Machine learning ensembles, neural network, hybrid and sparse regression approaches for weather based rainfed cotton yield forecast.

Cotton is a major economic crop predominantly cultivated under rainfed situations. The accurate prediction of cotton yield invariably helps farmers, industries, and policy makers. The final cotton yield is mostly determined by the weather patterns that prevail during the crop growing phase. Crop yield prediction with greater accuracy is possible due to the development of innovative technologies which analyses the bigdata with its high-performance computing abilities. Machine learning technologies can make yield prediction reasonable and faster and with greater flexibility than process based complex crop simulation models. The present study demonstrates the usability of ML algorithms for yield forecasting and facilitates the comparison of different models. The cotton yield was simulated by employing the weekly weather indices as inputs and the model performance was assessed by nRMSE, MAPE and EF values. Results show that stacked generalised ensemble model and artificial neural networks predicted the cotton yield with lower nRMSE, MAPE and higher efficiency compared to other models. Variable importance studies in LASSO and ENET model found minimum temperature and relative humidity as the main determinates of cotton yield in all districts. The models were ranked based these performance metrics in the order of Stacked generalised ensemble > ANN > PCA ANN > SMLR ANN > LASSO> ENET > SVM > PCA SMLR > SMLR SVM > SMLR. This study shows that stacked generalised ensembling and ANN method can be used for reliable yield forecasting at district or county level and helps stakeholders in timely decision-making.

Pharmacophore-based virtual screening of ZINC database, molecular modeling and designing new derivatives as potential HDAC6 inhibitors.

To date, many HDAC6 inhibitors have been identified and developed but none is clinically approved as of now. Through this study, we aim to obtain novel HDAC6 selective inhibitors and provide new insights into the detailed structural design of potential HDAC6 inhibitors. A HypoGen-based 3D QSAR HDAC6 pharmacophore was built and used as a query model to screen approximately 8 million ZINC database compounds. First, the ZINC Database was filtered using ADMET, followed by pharmacophore-based library screening. Using fit value and estimated activity cutoffs, a final set of 54 ZINC hits was obtained that were further investigated using molecular docking with the crystal structure of human histone deacetylase 6 catalytic domain 2 in complex with Trichostatin A (PDB ID: 5EDU). Through detailed in silico screening of the ZINC database, we shortlisted three hits as the lead molecules for designing novel HDAC6 inhibitors with better efficacy. Docking with 5EDU, followed by ADMET and TOPKAT analysis of modified ZINC hits provided 9 novel potential HDAC6 inhibitors that possess better docking scores and 2D interactions as compared to the control ZINC hit molecules. Finally, a 50 ns MD analysis run followed by Protein-Ligand Interaction Energy (PLIE) analysis of the top scored hits provided a novel molecule N1 that showed promisingly similar results to that of Ricolinostat (a known HDAC6 inhibitor). The comparable result of the designed hits to established HDAC6 inhibitors suggests that these compounds might prove to be successful HDAC6 inhibitors in future. Designed novel hits that might act as good HDAC6 inhibitors derived from ZINC database using combined molecular docking and modeling approaches.

Bactericidal activity of esculetin is associated with impaired cell wall synthesis by targeting glutamate racemase of Neisseria gonorrhoeae.

Neisseria gonorrhoeae (NG), the causative organism of gonorrhea, has been classified by the World Health Organization as 'Priority' two organism owing to its increased resistance to antibiotics and even failure of recommended dual therapy with ceftriaxone and azithromycin. As a result, the general and reproductive health of infected individuals is severely compromised. The imminent public health catastrophe of antimicrobial-resistant gonococci cannot be understated, as t he of severe complications and sequelae of infection are not only increasing but their treatment has also become more expensive. Tenacious attempts are underway to discover novel drug targets as well as new drugs to fight against NG. Therefore, a considerable number of phytochemicals have been tested for their remedial intercession via targeting bacterial proteins. The MurI gene encodes for an enzyme called glutamate racemase (MurI) that is primarily involved in peptidoglycan (PG) biosynthesis and is specific to the bacterial kingdom and hence can be exploited as a potential drug target for the treatment of bacterial diseases. Accordingly, diverse families of phytochemicals were screened in silico for their binding affinity with N. Gonorrhoeae MurI (NG-MurI) protein. Esculetin, one of the shortlisted compounds, was evaluated for its functional, structural, and anti-bacterial activity. Treatment with esculetin resulted in growth inhibition, cell wall damage, and altered permeability as revealed by fluorescence and electron microscopy. Furthermore, esculetin inhibited the racemization activity of recombinant, purified NG-MurI protein, one of the enzymes required for peptidoglycan biosynthesis. Our results suggest that esculetin could be further explored as a lead compound for developing new drug molecules against multidrug-resistant strains.

Characterizing patterns of seasonal drought stress for use in common bean breeding in East Africa under present and future climates.

Common bean (Phaseolus vulgaris L.) is the second most important source of dietary protein and the third most important source of calories in Africa, especially for the poor. In East Africa, drought is an important constraint to bean production. Therefore, breeding programs in East Africa have been trying to develop drought resistant varieties of common bean. To do this, breeders need information about seasonal drought stress patterns including their onset, intensity, and duration in the target area of the breeding program, so that they can mimic this pattern during field trials. Using the Decision Support for Agrotechnology Transfer (DSSAT) v4.7 model together with historical and future (Coupled Model Inter-comparison Project 6, CMIP6) climate data, this study categorized Ethiopia, Tanzania, and Uganda into different target population of environments (TPEs) based on historical and future seasonal drought stress patterns. We find that stress-free conditions generally dominate across the three countries under historical conditions (50-80% frequency). These conditions are projected to increase in frequency in Ethiopia by 2-10% but the converse is true for Tanzania (2-8% reduction) and Uganda (17-20% reduction) by 2050 depending on the Shared Socioeconomic Pathway (SSP). Accordingly, by 2050, terminal drought stresses of various intensities (moderate, severe, extreme) are prevalent in 34% of Uganda, around a quarter of Ethiopia, and 40% of the bean growing environments in Tanzania. The TPEs identified in each country serve as a basis for prioritizing breeding activities in national programs. However, to optimize resource use in international breeding programs to develop genotypes that are resilient to future projected stress patterns, we argue that common bean breeding programs should focus primarily on identifying genotypes with tolerance to severe terminal drought, with co-benefits in relation to adaptation to moderate and extreme terminal drought. Little to no emphasis on heat stress is warranted by 2050s.

Computational studies to identify the common type-I and type-II inhibitors against the CDK8 enzyme.

In this study, multicomplex-based pharmacophore modeling was conducted on the structural proteome of the two states of CDK8 protein, that is, DMG-in and out. Three pharmacophores having six, five, and four features were selected as the representative models to conduct the virtual screening process using the prepared drug-like natural product database. The screened candidates were subjected to molecular docking studies on DMG-in (5XS2) and out (4F6U) conformation of the CDK8 protein. Subsequently, the common four docked candidates of 5XS2 and 4F6U were selected to perform the molecular dynamics simulation studies. Apart from one of the complexes of DMG-in (5XS2-UNPD163102), all other complexes displayed stable dynamic behavior. The interaction and stability studies of the docked complexes were compared with the references selected from the two conformations (DMG-in and out) of the protein. The current work leads to the identification of three common DMG-in and out hits with diverse scaffolds which can be employed as the initial leads for the design of the novel CDK8 inhibitors.

Integrative multiomics and in silico analysis revealed the role of ARHGEF1 and its screened antagonist in mild and severe COVID-19 patients.

COVID-19 is a sneaking deadly disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid increase in the number of infected patients worldwide enhances the exigency for medicines. However, precise therapeutic drugs are not available for COVID-19; thus, exhaustive research is critically required to unscramble the pathogenic tools and probable therapeutic targets for the development of effective therapy. This study utilizes a chemogenomics strategy, including computational tools for the identification of viral-associated differentially expressed genes (DEGs), and molecular docking of potential chemical compounds available in antiviral, anticancer, and natural product-based libraries against these DEGs. We scrutinized the messenger RNA expression profile of SARS-CoV-2 patients, publicly available on the National Center for Biotechnology Information-Gene Expression Omnibus database, stratified them into different groups based on the severity of infection, superseded by identification of overlapping mild and severe infectious (MSI)-DEGs. The profoundly expressed MSI-DEGs were then subjected to trait-linked weighted co-expression network construction and hub module detection. The hub module MSI-DEGs were then exposed to enrichment (gene ontology + pathway) and protein-protein interaction network analyses where Rho guanine nucleotide exchange factor 1 (ARHGEF1) gene conjectured in all groups and could be a probable target of therapy. Finally, we used the molecular docking and molecular dynamics method to identify inherent hits against the ARHGEF1 gene from antiviral, anticancer, and natural product-based libraries. Although the study has an identified significant association of the ARHGEF1 gene in COVID19; and probable compounds targeting it, using in silico methods, these targets need to be validated by both in vitro and in vivo methods to effectively determine their therapeutic efficacy against the devastating virus.

Reckoning apigenin and kaempferol as a potential multi-targeted inhibitor of EGFR/HER2-MEK pathway of metastatic colorectal cancer identified using rigorous computational workflow.

In the past two decades, the treatment of metastatic colorectal cancer (mCRC) has been revolutionized as multiple cytotoxic, biological, and targeted drugs are being approved. Unfortunately, tumors treated with single targeted agents or therapeutics usually develop resistance. According to pathway-oriented screens, mCRC cells evade EGFR inhibition by HER2 amplification and/or activating Kras-MEK downstream signaling. Therefore, treating mCRC patients with dual EGFR/HER2 inhibitors, MEK inhibitors, or the combination of the two drugs envisaged to prevent the resistance development which eventually improves the overall survival rate. In the present study, we aimed to screen potential phytochemical lead compounds that could multi-target EGFR, HER2, and MEK1 (Mitogen-activated protein kinase kinase) using a computer-aided drug design approach that includes molecular docking, endpoint binding free energy calculation using MM-GBSA, ADMET, and molecular dynamics (MD) simulations. Docking studies revealed that, unlike all other ligands, apigenin and kaempferol exhibit the highest docking score against all three targets. Details of ADMET analysis, MM/GBSA, and MD simulations helped us to conclusively determine apigenin and kaempferol as potentially an inhibitor of EGFR, HER2, and MEK1 apigenin and kaempferol against mCRC at a systemic level. Additionally, both apigenin and kaempferol elicited antiangiogenic properties in a dose-dependent manner. Collectively, these findings provide the rationale for drug development aimed at preventing CRC rather than intercepting resistance.

Impacts, Tolerance, Adaptation, and Mitigation of Heat Stress on Wheat under Changing Climates.

Heat stress (HS) is one of the major abiotic stresses affecting the production and quality of wheat. Rising temperatures are particularly threatening to wheat production. A detailed overview of morpho-physio-biochemical responses of wheat to HS is critical to identify various tolerance mechanisms and their use in identifying strategies to safeguard wheat production under changing climates. The development of thermotolerant wheat cultivars using conventional or molecular breeding and transgenic approaches is promising. Over the last decade, different omics approaches have revolutionized the way plant breeders and biotechnologists investigate underlying stress tolerance mechanisms and cellular homeostasis. Therefore, developing genomics, transcriptomics, proteomics, and metabolomics data sets and a deeper understanding of HS tolerance mechanisms of different wheat cultivars are needed. The most reliable method to improve plant resilience to HS must include agronomic management strategies, such as the adoption of climate-smart cultivation practices and use of osmoprotectants and cultured soil microbes. However, looking at the complex nature of HS, the adoption of a holistic approach integrating outcomes of breeding, physiological, agronomical, and biotechnological options is required. Our review aims to provide insights concerning morpho-physiological and molecular impacts, tolerance mechanisms, and adaptation strategies of HS in wheat. This review will help scientific communities in the identification, development, and promotion of thermotolerant wheat cultivars and management strategies to minimize negative impacts of HS.

Smallholder farmer perceptions about the impact of COVID-19 on agriculture and livelihoods in Senegal.

CONTEXT: The global COVID-19 pandemic has produced a variety of unanticipated shocks to farming and socio-economic systems around the world. In case of Senegal, the country was already facing number of challenges at the inception of the pandemic, including high rates of poverty, prevalence of food insecurity, combined with other biophysical and socioeconomic challenges faced generally in Sub-Saharan Africa. OBJECTIVE: To understand farmer perceptions of the potential impacts of COVID-19 on agricultural systems and social well-being of smallholder farmers in Senegal. Particular attention was given to potential vulnerabilities and resilience in the targeted farming systems. METHODS: A survey was developed to better understand smallholder farmer perceptions regarding the anticipated impacts of COVID-19 on their agriculture practices and social well-being. The survey was administered (between June 5 and June 20) with smallholder farmers (n = 872) in 14 regions covering all agroecological zones. Variables of interest included perceptions of potential impact on farming systems, agricultural productivity, communities, economics, markets, labor, gendered division of labor, food security, and community well-being. RESULTS AND CONCLUSIONS: Across the three farming systems examined (cropping, livestock, and horticulture) significant majorities expressed concerns related to access to inputs, ability to plant (cropping, horticulture), reduction of yields (cropping, horticulture), ability to feed livestock, ability to sell livestock, and the ability to hire labor (horticulture). The majority of respondents also expressed concern that COVID-19 would make it more difficult to get enough food on a regular basis for their household (82.5%); that the markets where they purchase food will either be closed or significantly disrupted (79.5%); that the price of food would increase (73.5%); and the market where they sell their produce/livestock will be either closed or significantly disrupted (73.2%). SIGNIFICANCE: Anticipated impacts of COVID-19 on agriculture will be felt on both the biophysical aspects such as production and access to inputs and socioeconomic aspects such as access to labor, markets, or rapid shifts in demand. Results support the need to use farming systems approach to gather perceived and actual impacts of COVID-19 and warrants a more in-depth examination of agronomic and biophysical issues as well as the impact on the livelihoods and social well-being of families at community and household levels. Further examination will help identify the characteristics that strengthen smallholder farming systems resilience to adjust to anticipated and unanticipated shocks, such as COVID-19, to decrease the negative impacts and increase the rate of recovery.

Snx10 and PIKfyve are required for lysosome formation in osteoclasts.

Bone resorption and organelle homeostasis in osteoclasts require specialized intracellular trafficking. Sorting nexin 10 (Snx10) is a member of the sorting nexin family of proteins that plays crucial roles in cargo sorting in the endosomal pathway by its binding to phosphoinositide(3)phosphate (PI3P) localized in early endosomes. We and others have shown previously that the gene encoding sorting Snx10 is required for osteoclast morphogenesis and function, as osteoclasts from humans and mice lacking functional Snx10 are dysfunctional. To better understand the role and mechanisms by which Snx10 regulates vesicular transport, the aim of the present work was to study PIKfyve, another PI3P-binding protein, which phosphorylates PI3P to PI(3,5)P2. PI(3,5)P2 is known to be required for endosome/lysosome maturation, and the inhibition of PIKfyve causes endosome enlargement. Overexpression of Snx10 also induces accumulation of early endosomes suggesting that both Snx10 and PIKfyve are required for normal endosome/lysosome transition. Apilimod is a small molecule with specific, nanomolar inhibitory activity on PIKfyve but only in the presence of key osteoclast factors CLCN7, OSTM1, and Snx10. This observation suggests that apilimod's inhibitory effects are mediated by endosome/lysosome disruption. Here we show that both Snx10 and PIKfyve colocalize to early endosomes in osteoclasts and coimmunoprecipitate in vesicle fractions. Treatment with 10 nM apilimod or genetic deletion of PIKfyve in cells resulted in the accumulation of early endosomes, and in the inhibition of osteoclast differentiation, lysosome formation, and secretion of TRAP from differentiated osteoclasts. Snx10 and PIKfyve also colocalized in gastric zymogenic cells, another cell type impacted by Snx10 mutations. Apilimod-specific inhibition of PIKfyve required Snx10 expression, as it did not inhibit lysosome biogenesis in Snx10-deficient osteoclasts. These findings suggest that Snx10 and PIKfyve are involved in the regulation of endosome/lysosome homeostasis via the synthesis of PI(3,5)P2 and may point to a new strategy to prevent bone loss.

Circulating PAMM, a novel antioxidant and anti-inflammatory protein, is elevated in acute SCI.

BACKGROUND: Peroxiredoxin activated in M-CSF stimulated monocytes (PAMM) is a novel protein produced by adipocytes with putative redox regulatory and anti-inflammatory properties. Because acute spinal cord injury (SCI) is associated with oxidative stress and neuroinflammation and because PAMM can be detected in systemic circulation, we hypothesized that acute neuro-trauma might induce changes in circulating PAMM expression. Specifically, we hypothesized that PAMM levels might vary based on the presence or absence of acute, traumatic SCI. We therefore investigated circulating PAMM levels in adults with and without acute traumatic SCI. METHODS: We studied 105 men and women (54 with SCI and 51 without SCI). Participants with SCI were admitted for acute rehabilitation within 1 month after injury. Serum samples were obtained during hospitalization and stored at - 80 °C until batch analysis. Total PAMM was quantified by ELISA assay (MyBiosource, Cat. No: MBS9327247) with a detection limit of 0.25 ng/ml. Separate multivariate models including age, BMI, and injury severity were assessed to determine significant clinical predictors of change in PAMM levels. RESULTS: When adjusting for BMI, age, and gender, mean change in PAMM levels were greatest in participants with motor complete SCI compared to able-bodied (1.65 ng/ml versus 0.94 ng/ml, p = 0.003). This model explained 26% of the variation in change in circulating PAMM levels. CONCLUSIONS: Our results suggest that PAMM may be a novel biomarker of neurological injury or of native anti-inflammatory responses to neurological injury. More work is needed to establish the role of PAMM and other adipocyte-derived factors in the acute response to neurotrauma.

New simple molecular fluorescent probes for rapid and highly selective sensing of hydrazine by aggregate-induced emission.

With an aim towards the design of efficient and straightforward fluorescent probes for hydrazine, the synthesis of (2-acetoxyaryl) methylene diacetate derivatives (1-4) was carried out by reacting substituted aromatic α-hydroxy aldehydes with acetyl chloride and sodium acetate in excellent yields. As a preliminary investigation, the ability of probe 1 was examined for the detection of substituted aliphatic and aromatic amines, amino acids, and other ions in Britton-Robinson buffer solution (50 mM, water/ethanol v/v of 99/1 at pH 7.4). Probe 1 selectively exhibited an intense blue fluorescence with hydrazine in less than 2 minutes, whereas light green or no fluorescence was noticed with substituted amines and amino acids. Among all the probes employed (1-4) in the present study, probes 1 and 2 were found efficient towards the rapid detection of hydrazine. Furthermore, the fluorescence sensing ability of probes 1 and 2 was tested not only under varying pH conditions but also by varying water-fraction from 0-99%. Moreover, the detection limits of hydrazine using 1 and 2 were found as 8.4 and 8.7 ppb, respectively, which is less than the acceptable limit as per the standards of the US Environment Protection Agency. In this contribution, the probes 1 and 2 demonstrate rapid, selective, sensitive, and ratiometric detection of highly toxic hydrazine by OFF-ON fluorescence switch in water samples as well as living cells.

Identification of natural compound inhibitors against PfDXR: A hybrid structure-based molecular modeling approach and molecular dynamics simulation studies.

In the present contribution, multicomplex-based pharmacophore studies were carried out on the structural proteome of Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase. Among the constructed models, a representative model with complementary features, accountable for the inhibition was used as a primary filter for the screening of database molecules. Auxiliary evaluations of the screened molecules were performed via drug-likeness and molecular docking studies. Subsequently, the stability of the docked inhibitors was envisioned by molecular dynamics simulations, principle component analysis, and molecular mechanics-Poisson-Boltzmann surface area-based free binding energy calculations. The stability assessment of the hits was done by comparing with the reference (beta-substituted fosmidomycin analog, LC5) to prioritize more potent candidates. All the complexes showed stable dynamic behavior while three of them displayed higher binding free energy compared with the reference. The work resulted in the identification of the compounds with diverse scaffolds, which could be used as initial leads for the design of novel PfDXR inhibitors.

FKBP12: A partner of Snx10 required for vesicular trafficking in osteoclasts.

Osteoclasts employ highly specialized intracellular trafficking controls for bone resorption and organelle homeostasis. The sorting nexin Snx10 is a (Phosphatidylinositol 3-phosphate) PI3P-binding protein, which localizes to osteoclast early endosomes. Osteoclasts from humans and mice lacking functional Snx10 are severely dysfunctional. They show marked impairments in endocytosis, extracellular acidification, ruffled border formation, and bone resorption, suggesting that Snx10 regulates membrane trafficking. To better understand how SNx10 regulates vesicular formation and trafficking in osteoclasts, we set out on a search for Snx10 partners. We performed a yeast two-hybrid screening and identified FKBP12. FKBP12 is expressed in receptor activator of nuclear factor kB ligand-stimulated RAW264.7 monocytes, coimmunoprecipitates with Snx10, and colocalizes with Snx10 in osteoclasts. We also found that FKBP12, Snx10, and early endosome antigen 1 (EEA1) are present in the same subcellular fractions obtained by centrifugation in sucrose gradients, which confirms localization of FKBP12 to early endosomes. Taken together, these results indicate that Snx10 and FKBP12 are partners and suggest that Snx10 and FKBP12 are involved in the regulation of endosome/lysosome homeostasis via the synthesis. These findings may suggest novel therapeutic approaches to control bone loss by targeting essential steps in osteoclast membrane trafficking.

Ethambutol targets the glutamate racemase of Mycobacterium tuberculosis-an enzyme involved in peptidoglycan biosynthesis.

Increasing drug resistance in pathogens including Mycobacterium tuberculosis (MTB) has been ascribed to mutations in the known target genes. However, many of these drugs have multiple targets; some of which have not been identified so far. Understanding the mechanism of action of these drugs holds a great promise in better management of disease especially by drug-resistant strains. In this study, we report glutamate racemase (MurI), a crucial enzyme of phase I peptidoglycan (PG) biosynthesis pathway of MTB, as an additional target of ethambutol (EMB). The effect on EMB on the MurI protein at structural and functional level was studied using different spectroscopic, biochemical, and insilico approaches. Spectroscopic analysis revealed that EMB-modified protein undergoes conformational alterations. Furthermore, in vitro racemization studies of the MurI protein suggest that EMB decreases its functional activity. Docking studies revealed that EMB interacts with most of the active residues at the binding site and blocks the binding pocket. Overall, data suggests that EMB, a primary drug used for the treatment of tuberculosis (TB), acts as a competitive inhibitor of substrate for binding to mycobacterial MurI protein. The study also points out to our lacunae in understanding the site and mechanism of action of existing drugs. Furthermore, glutamate racemase is a conserved protein of the bacterial kingdom; therefore, ethambutol could be a promising candidate as a broad-spectrum antibiotic for many other bacterial diseases.

In search of the representative pharmacophore hypotheses of the enzymatic proteome of Plasmodium falciparum: a multicomplex-based approach.

Drug resistance has made malaria an untreatable disease and therefore intensified the need for the development of new drugs and the identification of potential drug targets. In this pursuit, in silico efforts made in the past have not shown significant responses. Therefore, in the present work, the multicomplex-based pharmacophore modeling approach was employed to construct the pharmacophores of the 16 selected Plasmodium falciparum (Pf) targets. All the constructed hypotheses (153) were screened against a focused dataset made up of experimental actives of the chosen targets (3705 inhibitors). The rationale was to check the affinity of the inhibitors for the off-targets. Subsequently, the constructed hypotheses from each target were pooled based on the feature types and the pooled-hypotheses were then clustered to offer an insight about the pharmacophore similarity. Tanimoto similarity index was also calculated to look for the similarity among the inhibitors belonging to different Pf targets. Overall, the work was accomplished to bid healthier perceptive of the pharmacophore-based virtual screening and abet in providing guiding principles for the construction of stringent pharmacophores that can be employed for the screening.

Identification of PfENR inhibitors: A hybrid structure-based approach in conjunction with molecular dynamics simulations.

In the current study, we have constructed receptor-based pharmacophore models by exploiting the Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR) structural proteome. The derived models were subjected to a series of validation procedures to list the representative hypotheses that can be used for the screening of the Drug-like Diverse Database. A set of 739 molecules was retrieved and analyzed for the adsorption, distribution, metabolism, excretion and toxicity (ADMET) and drug-likeness attributes. The filtered drug-like molecules (64) were then subjected to molecular docking and HYDE assessment studies. The hybrid structure-based approach yielded 4 molecules, UKR1308259, ENA1096786, UKR403454, and ASI51224, as PfENR inhibitors. The stability of these inhibitors was assessed using molecular mechanics-generalized born surface area approach-based free binding energy calculations and molecular dynamics simulations. Molecular mechanics-generalized born surface area calculations and molecular dynamics simulations showed that UKR1308259, ENA1096786, and ASI51224 were more potent PfENR inhibitors. The rationale behind the current work was to identify orally available inhibitor molecules with diverse scaffolds that could serve as initial leads for the drug design against PfENR.

Exploration of Mycobacterium tuberculosis structural proteome: An in-silico approach.

Pharmacophore approaches are of central contour in drug discovery. However, the dependence of ligand-based pharmacophore model on appropriate training set molecules and typical use of apo-protein or single protein-ligand complex for the construction of structure-based pharmacophore models might skip some vital information. Therefore, multiple-complex based approach was employed for the construction of pharmacophore models of the Mycobacterium structural proteome. Moreover, the strategy of clustering of common pharmacophore hypotheses was made to gain an insight about the pharmacophore-similarity across the protein classes and share of features among the inhibitors. Rationale behind the present work was to present the scenario of virtual screening and guiding principle for designing efficient inhibitor by taking into account the available pharmacophoric space.

Probing the opportunities for designing anthelmintic leads by sub-structural topology-based QSAR modelling.

A quantitative structure-activity (QSAR) model has been developed for enriched tubulin inhibitors, which were retrieved from sequence similarity searches and applicability domain analysis. Using partial least square (PLS) method and leave-one-out (LOO) validation approach, the model was generated with the correlation statistics of [Formula: see text] and [Formula: see text] of 0.68 and 0.69, respectively. The present study indicates that topological descriptors, viz. BIC, CH_3_C, IC, JX and Kappa_2 correlate well with biological activity. ADME and toxicity (or ADME/T) assessment showed that out of 260 molecules, 255 molecules successfully passed the ADME/T assessment test, wherein the drug-likeness attributes were exhibited. These results showed that topological indices and the colchicine binding domain directly influence the aetiology of helminthic infections. Further, we anticipate that our model can be applied for guiding and designing potential anthelmintic inhibitors.