations revealed that the identified compounds formed stable interactions with the active site of EGFR, indicating their potential as inhibitors. The in-silico ADME and toxicity studies showed that the compounds had favorable drug-likeness properties and low toxicity, further supporting their potential as therapeutic agents. Finally, performed DFT studies on the best-selected ligands to gain further insights into their electronic properties. The findings of this study provide important insights into the potential of benzimidazole-1,2,3-triazole hybrids as promising EGFR inhibitors for the treatment of lung cancer. This research opens up a new avenue for the discovery and development of potent and selective EGFR inhibitors for the treatment of lung cancer.Communicated by Ramaswamy H. Sarma.

Intervertebral disc degeneration (IDD) is a progressive and chronic disease, the mechanisms have been studied extensively as a whole, while the cellular heterogeneity of cells in nucleus pulposus (NP) tissues remained controversial for a long time. This study conducted integrated analysis through single-cell sequencing analysis, weighted gene co-expression network analysis (WGCNA), and differential expression analysis, to systematically decipher the longitudinal alterations of distinct NP subtypes, and also analyzed the most essential genes in the development of IDD. Then, this study further conducted structural biology method to discover the potential lead compounds through a suite of advanced approaches like high-throughput screening (HTVS), pharmaceutical characteristics assessment, CDOCKER module as well as molecular dynamics simulation, etc., aiming to ameliorate the progression of IDD. Totally 5 NP subpopulations were identified with distinct biological functions based on their unique gene expression patterns. The predominant dynamics changes mainly involved RegNPs and EffNPs, the RegNPs were mainly aggregated in normal NP tissues and drastically decreased in degenerative NP, while EffNPs, as pathogenic subtype, exhibited opposite phenomenon. Importantly, this study further reported the essential roles of Menaquinone in alleviating degenerative NP cells for the first time, which could provide solid evidence for the application of nutritional therapy in the treatment of IDD. This study combined scRNA-seq, bulk-RNA seq and HTVS techniques to systematically decipher the longitudinal changes of NP subtypes during IDD. EffNPs were considered to be 'chief culprit' in IDD progression, while the novel natural drug Menaquinone could reverse this phenomenon.Communicated by Ramaswamy H. Sarma.

Beclin 1 is a key autophagy regulator that also plays significant roles in other intracellular processes such as vacuolar protein sorting. Beclin 1 protein functions as a scaffold in the formation of a multiprotein assemblage during autophagy. Beclin 1 is involved in various diseases such as cancers, neurodegenerative and autophagy-related disorders. In this study, we have used various in silico tools to scan beclin 1 at the molecular level to find its molecular signatures. We have predicted and analysed deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) of beclin 1 causing alterations in its structure and also affecting its interactions with other proteins. In total, twelve coding region deleterious variants were predicted using sequence-based tools and nine were predicted using various structure-based tools. The molecular dynamics (MD) simulations revealed an altered stability of the native structure due to the introduction of mutations. Destabilization of beclin 1 ECD domain was observed due to nsSNPs W300R and E302K. Beclin 1 deleterious nsSNPs were predicted to show significant effects on beclin 1 interactions with ATG14L1, UVRAG and VPS34 proteins and were also predicted to alter the protein-protein interface of beclin 1 complexes. Additionally, beclin 1 was predicted to have thirty-one potential phosphorylation and three ubiquitination sites. In conclusion, the molecular details of beclin 1 could help in the better understanding of its functioning. The study of nsSNPs and their effect on beclin 1 and its interactions might aid in understanding the basis of anomalies caused due to beclin 1 dysfunction.Communicated by Ramaswamy H. Sarma.

The protein kinase Wee1 plays a vital role in the G2/M cell cycle checkpoint activation, triggered by double-stranded DNA disruptions. It fulfills this task by phosphorylating and consequently deactivating the cyclin B linked to Cdk1/Cdc2 at the Tyr15 residue, leading to a G2 cell cycle halt and subsequent delay of mitosis post DNA damage. Despite advancements, only the Wee1 inhibitor MK1775 has made it to Phase II clinical trials, presenting a challenge in innovative chemical structure development for small molecule discovery. To navigate this challenge, we employed an e-pharmacophore model of the MK1775-WEE1 complex (PDB ID: 5V5Y), using in silico screening of FDA-approved drugs. We chose six drugs for analog creation, guided by docking scores, key residue interactions, and ligand occupancy. Utilizing the 'DrugSpaceX' database, we generated 2,776 analogues via expert-defined transformations. Our findings identified DE90612 as the top-ranked analogue, followed by DE363106, DE489678, DE395383, DE90548, DE689343, DE395019, and DE538066. These analogues introduced unique structures not found in other databases. A t-SNE structurally diversified distribution map unveiled promising transformations linked to Temozolomide for WEE1 inhibitor development. Simulations of the WEE1-DE90612 complex (a Temozolomide analogue) for 200 nanoseconds demonstrated stability, with DE90612 forging robust bonds with active site residues and sustaining vital contacts at ASN376 and CYS379. These results underscore DE90612's potential inhibitory properties at the WEE1 binding site, warranting additional in vitro and in vivo exploration for its anticancer activity. Our approach outlines a promising pathway for creating diverse WEE1 inhibitors with suitable biological properties for potential oncology therapeutics.Communicated by Ramaswamy H. Sarma.

Dengue fever is now one of the major global health concerns particularly for tropical and sub-tropical countries. However, there has been no FDA approved medication to treat dengue fever. Researchers are looking into DENV NS5 RdRp protease as a potential therapeutic target for discovering effective anti-dengue agents. The aim of this study to discover dengue virus inhibitor from a set of five compounds from Momordica charantia L. using a series of in-silico approaches. The compounds were docked into the active area of the DENV-2 NS5 RdRp protease to obtain the hit compounds. The successful compounds underwent additional testing for a study on drug-likeness similarity. Our study obtained Momordicoside-I as a lead compound which was further exposed to the Cytochrome P450 (CYP450) toxicity analysis to determine the toxicity based on docking scores and drug-likeness studies. Moreover, DFT studies were carried out to calculate the thermodynamic, molecular orbital and electrostatic potential properties for the lead compound. Moreover, the lead compound was next subjected to molecular dynamic simulation for 200 ns in order to confirm the stability of the docked complex and the binding posture discovered during docking experiment. Overall, the lead compound has demonstrated good medication like qualities, non-toxicity, and significant binding affinity towards the DENV-2 RdRp enzyme.Communicated by Ramaswamy H. Sarma.

A number of multidisciplinary methods have piqued the interest of researchers as means to accelerate and lower the cost of medication creation. The goal of this research was to find target proteins and then select a lead drug against SARS-CoV-2. The three-dimensional structure is taken from the RCSB PDB using its specific PDB ID 6lu7. Virtual screening based on pharmacophores is performed using Molecular Operating Environment software. We looked for a potent inhibitor in the FDA-approved database. For docking, AutoDock Vina uses Pyrx. The compound-target protein binding interactions were tested using BIOVIA Discovery Studio. The stability of protein and inhibitor complexes in a physiological setting was investigated using Desmond's Molecular Dynamics Simulation (MD simulation). According to our findings, we repurpose the FDA-approved drugs ZINC000169677008 and ZINC000169289767, which inhibit the activity of the virus's main protease (6lu7). The scientific community will gain from this finding, which might create new medicine. The novel repurposed chemicals were promising inhibitors with increased efficacy and fewer side effects.Communicated by Ramaswamy H. Sarma.

To explore the new mode of action and reduce side effects, making conjugates of existing drugs is becoming an attractive tool in the realm of medicinal chemistry. In this work, we exploited this approach and synthesized new conjugates to assess their activities against the enzymes involved in different pathological conditions. Specifically, we design and synthesized conjugates involving acetylsalicylic acid and sulfa drugs, validating the newly crafted conjugates using techniques like IR, ¹HNMR, ¹³CNMR, and elemental analysis. These conjugates underwent assessment for their ability to inhibit cyclooxygenase-2 (COX-2), urease enzymes, and their anti-inflammatory potential. A competitive mode of urease inhibition was observed for acetylsalicylic acid conjugated with sulfanilamide, sulfacetamide, and sulfadiazine with IC₅₀ of 2.49 ± 0.35 µM, 6.21 ± 0.28 µM, and 6.57 ± 0.44 µM, respectively. Remarkably, the acetylsalicylic acid-sulfamethoxazole conjugate exhibited exceptional anti-inflammatory activity, effectively curtailing induced edema by 83.7%, a result akin to the reference anti-inflammatory drug indomethacin's performance (86.8%). Additionally, it demonstrated comparable COX-2 inhibition (75.8%) to the reference selective COX-2 inhibitor celecoxib that exhibited 77.1% inhibition at 10 µM concentration. To deepen our understanding, we employed molecular docking techniques to predict the binding interactions of competitive inhibitors with COX-2 and urease receptors. Additionally, MD simulations were carried out, confirming the stability of inhibitor-target complexes throughout the simulation period, devoid of significant conformational changes. Collectively, our research underscores the potential of coupling approved medicinal compounds to usher in novel categories of pharmacological agents, holding promise for addressing a wide spectrum of pathological disorders involving COX-2 and urease enzymes.Communicated by Ramaswamy H. Sarma.

Danzhi-xiaoyao-San (DZXYS), a Traditional Chinese Medicine, plays an essential role in the clinical treatment of depression, but its mechanisms in humans remain unclear. To investigate its pharmacological effects and mechanisms as an add-on therapy for depression, we conducted a double-blind, placebo-controlled trial with depressed patients receiving selective serotonin reuptake inhibitors (SSRIs). Serum and fecal samples were collected for metabolomic and microbiome analysis using UHPLC-QTRAP-MS/MS and 16S rRNA gene sequencing technologies, respectively. Depression symptoms were assessed using the 24-item Hamilton Depression Scale. We employed network pharmacology, metabolomics, and molecular docking to identify potential targets associated with DZXYS. We also examined the correlation between gut microbes and metabolites to understand how DZXYS affects the microbiota-gut-brain axis. The results showed that DZXYS combined with SSRIs was more effective than SSRIs alone in improving depression. We identified 39 differential metabolites associated with DZXYS treatment and found seven upregulated metabolic pathways. The active ingredients quercetin and luteolin were docked to targets (AVPR2, EGFR, F2, and CDK6) associated with the enriched pathways 'pancreatic cancer' and 'phospholipase D signaling pathway', which included the metabolite lysophosphatidic acid [LPA(0:0/16:0)]. Additionally, we identified 32 differential gut microbiota species related to DZXYS treatment, with Bacteroides coprophilus and Ruminococcus gnavus showing negative correlations with specific metabolites such as L-2-aminobutyric acid and LPA(0:0/16:0). Our findings indicate that DZXYS's antidepressant mechanisms involve multiple targets, pathways, and the regulation of LPA and the microbiota-gut-brain axis. These insights from our systems pharmacology analysis contribute to a better understanding of DZXYS's potential pharmacological mechanisms in depression treatment.Communicated by Ramaswamy H. Sarma.

The PI3K class I is composed of four PI3K isoforms that serve as regulatory enzymes governing cellular metabolism, proliferation, and survival. The hyperactivation of PI3Kα is observed in various types of cancer and is linked to poor prognosis. Unfortunately, the development inhibitors selectively targeting one of the isoforms remains challenging, with only few agents in clinical use. The main difficulty arises from the high conservation among residues at the ATP-binding pocket across isoforms, which also serves as target pocket for inhibitors. In this work, molecular dynamics and quantum calculations were performed to investigate the molecular features guiding the binding of selective inhibitors, alpelisib and GDC-0326, into the ATP-binding pocket of PI3Kα. While molecular dynamics allowed crystallographic coordinates to relax, the interaction eergy between each amino acid residues and inhibitors was obtained by combining the Molecular Fractionation with Conjugated Caps scheme with Density Functional Theory calculations. In addition, the atomic charge of ligands in the bound and unbound (free) was calculated. Results indicated that the most relevant residues for the binding of alpelisib are Ile932, Glu859, Val851, Val850, Tyr836, Met922, Ile800, and Ile848, while the most important residues for the binding of GDC-0326 are Ile848, Ile800, Ile932, Gln859, Glu849, and Met922. In addition, residues Trp780, Ile800, Tyr836, Ile848, Gln859 Val850, Val851, Ile932 and Met922 are common hotspots for both inhibitors. Overall, the results from this work contribute to improving the understanding of the molecular mechanisms controlling selectivity and highlight important interactions to be considered during the rational design of new agents.Communicated by Ramaswamy H. Sarma.