Prospectively, agroecosystems for the growth of crops provide the potential fertile, productive, and tropical environment which attracts infestation by weedy plant species that compete with the primary crop plants. Infestation by weed is a major biotic stress factor faced by pigeonpea that hampers the productivity of the crop. In the modern era with the development of chemicals the problem of weed infestation is dealt with armours called herbicides. The most widely utilized, post-emergent, broad-spectrum herbicide has an essential active ingredient called glyphosate. Glyphosate mechanistically inhibits a chloroplastic enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) by competitively interacting with the PEP binding site which hinders the shikimate pathway and the production of essential aromatic amino acids (Phe, Tyr, Trp) and other secondary metabolites in plants. Moreover, herbicide spray for weed management is lethal to both the primary crop and the weeds. Therefore, it is critical to develop herbicide-resistant crops for field purposes to reduce the associated yield and economic losses. In this study, the in-silico analysis drove the selection and validation of the point mutations in the conserved region of the EPSPS gene, which confers efficient herbicide resistance to mutated-CcEPSPS enzyme along with the retention of the normal enzyme function. An optimized in-silico validation of the target mutation before the development of the genome-edited resistant plant lines is a prerequisite for testing their efficacy as a proof of concept. We validated the combination of GATIPS mutation for its no-cost effect at the enzyme level via molecular dynamic (MD) simulation.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.

This research explored novel antidiabetic drugs from natural sources using the Ayurvedic Rasayana herb Ichnocarpus frutescens through invitro enzyme assay, kinetics study, and computational approaches. Invitro enzyme inhibition assay demonstrated the promising inhibitory activity of root extract against alpha-amylase (α-A) and alpha-glucosidase (α-G) enzyme with IC50 value 7.34 ± 0.22 mg/ml and 4.40 ± 0.25 mg/ml respectively. Enzyme kinetic study revealed the competitive inhibition of both proteins by Ichnocarpus frutescens extract. High-Resolution Liquid Chromatography Mass Spectrometer and Docking study revealed the better binding energy of phytoconstituents 23-Acetoxysoladulcidine, Atrovirinone, Bismurrayaquinone A, Lamprolobine, Zygadenine, and Gambiriin A3 than standard drug acarbose. Molecular modelling showed stable protein-ligands binding interaction during the 100 ns simulation. It revealed comparable Root Mean Square Deviation, Radius of Gyration, and Solvent Accessible Surface Area of these compounds with acarbose. The active site residues of both proteins remained stable and showed significantly less Root Mean Square Fluctuation. Molecular Mechanics with Generalised Bonn Surface Area analysis has illustrated the similar inhibitory activity of Zygadenine for α-A, 23-Acetoxysoladulcidine, and Gambiriin A3 for α-G protein, compared to the FDA-approved drug acarbose. Thus, the study suggested that the root of Ichnocarpus frutescens can be used as α-A and α-G inhibitors and be considered a compelling lead for the medication of type 2 diabetes.Communicated by Ramaswamy H. Sarma.

Erratum in J Biomol Struct Dyn. 2023 Sep 9;:1.

In our study, a series of novel 4-aminophenol benzamide-1,2,4-oxadiazole hybrid analogues have been designed and synthesized by condensing 4-hydroxyphenyl arylamides (3a-c) and 5-chloromethyl-3-aryl-1,2,4-oxadiazoles (6a-d). The structure of the synthesised compounds was verified by various spectroscopic techniques (1H NMR, 13C NMR, IR and LC-MS). All the prepared compounds were subjected to in silico and in vitro antiproliferative study against TNBC cell lines MDA-MB-468 and MDA-MB-231. The investigations revealed that compound 7k significantly promoted apoptosis against MDA-MB-468 and MDA-MB-231 cells with IC50 values of 22.31 µM and 26.27 µM, respectively. Compound 7k interacted with crucial active sites of MAPK and exhibited the highest docking score of -7.06 kcal/mol. Docking was validated with molecular dynamic studies with simulation for 100 ns, depicting various stable interactions with MAPK. Consequently, 7k forms stable H-Bonds and π-π stacking with amino acid residues along with π-cation. Our investigations reveal that the in vitro antiproliferative study of 7k was in good correlation with the in silico studies. Hence, 7k serves as a potential novel lead for the inhibition of TNBCs by downregulating MAPK P38.Communicated by Ramaswamy H. Sarma.

Mycobacterium tuberculosis (Mtb) is one of the major causes of death worldwide and there is a pressing need for the development of novel drug leads. The Imidazole Glycerol Phosphate Dehydratase (IGPD) of Mtb is one of the key enzymes in the histidine biosynthesis pathway and has been recognized as the potentially underexploited drug target for anti-tuberculosis treatment. In the present study, 6063 structurally diverse plant secondary metabolites (PSM) were screened for their efficiency in inhibiting the catalytic activity of IGPD through molecular docking. The top 150 PSMs with the lowest binding energy represent the chemical classes, including Tannins (34%), Flavonoid Glycosides (14%), Terpene Glycosides (10%), Steroid Lactones (9.3%), Flavonoids (6.6%), Steroidal Glycosides (4.6%), etc. Bismahanine, Ashwagandhanolide, and Daurisoline form stable IGPD-inhibitor complexes with binding free energies of -291.3 ± 16.5, -279.0 ± 25.0, and -279.8 ± 17.6 KJ/mol, respectively, as determined by molecular dynamics simulations. These PSM demonstrated strong H-bond interactions with the amino acid residues Ile279, Arg281, and Lys276 in the catalytic region of IGPD, as revealed by structural snapshots. On the basis of our findings, these three PSM could be considered as possible leads against IGPD and should be explored in vitro and in vivo.Communicated by Ramaswamy H. Sarma.

The research aims to envisage small molecule inhibitors targeting the C-X-C motif chemokine ligand 10 (CXCL10) of the JAK/STAT pathway. CXCL10 plays a significant role in inducing auto-immunity in vitiligo through JAK/STAT pathway. To accomplish the aim, structure-based virtual screening with fundamental search limits, e.g., molecular weight (MW ≤ 500 Da), hydrogen bond donor (HBD ≤ 5), hydrogen bond acceptor (HBA ≤ 10), and lipophilicity (logP ≤ 5) was used to screen investigational molecules from MCULE database. The SBVS-ligand hits were sifted through toxicity profiling followed by filtration through the Brain or IntestinaL EstimateD-Egg model to check the human intestinal abortion and blood-brain barrier permeation based on two physicochemical properties, including topological surface area and WLOGP. The BOILED-Egg filtered compounds were passed through drug-likeness features other than Pfizer's Lipinski rule of five, viz., Ghose filters, Muegge filters, Egan parameters, and Veber filters, followed by medicinal chemistry's pan assay interference structure and Brenk alert investigation. Chemical compounds that comply with the above ADME descriptors were docked with target protein CXCL10 via AutoDock Vina. The stability of the top two ligand hits was assessed through dynamics simulations of 100 ns and principal component analysis and compared with the reference drugs Baicalein and EGCG. Based on the findings of Gibbs free energy of binding, ADME profiling, medicinal chemistry attributes depiction, root-mean-square deviation, root-mean-square fluctuation, solvent accessible surface area, the free energy of solvation, the radius of gyration, and PCA, MCULE2726078782-0-2 was found better than potential reference drug Baicalein.Communicated by Ramaswamy H. Sarma.

Erratum in J Biomol Struct Dyn. 2023 Aug 8;:1.

Lung cancer is still the most frequent cause of cancer-related death, accounting for nearly two million cases yearly. As cancer is a multifactorial disease, developing novel molecular therapeutics that can simultaneously target multiple associated cellular processes has become necessary. Ion channels are diverse regulators of cancer-related processes such as abnormal proliferation, invasion, migration, tumor progression, inhibition of apoptosis, and chemoresistance. Among the various families of ion channels, the transient receptor potential canonical channel family steps out in the context of lung cancer, as several members have been postulated as prognostic markers for lung cancer. Phytochemicals have been found to have health benefits in the treatment of a variety of diseases and disorders. Among phytochemicals, monoterpenes are effective in treating both the early and late stages of cancer. The molecular docking interaction analysis was conducted to evaluate the binding potential of selected monoterpenes with TRPC3, TRPC4, TRPC5, and TRPC6 involved in different phases of carcinogenesis. Amongst the selected monoterpenes, thymoquinone exhibited the highest binding energy of -6.7 kcal/mol against the TRPC4 channel, and all amino acid binding residues were similar to those of the known inhibitor for TRPC4. In addition, molecular-dynamic simulation results parameters, such as RMSD, RMSF, and Rg, indicated that thymoquinone did not impact the protein compactness and exhibited stability during the interaction. The average interaction energy between thymoquinone and TRPC4 protein was -26.85 kJ/mol. In-silico Drug-likeness and ADMET profiling indicated that thymoquinone is a druggable candidate with minimal toxicity. We propose further investigation and evaluation of thymoquinone for lead optimization and drug development.Communicated by Ramaswamy H. Sarma.

Antimicrobial resistance is a major global threat. In an attempt to discover new compounds with improved efficiency and to overcome drug resistance, a library of 3960 compounds was designed as conformationally rigid analogues of oxiconazole with 2H-chroman-4-one, azole and substituted phenyl fragments. The antifungal and antibacterial activity of the compounds was evaluated using molecular docking studies in the active site of six fungal and four bacterial proteins to establish the binding affinity of the designed ligands. In-silico ADME and Lipinski's rule were used to establish the drug-likeness properties of the compounds. This study revealed that all the designed compounds had a high binding affinity with the target proteins and formed H-bond and π-π interactions. The identified hits have been subjected to molecular dynamics simulations to study protein-ligand complex stability. This study has led to the identification of important compounds that can be developed further as therapeutic agents against pathogenic fungi and bacteria.Communicated by Ramaswamy H. Sarma.

The two most serious global health challenges confronting human society today are autoimmune disorders (AIDs) and neurological diseases (NDs), both of which shorten people's lives and worsen the situation. Despite their extensive impact, statistics show that AIDs is associated with a higher risk of ND. Circular RNAs (circRNAs) are critical in several illnesses and disorders, especially AID and ND. Therefore, the present study focused on understanding the underlying causes of the pathophysiology of diseases such as AID and ND through in silico-based research. In order to determine how circRNAs are related to various disease pathways, this study examined the gene expression data sets for Rheumatoid arthritis (RA), Alzheimer's disease (AD), and atrial fibrillation (AF). Our study identified and analyzed two circRNAs, their respective host genes (DHTKD1 and RAN) and their related miRNAs, which could serve as potential markers for treating disorders like myotonic dystrophy type 1, spinocerebellar ataxia and fragile X syndrome. Further, the circRNA-derived peptide was identified and analysed with the molecular dynamics simulation (MDS) followed by a principal component (PC) based free energy landscape (FEL) profile. The computational results obtained here provide a basis for the development of therapeutics against AD, RA and AF. Moreover, further functional studies are needed to validate their role in disease aetiology and to provide a detailed understanding of their association with AID and ND.Communicated by Ramaswamy H. Sarma.