Balanced spatiotemporal arrangements of histone H3 and H4 posttranslational modifications are necessary for meiotic prophase I chromosome organization.

Dynamic nuclear architecture and chromatin organizations are the key features of the mid-prophase I in mammalian meiosis. The chromatin undergoes major changes, including meiosis-specific spatiotemporal arrangements and remodeling, the establishment of chromatin loop-axis structure, pairing, and crossing over between homologous chromosomes, any deficiencies in these events may induce genome instability, subsequently leading to failure to produce gametes and infertility. Despite the significance of chromatin structure, little is known about the location of chromatin marks and the necessity of their balance during meiosis prophase I. Here, we show a thorough cytological study of the surface-spread meiotic chromosomes of mouse spermatocytes for H3K9,14,18,23,27,36, H4K12,16 acetylation, and H3K4,9,27,36 methylation. Active acetylation and methylation marks on H3 and H4, such as H3K9ac, H3K14ac, H3K18ac, H3K36ac, H3K56ac, H4K12ac, H4K16ac, and H3K36me3 exhibited pan-nuclear localization away from heterochromatin. In comparison, repressive marks like H3K9me3 and H3K27me3 are localized to heterochromatin. Further, taking advantage of the delivery of small-molecule chemical inhibitors methotrexate (heterochromatin enhancer), heterochromatin inhibitor, anacardic acid (histone acetyltransferase inhibitor), trichostatin A (histone deacetylase inhibitor), IOX1 (JmjC demethylases inhibitor), and AZ505 (methyltransferase inhibitor) in seminiferous tubules through the rete testis route, revealed that alteration in histone modifications enhanced the centromere mislocalization, chromosome breakage, altered meiotic recombination and reduced sperm count. Specifically, IOX1 and AZ505 treatment shows severe meiotic phenotypes, including altering chromosome axis length and chromatin loop size via transcriptional regulation of meiosis-specific genes. Our findings highlight the importance of balanced chromatin modifications in meiotic prophase I chromosome organization and instability.

Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?

Bacterial resistance to antibiotics has been long recognized as a priority to address for human health. Among all micro-organisms, the so-called multi-drug resistant (MDR) bacteria, which are resistant to most, if not all drugs in our current arsenal, are particularly worrisome. The World Health Organization has prioritized the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) pathogens, which include four Gram-negative bacterial species. In these bacteria, active extrusion of antimicrobial compounds out of the cell by means of 'molecular guns' known as efflux pumps is a main determinant of MDR phenotypes. The resistance-nodulation-cell division (RND) superfamily of efflux pumps connecting the inner and outer membrane in Gram-negative bacteria is crucial to the onset of MDR and virulence, as well as biofilm formation. Thus, understanding the molecular basis of the interaction of antibiotics and inhibitors with these pumps is key to the design of more effective therapeutics. With the aim to contribute to this challenge, and complement and inspire experimental research, in silico studies on RND efflux pumps have flourished in recent decades. Here, we review a selection of such investigations addressing the main determinants behind the polyspecificity of these pumps, the mechanisms of substrate recognition, transport and inhibition, as well as the relevance of their assembly for proper functioning, and the role of protein-lipid interactions. The journey will end with a perspective on the role of computer simulations in addressing the challenges posed by these beautifully complex machineries and in supporting the fight against the spread of MDR bacteria.

Through-Bond-Driven Through-Space Interactions in a Fullerene C60 Noncovalent Dyad: An Unusual Strong Binding between Spherical and Planar π Electron Clouds and Culmination of Dyadic Fractals.

Hydrogen-bond-induced π-depletion as a criterion for π-stacking, a configurationally unique noncovalent strategy enabled an unconventional strong binding between the spherical N-fulleropyrrolidine (NFP) and the planar distributions of π electron clouds of three substituted pybates to form noncovalent fulleropyrrolidino-4-(pyrenyl) butanoate dyads of large computed interaction energies, varying between 37.49 and 44.93 kcal/mol. The geometrical distortion/bending of the alkyl tail of pybate in the noncovalent dyad was experimentally corroborated via UV-vis absorption spectroscopy, which translated into spectral broadening along with pronounced shifts in the n-π* transitions of the oxy-substituted pyrene in different solvents, ensuring through-bond interactions. Facile electron transfer through H-bond influenced the dynamic dispersive forces to be active, revealing the supremacy of through-bond over through-space interactions. The analyses of intermolecular forces using an absolutely localized molecular orbital-based energy decomposition analysis (ALMO-EDA) scheme revealed intricate insights into the intermolecular interactions and characteristic charge transfer; the dominance of forward electron transfer (pybate to NFP) over the reverse in offering stabilization was noted. Charge transfer was investigated further from natural bond orbital (NBO) and absolutely localized molecular orbital-based charge-transfer analysis (ALMO-CTA) methods, establishing the supremacy of donor-to-acceptor electron transfer over the reverse (acceptor-to-donor) one. The characteristic self-assembly of the noncovalent dyad in suitable solvents led to the formation of fractal networks via reaction-limited cluster aggregation with a fractal dimension of 2.37. Adoption of constrained molecular dynamics simulations indicated probable wrapping of pybates around NFP, leading to fractal-like assembly.

Healthcare performance management using integrated FUCOM-MARCOS approach: The case of India.

AIMS: The goal of this research is to propose a simpler and more efficient model for evaluating healthcare establishments (HCEs). With this motivation, this study aims to discover key performance indicators (KPIs) that affect HCE performance, present a ranking model for KPIs in Indian HCEs, and evaluate Indian HCEs using the identified and prioritised KPIs. MATERIAL AND METHODS: Through extensive literature review and expert opinions, this research identifies the various KPIs in HCEs, classifies them into six main categories, and prioritises them using the full consistency method (FUCOM). Further, well-known HCEs across northern India were evaluated and ranked using Measurement Alternatives and Ranking according to Compromise Solution. RESULTS: The 'technology adoption related indicators' is found as the most important main KPIs, whereas 'adequate number of hospital beds and bathrooms (IE5)' as the most dominating sub-category KPIs. Also, amongst the 20 evaluated Indian HCEs 'healthcare establishment-1 (HCE1)' was found to be the best performing HCE while 'healthcare establishment-12 (HCE12)' was found to be the worst-performing HCE. The stability and consistency of the results are ascertained by performing sensitivity analysis and comparing the results with other existing methodologies. CONCLUSION: The findings of this study are quite important for HCEs management to fully comprehend the key areas to improve upon so that managers can improve medical standards in a targeted manner. The developed prioritisation model and methodology shown in this paper will help and motivate managers and intellectuals of HCEs to evaluate and improve the HCE's performance.

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.

Prioritization of natural compounds against mycobacterium tuberculosis 3-dehydroquinate dehydratase: A combined in-silico and in-vitro study.

Enormous efforts have been endeavored to develop inhibitors against the potential therapeutic target, mycobacterium tuberculosis 3-dehydroquinate dehydratase (MtbDHQase) to combat resistance. Over a dozen of small molecules have been crystallized to characterize the structural basis of the inhibition. However, the studies accomplished so far, have not incorporated all the essential interactions of these complexes simultaneously, to identify the novel inhibitors. Therefore, an attempt was made to construct the pharmacophore models and identify the essential features that can be employed to prioritize the molecules against this target. Based on validation and expertise, we have identified such complimentary features from the natural compounds that can be used as initial hits. Subsequently, these hits were tested for their inhibitory roles in reducing the mycobacterium tuberculosis (Mtb) culture growth. Moreover, the docking simulations were performed to seek the possible interactions accountable for the activity of these candidates against MtbDHQase.

Efficiently functionalized oxacalix[4]arenes: Synthesis, characterization and exploration of their biological profile as novel HDAC inhibitors.

A series of novel substituted oxacalix[4]arene has been synthesized and explored for their biological profile by evaluating anticancer, antifungal and antibacterial properties. The derivatives have been characterized by various spectroscopic techniques such as IR, (1)H NMR, (13)C NMR and Mass spectrometry. Many compounds showed strong inhibition (MIC) in the range of ∼0-50 µM with interesting cytotoxic activities against Hela cells in particular. The compounds were theoretically evaluated by docking studies as potential histone deacetylase inhibitors (HDACi). The study indicates that compounds bound adequately with HDAC, and hence complemented the experimental findings.

Predicting binding events in very flexible, allosteric, multi-domain proteins.

Knowledge of the structures formed by proteins and small ligands is of fundamental importance for understanding molecular principles of chemotherapy and for designing new and more effective drugs. Due to the still high costs and to the several limitations of experimental techniques, it is most often desirable to predict these ligand-protein complexes in silico, particularly when screening for new putative drugs from databases of millions of compounds. While virtual screening based on molecular docking is widely used for this purpose, it generally fails in mimicking binding events associated with large conformational changes in the protein, particularly when the latter involve multiple domains. In this work, we describe a new methodology aimed at generating bound-like conformations of very flexible and allosteric proteins bearing multiple binding sites. Validation was performed on the enzyme adenylate kinase (ADK), a paradigmatic example of proteins that undergo very large conformational changes upon ligand binding. By only exploiting the unbound structure and the putative binding sites of the protein, we generated a significant fraction of bound-like structures, which employed in ensemble-docking calculations allowed to find native-like poses of substrates, inhibitors, and catalytically incompetent binders. Our protocol provides a general framework for the generation of bound-like conformations of flexible proteins that are suitable to host different ligands, demonstrating high sensitivity to the fine chemical details that regulate protein's activity. We foresee applications in virtual screening for difficult targets, prediction of the impact of amino acid mutations on structure and dynamics, and protein engineering.

Glutathione peroxidase (GPX1) - Selenocysteine metabolism preserves the follicular fluid's (FF) redox homeostasis via IGF-1- NMD cascade in follicular ovarian cysts (FOCs).

Follicular ovarian cysts (FOCs) are characterized by follicles in the ovaries that are >20 mm in diameter and persist for >10 days without the corpus luteum, leading to anovulation, dysregulation of folliculogenesis and subfertility in humans and livestock species. Despite their clinical significance, the precise impact of FOCs on oocyte reserve, maturation, and quality still needs to be explored. While FOCs are observed in both human and livestock populations, they are notably prevalent in livestock species. Consequently, livestock species serve as valuable models for investigating the molecular intricacies of FOCs. Thus, in this study, using goat FOCs, we performed integrated proteomic, metabolomic and functional analyses to demonstrate that oocyte maturation is hampered due to increased reactive oxygen species (ROS) in FOCs follicular fluid (FF) via downregulation of glutathione peroxidase (GPX1), a critical antioxidant seleno enzyme required to negate oxidative stress. Notably, GPX1 reduction was positively correlated with the FF's decline of free selenium and selenocysteine metabolic enzymes, O-phosphoryl-tRNA (Sec) selenium transferase (SEPSECS) and selenocysteine lyase (SCLY) levels. Adding GPX1, selenocysteine, or selenium to the culture media rescued the oocyte maturation abnormalities caused by FOCs FF by down-regulating the ROS. Additionally, we demonstrate that substituting GPX1 regulator, Insulin-like growth factor-I (IGF-1) in the in vitro maturation media improved the oocyte maturation in the cystic FF by down-regulating the ROS activity via suppressing Non-sense-mediated decay (NMD) of GPX1. In contrast, inhibition of IGF-1R and the target of rapamycin complex 1 (mTORC1) hampered the oocyte maturation via NMD up-regulation. These findings imply that the GPX1 regulation via selenocysteine metabolism and the IGF-1-mediated NMD may be critical for the redox homeostasis of FF. We propose that GPX1 enhancers hold promise as therapeutics for enhancing the competence of FOCs oocytes. However, further in vivo studies are necessary to validate these findings observed in vitro.

Computational investigation of binding of chloroquinone and hydroxychloroquinone against PLPro of SARS-CoV-2.

Novel coronavirus SARS-CoV-2 has infected 18 million people with 700,000+ mortalities worldwide and this deadly numeric figure is rapidly rising. With very few success stories, the therapeutic targeting of this epidemic has been mainly attributed to main protease (Mpro), whilst Papain-like proteases (PLpro) also plays a vital role in the processing of replicase polyprotein. Multifunctional roles of PLpro such as viral polypeptide cleavage, de-ISGlyation and immune suppression have made it a promising drug target for therapeutic interventions. Whilst there have been a number of studies and others are on-going on repurposing and new-small molecule screening, albeit previously FDA approved drugs viz. Chloroquine (CQ) and Hydroxychloroquine (HCQ) have only been found effective against this pandemic. Inspired by this fact, we have carried out molecular docking and dynamics simulation studies of FDA approved CQ and HCQ against SARS-CoV-2 PLpro. The end aim is to characterise the binding mode of CQ and HCQ and identify the key amino acid residues involved in the mechanism of action. Further, molecular dynamics simulations (MDS) were carried out with the docked complex to search for the conformational space and for understanding the integrity of binding mode. We showed that the CQ and HCQ can bind with better binding affinity with PLpro as compared to reference known PLpro inhibitor. Based on the presented findings, it can be anticipated that the SARS-CoV-2 PLpro may act as molecular target of CQ and HCQ, and can be projected for further exploration to design potent inhibitors of SARS-CoV-2 PLpro in the near future.

Structural differences in 3C-like protease (Mpro) from SARS-CoV and SARS-CoV-2: molecular insights revealed by Molecular Dynamics Simulations.

Novel coronavirus SARS-CoV-2 has infected millions of people with thousands of mortalities globally. The main protease (Mpro) is vital in processing replicase polyproteins. Both the CoV's Mpro shares 97% identity, with 12 mutations, but none are present in the active site. Although many therapeutics and vaccines are available to combat SARS-CoV-2, these treatments may not be practical due to their high mutational rate. On the other hand, Mpro has a high degree of conservation throughout variants, making Mpro a stout drug target. Here, we report a detailed comparison of both the monomeric Mpro and the biologically active dimeric Mpro using MD simulation to understand the impact of the 12 divergent residues (T35V, A46S, S65N, L86V, R88K, S94A, H134F, K180N, L202V, A267S, T285A and I286L) on the molecular microenvironment and the interaction between crucial residues. The present study concluded that the change in the microenvironment of residues at the entrance (T25, T26, M49 and Q189), near the catalytic site (F140, H163, H164, M165 and H172) and in the substrate-binding site (V35, N65, K88 and N180) is due to 12 mutations in the SARS-CoV-2 Mpro. Furthermore, the involvement of F140, E166 and H172 residues in dimerization stabilizes the Mpro dimer, which should be considered. We anticipate that networks and microenvironment changes identified here might guide repurposing attempts and optimization of new Mpro inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02089-6.

Binding Insight of Anti-HIV Phytocompounds with Prime Targets of HIV: A Molecular Dynamics Simulation Analysis.

BACKGROUND: Despite intense efforts, AIDS is difficult to tackle by current anti-retroviral therapy (ART) due to its side effects; therefore, there is an urgent need to discover potential, multitarget and low-cost anti-HIV compounds. OBJECTIVE: We have shown that few phytocompounds can potentially inhibit the prime targets of HIV namely GP120 envelope protein, reverse transcriptase, protease, integrase and ribonulcease. In this study, top ranked prioritized compounds were subjected to Molecular Dynamics (MD) simulation in order to study the conformational dynamics and integrity of crucial interaction in the receptor sites. METHODS: The system was built for selected protein-ligand complex using TIP3P water model and OPLS_2005 force field. Trajectories were recorded up to 20 ns simulation time in Desmond module of Schrödinger software. RESULTS: As a result of a comprehensive analysis of molecular properties and dynamics of the complexes, it has been concluded that Chebulic acid, Curcumin and Mulberroside C could be developed as envelope glycoprotein GP120 inhibitor, reverse transcriptase inhibitor and protease inhibitor respectively. However, the fluctuation of Chebulic acid with respect to integrase and ribonuclease protein was higher during the simulation. CONCLUSION: These findings can aid in the designing of the structural properties for more effective anti-HIV compounds against the given targets.

Pharmacophore modeling, molecular docking and molecular dynamics simulation for screening and identifying anti-dengue phytocompounds.

Dengue is a fast spreading mosquito borne viral disease that poses a serious threat to human health. Lack of therapeutic drugs and vaccines signify that more resources need to be explored. Accumulated evidence has suggested that plants offer a vast reservoir for antiviral drug discovery which are safe for human consumption. Plant-based drug discovery is a complex and time-consuming process as plants possess rich repository of chemically diverse compounds. Various in silico methods can make this process simple and economic. We, therefore, performed pharmacophore mapping, molecular docking, molecular dynamics (MD) simulations and ADME (absorption, distribution, metabolism, excretion) prediction to screen potential candidates against dengue. In particular, combined pharmacophore mapping and molecular docking were used to prioritize the potentially active ligands from a ligand library. Biological activities of plant based ligands were predicted using 3D-QSAR pharmacophore modeling. Interaction between proteins, namely, envelope G protein, NS2B/NS3 protease, NS5 methyltransferase, NS1, NS5 polymerase and active plant-based ligands (pIC50 > 5.1) were analyzed using molecular docking. Best docked complex, namely, envelope G protein-mulberroside C, NS2B-NS3 protease-curcumin, NS5 methyltransferase-chebulic acid, NS1-mulberroside A, NS5 methyltransferase-punigluconin and NS5 methyltransferase-chebulic acid were further subjected to MD simulations study to assess the fluctuation and conformational changes during protein-ligand interaction. ADME studies were performed to assess their drug-likeness properties. Collectively, these in silico results helped to identify the potential plant-based hits against the various receptors of dengue virus which can be further validated by bioactivity-based experiments.Communicated by Ramaswamy H. Sarma.

Clinical and Cyto-Morphological Characterization of Triple Negative Breast Cancer.

OBJECTIVE: Triple negative breast cancer (TNBC), despite being the uncommon subtype, contributes a major portion to mortality and associated with poor prognosis. The purpose of this study was to evaluate the cytological criteria for the diagnosis of TNBC through fine-needle aspiration cytology (FNAC). MATERIAL AND METHOD: Clinical, cytological, histological, and immunohistochemical (IHC) data of 256 patients were evaluated, and patient were classified as TNBC and non-TNBC phenotype by IHC. All cytological specimens were reviewed for 12 criteria: cellularity, tubule/gland formation, syncytial clusters, large bare nuclei, nuclear atypia, chromatin pattern, cell borders, nucleolus, cytoplasm, lymphocytic infiltrate, calcification, and necrosis. The Fischer's exact test was used to show test association. RESULT: Out of 256 patients, 82 patients were TNBC, and 174 patients were non-TNBC. TNBC phenotype showed statistically significant association to cellularity, tubule/gland formation, syncytial cluster formation, bare nuclei, nuclear atypia, cell borders, lymphocyte infiltration, and necrosis. CONCLUSION: FNAC can be helpful in making diagnosis of TNBC and along with ER, PR, HER2 characterization, helpful in planning treatment strategy, saving time, manpower, and resources in the patient management.

Structure-based identification of novel sirtuin inhibitors against triple negative breast cancer: An in silico and in vitro study.

Triple-negative breast cancer (TNBC) is an aggressive disease exemplified by a poor prognosis, greater degrees of relapse, the absence of hormonal receptors for coherent utilization of targeted therapy, poor response to currently available therapeutics and development of chemoresistance. Aberrant activity of sirtuins (SIRTs) has strong implications in the metastatic and oncogenic progression of TNBC. Synthetic SIRT inhibitors are effective, however, they have shown adverse side effects emphasizing the need for plant-derived inhibitors (PDIs). In the current study, we identified potential plant-derived sirtuin inhibitors using in silico approach i.e. molecular docking, ADMET and molecular dynamics simulations (MD). Docking studies revealed that Sulforaphane, Kaempferol and Apigenin exhibits the highest docking scores against SIRT1 & 5, 3 and 6 respectively. ADMET analysis of above hits demonstrated drug-like profile. MD of prioritized SIRTs-PDIs complexes displayed stability with insignificant deviations throughout the trajectory. Furthermore, we determined the effect of our prioritized molecules on cellular viability, global activity as well as protein expression of sirtuins and stemness of TNBC cells utilizing in vitro techniques. Our in vitro findings complements our in silico results. Collectively, these findings provide a better insight into the structural basis of sirtuin inhibition and can facilitate drug design process for TNBC management.

New Class of Supramolecular Bowl-Shaped Columnar Mesogens Derived from Thiacalix[4]arene Exhibiting Gelation and Organic Light-Emitting Diodes Applications.

A new class of blue light-emitting bowl-shaped mesogens with the thiacalix[4]arene core appended with 1,3,4-thiadiazole derivatives having peripheral alkoxy side chains have been synthesized and well characterized. The liquid crystalline behavior of present synthesized derivatives was examined by optical polarizing microscopy, differential scanning calorimetry, and X-ray diffraction studies. It was observed that these thiacalix[4]arene derivatives were capable of stabilizing the observed Colh phase with a higher temperature range. The cone-shaped thiacalix[4]arene-based liquid crystals with peripheral alkoxy side chains able to pack into the columns with enriched intermolecular interactions and thermal behavior. All derivatives showed blue luminescence in solution, solid thin-film, and gelation state. The hexagonal columnar phase and emissive nature of thiadiazole-based thiacalixarene compounds having xerogel behavior make them favorable in the application of emissive electronic display devices. The electrochemical properties of these thiacalixarene-based compounds demonstrate the effect of alkyl side chain on the highest occupied molecular orbital-lowest unoccupied molecular orbital energy levels and also exhibited lower electron band gaps. The electroluminescence behavior of the compound 10c was examined as emissive layers in the fabrication of organic light-emitting diodes.

A DFT study of inclusion complexes of substituted calix[n]arenes with dasatinib and lapatinib.

Herein, we have presented the results of Density Functional Theory (DFT) based calculations of inclusion complexes of lapatinib and dasatinib with calix[n]arene macrocycles. A total of 48 calix [n]arene complexes were modeled via considering varied ring sizes (n = 4,5,6,8) and upper-rim functionalization viz. SO3H, tert-Butyl, iso-Propyl, COOH, C2H5OH, and C2H5NH2. From the results of multilevel molecular docking, DFT energetics, and reactivity descriptors; it has been demonstrated that dasatinib form optimal complexes with calix 4f, 3f (-35 to -40 kcal/mol). Moreover, for lapatinib, hosts 3f, 4a, 1f, 3d have the capability to generate promising complexes (>35 kcal/mol). Based on counterpoise corrected binding energies (Ebind) and global reactivity descriptors, we anticipate that the proposed complexes can vitally be used as analogous to carrier-mediated-drug-delivery.

Identification of InhA inhibitors: A combination of virtual screening, molecular dynamics simulations and quantum chemical studies.

In the present work, multiple pharmacophore-based virtual screening of the SPECS natural product database was carried out to identify novel inhibitors of the validated biological target, InhA. The pharmacophore models were built from the five different groups of the co-crystallized ligands present within the active site. The generated models with the same features from each group were pooled and subjected to the test set validation, receiver-operator characteristic analysis and Güner-Henry studies. A set of five hypotheses with sensitivity > 0.5, specificity > 0.5, area under curve (AUC) > 0.7, and goodness of hit score > 0.7 were retrieved and exploited for the virtual screening. The common hits (87 molecules) obtained from these hypotheses were processed via drug-likeness filters. The filtered molecules (27 molecules) were compared for the binding modes and the top scored molecules (12 molecules) along with the reference (triclosan (TCL), docking score = -11.65 kcal/mol) were rescored and reprioritized via molecular mechanics-generalized Born surface area approach. Eventually, the stability of reprioritized (10 molecules) docked complexes was scrutinized via molecular dynamics simulations. Moreover, the quantum chemical studies of the dynamically stable compounds (9 molecules) were performed to understand structural features essential for the activity. Overall, the protocol resulted in the recognition of nine lead compounds that can be targeted against InhA.

First protein drug target's appraisal of lead-likeness descriptors to unfold the intervening chemical space.

Despite the advances in combinatorial chemistry, high throughput and virtual screening experiments, plethora of clinical studies disquiet due to lead and drug-likeness attritions. For mitigation, the knowledge of physicochemical properties are really useful for guiding and selection of compounds from libraries dictated by certain rule of thumbs. However, robust bio-technological and instrumental innovations have created exponential increase in novel compounds and databases which compelled rethinking of the evaluation procedures. Known descriptive molecular property filters proposed by Lipinski, Verber and Hann are not efficient enough to encompass long array of compounds. Moreover, these filters do not take into account the specificity of biological target. In this pursuit, we have tried to appraise eight molecular properties for two major classes of biological targets viz membrane proteins and ion channels binding ligands. These molecular properties were utilized to search for the specific attributes that can be identified as an intervening space for dictating the biological activity.