Nitrile stabilized synthesis of pyrrolidine and piperidine derivatives via tandem alkynyl aza-Prins-Ritter reactions.

An efficient methodology for the synthesis of N-(pyrrolidine-3-ylidenemethyl)acetamides mediated by triflic acid in good yields with separable Z/E isomers within a short reaction time has been demonstrated. The reaction involves the initial formation of the pyrrolidin-3-ylidenemethylium carbocation via the Prins cyclization reaction followed by the Ritter reaction to produce N-(pyrrolidine-3-ylidenemethyl)acetamides. This methodology is also used for the synthesis of their piperidine derivatives.

The ChaC1 active site: Defining the residues and determining the role of ChaC1-exclusive residues in the structural and functional stability.

The glutathione degrading enzyme ChaC1 is highly upregulated in several cancers and viral infections making it a potential pharmacological target for cancer therapy. As an enzyme, however, ChaC1 has a relatively high Km (~2 mM) towards its natural substrate, and therefore finding its inhibitors becomes very difficult. Given this limitation, a careful mapping of the active site has become necessary. In the current study, the enzyme-substrate complex was generated by docking glutathione with the modeled hChaC1 structure. Using a combination of in silico and wet lab approaches, the active site residues forming direct interactions with the substrate glutathione were identified and validated. Furthermore, the role of residues exclusively conserved in the ChaC family and forming the surface of the active site were also explored for their putative role in active site stabilization. Mutants of these residues have been analysed for their structural stability and interaction with the substrate through MD simulations and MMGBSA binding energy calculations. These findings were experimentally validated by assessment of their function through in vivo assays in yeast. The experimental evidences along with the molecular modeling suggest that residues 38'YGSL'41, D68, R72, E115, and Y143 are responsible for high affinity binding of hChaC1 with the substrate/inhibitor, whereas the residues exclusive to the ChaC family are required for the structural stability of the enzyme and its active site. Such a characterization of essential active site and conserved residues is significant as a key step toward rational design of novel inhibitors of the ChaC1 enzyme.

Alpha-1-antitrypsin in serum exosomes and pericardial fluid exosomes is associated with severity of rheumatic heart disease.

Rheumatic heart disease (RHD) is an autoimmune sequel of pharyngitis and rheumatic fever that leads to permanent heart valve damage, especially the mitral valves. The mitral valves, which are responsible for the binding of auto-antibodies during immune response generation, lead to valve scarring and eventually valves dysfunction. Recently, exosomes (EXOs), the nano-sized vesicles, which range in size from 30 to 150 nm, are reported in various cardiovascular physiological and pathological processes. These vesicles are found in several body fluids such as plasma, serum, and also in cell culture media. Exosomal cargo contains proteins, which are taken up by the recipient cells and modulate the cellular characteristics. The role of exosomal proteins in RHD is still obscure. Hence, the present study has been designed to unveil the exosomal proteins in disease severity during RHD. In this study, the exosomes were isolated from biological fluids (serum and pericardial fluid) of RHD patients as well as from their respective controls. Protein profiling of these isolated exosomes revealed that alpha-1 antitrypsin is up-regulated in the biological fluids of RHD patients. The enhanced levels of exosomal alpha-1 antitrypsin, were further, validated in biological samples and mitral valve tissues of RHD patients, to correlate with the disease severity. These findings suggest an association of increased levels of exosomal alpha-1 antitrypsin with the RHD pathogenesis.

Study of MicroRNA (miR-221-3p, miR-133a-3p, and miR-9-5p) Expressions in Oral Submucous Fibrosis and Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the common types of cancer. Its progression follows a transition from oral potentially malignant disorders (OPMDs) such as oral submucous fibrosis (OSMF). Epigenetic modifiers, especially microRNAs (miRNAs), have an appreciable role in the regulation of various carcinogenic pathways which are being used as biomarkers. miRNAs may also be helpful in the differentiation of oral submucous fibrosis from oral squamous cell carcinoma. Three miRNAs, miR-221-3p, miR133a-3p, and miR-9-5p, were found differentially expressed in many cancers in the literature search supported by our preliminary database search-based screening. The literature and our functional enrichment analysis in an earlier study have reported these miRNAs to regulate carcinogenesis at various steps. In the present study, the expression of these miRNAs was examined in 34 histopathologically confirmed OSCC, 30 OSMF, and 29 control (healthy volunteers) human samples. There was a significant downregulation of miRNA-133a-3p in OSCC compared to OSMF and controls, whereas there was up-regulation in oral submucous fibrosis compared to controls. There was no significant difference in the expression of miR-221-3p between OSCC and OSMF, but an upregulation in OSCC compared to controls. miR-9-5p was also found upregulated in both OSCC and OSMF. Further, miR-133a-3p expression was negatively correlated with age, smoking, drinking status, and AJCC staging, whereas miR-9-5p expression was only positively associated with tobacco/ areca nut chewing. The ROC plots, logistic regression model generated, and the correlation between the expression of miR-9-5p and miR-133a-3p in blood and tissue suggests that these could be used as risk stratification biomarkers.

Dynamics based pharmacophore models for screening potential inhibitors of mycobacterial cyclopropane synthase.

The therapeutic challenges in the treatment of tuberculosis demand multidisciplinary approaches for the identification of potential drug targets as well as fast and accurate techniques to screen huge chemical libraries. Mycobacterial cyclopropane synthase (CmaA1) has been shown to be essential for the survival of the bacteria due to its critical role in the synthesis of mycolic acids. The present study proposes pharmacophore models based on the structure of CmaA1 taking into account its various states in the cyclopropanation process, and their dynamic nature as assessed using molecular dynamics (MD) simulations. The qualities of these pharmacophore models were validated by mapping 23 molecules that have been previously reported to exhibit inhibitory activities on CmaA1. Additionally, 1398 compounds that have been shown to be inactive for tuberculosis were collected from the ChEMBL database and were screened against the models for validation. The models were further validated by comparing the results from pharmacophore mapping with the results obtained from docking these molecules with the respective protein structures. The best models are suggested by validating all the models based on their screening abilities and by comparing with docking results. The models generated from the MD trajectories were found to perform better than the one generated based on the crystal structure demonstrating the importance of incorporating receptor flexibility in drug design.

Molecular dynamics investigation of the active site dynamics of mycobacterial cyclopropane synthase during various stages of the cyclopropanation process.

Mycobacterial cyclopropane synthase 1 (CmaA1) is one of the most important drug targets in anti tuberculosis drug discovery as it is responsible for cis-cyclopropanation at the distal position of unsaturated mycolates, which is an essential step for the pathogenicity, persistence and drug resistance. Five representative models of CmaA1 which correspond to different stages in the cyclopropanation process have been studied using molecular dynamics (MD) simulations. The MD simulations and structural analyses provide a detailed account of the structural changes in the active sites of CmaA1. CmaA1 has two distinct binding sites, i.e., cofactor binding site (CBS) and acyl substrate binding site (ASBS). The apo state of CmaA1 corresponds to a closed conformation where the CBS is inaccessible due to the existence of H-bond between Pro202 of loop10 (L10) and Asn11 of N-terminal α1 helix. However, cofactor binding leads to the breaking of this H-bond and thus the H-bond is absent in the holo form. The hydrophobic side chains orient towards the inner side of the ASBS upon cofactor binding to create a hydrophobic environment for the substrate. The cofactor and substrate tend to come close to each other facilitated by opening of L10 to exchange the methyl group from the cofactor to the substrate. The MD study also revealed that the system tends to regain the apo conformation within 40ns after releasing the product.

Aspirin as a potential drug repurposing candidate targeting estrogen receptor alpha in breast cancer: a molecular dynamics and in-vitro study.

Estrogen receptor alpha (ERα) is expressed by 70% of breast cancers (BCs). Any deregulation in ERα signaling is crucial for the initiation and progression of BC. Because of development of resistance to anti-estrogenic compounds, repurposing existing drugs is an apt strategy to avoid a long drug-discovery process. Substantial epidemiologic evidence suggests that Aspirin use reduces the risk of different cancers including BC, while its role as an adjuvant or a possible antineoplastic agent in cancer treatment is being investigated. In this study, we attempted to explore possibilities of ERα inhibition by Aspirin which may act through competitive binding to the ligand binding domain (LBD) of ERα. A list of 48 ERα-LBD crystal structures bound with agonists, antagonists, and selective ER modulators (SERMs) was thoroughly analysed to determine interaction patterns specific to each ligand category. Exhaustive docking and 500 ns molecular dynamics (MD) studies were performed on three ERα - Aspirin complexes generated using agonist, antagonist, and SERM-bound crystal structures. Besides, three ERα crystal structures bound to agonist, antagonist, and SERM respectively were also subjected to MD simulations. Aspirin showed good affinity to LBD of ERα. Comparative analyses of binding patterns, conformational changes and molecular interaction profiles from the docking results and MD trajectories suggests that Aspirin was most stable in complex generated using SERM bound crystal structure of ERα and showed interactions with Gly-521, Ala-350, Leu-525 and Thr-347 like SERMs. In addition, in-vitro assays, qPCR, and immunofluorescent assay demonstrated the decline in the expression of ERα in MCF-7 upon treatment with Aspirin. These preliminary bioinformatical and in-vitro findings may form the basis to consider Aspirin as a potential candidate for targeting ERα, especially in tamoxifen-resistant cancers.Communicated by Ramaswamy H. Sarma.

Glucose 6-phosphate dehydrogenase variants increase NADPH pools for yeast isoprenoid production.

Isoprenoid biosynthesis has a significant requirement for the co-factor NADPH. Thus, increasing NADPH levels for enhancing isoprenoid yields in synthetic biology is critical. Previous efforts have focused on diverting flux into the pentose phosphate pathway or overproducing enzymes that generate NADPH. In this study, we instead focused on increasing the efficiency of enzymes that generate NADPH. We first established a robust genetic screen that allowed us to screen improved variants. The pentose phosphate pathway enzyme, glucose 6-phosphate dehydrogenase (G6PD), was chosen for further improvement. Different gene fusions of G6PD with the downstream enzyme in the pentose phosphate pathway, 6-phosphogluconolactonase (6PGL), were created. The linker-less G6PD-6PGL fusion displayed the highest activity, and although it had slightly lower activity than the WT enzyme, the affinity for G6P was higher and showed higher yields of the diterpenoid sclareol in vivo. A second gene fusion approach was to fuse G6PD to truncated HMG-CoA reductase, the rate-limiting step and also the major NADPH consumer in the pathway. Both domains were functional, and the fusion also yielded higher sclareol levels. We simultaneously carried out a rational mutagenesis approach with G6PD, which led to the identification of two mutants of G6PD, N403D and S238QI239F, that showed 15-25% higher activity in vitro. The diterpene sclareol yields were also increased in the strains overexpressing these mutants relative to WT G6PD, and these will be very beneficial in synthetic biology applications.

smProdrugs: A repository of small molecule prodrugs.

In modern drug discovery and development, the prodrug approach has become a crucial strategy for enhancing the pharmacokinetic profiles of drugs. A prodrug is a chemical compound, which gets metabolized into a pharmacologically active form (drug) inside the body after its administration. In the current work, we report 'smProdrugs' (http://cheminfolab.in/databases/prodrug/), which is one of the first exclusive databases on small molecule prodrugs. It stores the structures, physicochemical properties and experimental ADMET data manually curated from literature. SmProdrugs lists 626 small molecule prodrugs and their active compounds with the above mentioned experimental data from 1808 research articles and 61 patents have been stored. The information page of each record gives the structures and properties of the prodrug and the active drug side by side which makes it easy for the user to instantly compare them. The structural modifications in the prodrug/active drugs are highlighted in a different colour for easy comparison. Experimental data has been curated from the downloaded PubMed and patent articles and were catalogued in a tabular form with more than 25 fields under sub-sections i) name and structures of the prodrugs and their active compounds, ii) mode of activation of the prodrug and enzyme/biocatalyst involved in the conversion, iii) indications/disease, iv) pharmacological target, v) experimental pharmacokinetic properties such as solubility, absorption, volume of distribution, half-life, clearance etc. and vi) information on the purpose/gain from the prodrug strategies. Considering the ever expanding utility of the prodrug approach smProdrugs will be of great use to the scientific community working on rational design of small molecule prodrugs.

Virtual screening of gut microbiome bacteriocins as potential inhibitors of stearoyl-CoA desaturase 1 to regulate adipocyte differentiation and thermogenesis to combat obesity.

The gut bacterial strains and their metabolites have been shown to play a significant role in obesity, but the molecular mechanisms underlying this association are largely unresolved. Obesity is a multifactorial problem and is controlled by various mechanisms and pathways to produce and store fat cells. Bacteriocins are secondary metabolites produced by gut bacteria to defend themselves against their competitors. Recently, they have gained great attention due to their role in metabolic disorders, including obesity. Stearoyl-CoA desaturase 1 (SCD1) is a key enzyme involved in the differentiation of adipocytes. The aim of this study is to show the regulation of SCD1 by bacteriocins and thus their importance in obesity control. We screened the human gut bacteriome for the presence of bacteriocins, predicted their structures, and showed their inhibitory role by molecular docking with SCD1. Further, to confirm the docking results, MDS of six top scoring SCD1-bacteriocin complexes were carried out for 100 ns. These six bacteriocins namely, Plantaricin S-beta, Carnolysin, Lactococcin B, Bacteriocin Iic, Plantaricin N, and Thermophilin A, with strong binding affinities, are primarily produced by bacterial strains from the Lactobacillaeacea family. These findings can be the basis of further experiments for enhanced understanding of the underlying mechanisms for obesity control, specifically bacteriocins driven regulation of the SCD1 enzyme. In addition, a consortium of bacterial strains producing these bacteriocins can be developed and used as probiotics for the amelioration of obesity and other metabolic complications.Communicated by Ramaswamy H. Sarma.

Structure-based drug repurposing: Traditional and advanced AI/ML-aided methods.

The current global health emergency in the form of the Coronavirus 2019 (COVID-19) pandemic has highlighted the need for fast, accurate, and efficient drug discovery pipelines. Traditional drug discovery projects relying on in vitro high-throughput screening (HTS) involve large investments and sophisticated experimental set-ups, affordable only to big biopharmaceutical companies. In this scenario, application of efficient state-of-the-art computational methods and modern artificial intelligence (AI)-based algorithms for rapid screening of repurposable chemical space [approved drugs and natural products (NPs) with proven pharmacokinetic profiles] to identify the initial leads is a powerful option to save resources and time. Structure-based drug repurposing is a popular in silico repurposing approach. In this review, we discuss traditional and modern AI-based computational methods and tools applied at various stages for structure-based drug discovery (SBDD) pipelines. Additionally, we highlight the role of generative models in generating molecules with scaffolds from repurposable chemical space.

Virtual repurposing of ursodeoxycholate and chenodeoxycholate as lead candidates against SARS-Cov2-Envelope protein: A molecular dynamics investigation.

Drug repurposing is an apt choice to combat the currently prevailing global threat of COVID-19, caused by SARS-Cov2in absence of any specific medication/vaccine. The present work employs state of art computational methods like homology modelling, molecular docking and molecular dynamics simulations to evaluate the potential of two widely used surfactant drugs namely chenodeoxycholate(CDC) and ursodeoxycholate (UDC), to bind to the envelope protein of SARS-Cov2(SARS-Cov2-E).The monomeric unit of SARS-Cov2-E was modelled from a close homologue (>90% sequence identity) and a pentameric assembly was modelled using symmetric docking, followed by energy minimization in a DPPC membrane environment. The minimized structure was used to generate best scoring SARS-Cov2-E-CDC/UDC complexes through blind docking. These complexes were subjected to 230 ns molecular dynamics simulations in triplicates in a DPPC membrane environment. Comparative analyses of structural properties and molecular interaction profiles from the MD trajectories revealed that, both CDC and UDC could stably bind to SARS-Cov2-E through H-bonds, water-bridges and hydrophobic contacts with the transmembrane-channelresidues.T30 was observed to be a key residue for CDC/UDC binding. CDC/UDC binding affected the H-bonding pattern between adjacent monomeric chains, slackening the compact transmembrane region of SARS-Cov2-E. Additionally, the polar functional groups of CDC/UDC facilitated entry of a large number of water molecules into the channel. These observations suggest CDC/UDC as potential candidates to hinder the survival of SARS-Cov2 by disrupting the structure of SARS-Cov2-E and facilitating the entry of solvents/polar inhibitors inside the viral cell.Communicated by Ramaswamy H. Sarma.

Differential Expression of Zinc-Dependent HDAC Subtypes and their Involvement in Unique Pathways Associated with Carcinogenesis.

OBJECTIVE: The present study aims to identify the effect of ZnHDACs expression on the survival of the patients. Further, reveal the unique and common genes associated with each ZnHDACs and their associated pathways. METHODS: The patient data was obtained from the Cancer Genome Atlas Program (TCGA) database and was analyzed using cBioportal and Gene Expression Profiling Interactive Analysis 2(GEPIA2) online tools. Protein-protein interactions and functional interactomic analysis were done using STRING, DAVID, and KEGG pathway databases. RESULTS: HDAC1, 2, 8, 11 were over-expressed and, HDAC4, 5, 6, 7, and 10 were down-regulated in all the cancer types, but there are few exceptional expression patterns such as HDAC7 and HDAC10 overexpression in HNSC, HDAC3 down-regulation in LUAD, and PRAD. The unique genes interacting with each ZnHDACs provided a better understanding of ZnHDAC's putative role in carcinogenesis. The present study reported that JARID2, stem cell regulation gene uniquely interacts with HDAC1, BPTF-CHRAC-BAZIA axis, enzymes for chromatin modeling selectively interacting with only HDAC2, HDAC3 in H2A acetylation via DMAP1 and YEATS4. HDAC6 associated unique genes regulate protein stability, HDAC7 in subnuclear localization and splicing, HDAC8 in telomere maintenance, HDAC9 in chromosomal rearrangements, and HDAC11 in maintaining histone core and folding. CONCLUSION: The unique genes and pathways associated with a particular ZnHDACs could provide a wide window for interrogating these genes for obtaining putative drug targets.

A functionally divergent transcription elongation factor 1-like protein in Toxoplasma gondii.

Zinc ribbons, one of the largest fold groups among zinc fingers, often include proteins involved in the transcription machinery. Here, we identify and characterize one such zinc ribbon-bearing protein in the apicomplexan parasite Toxoplasma gondii, annotated as putative transcription elongation factor 1 (ELF1), with predicted functions in transcription and chromatin maintenance. We show that this ELF1 homolog, referred to as T. gondii ELF1-like divergent (TgELD), is expressed in both tachyzoite and bradyzoite developmental stages. TgELD associates with the cytoskeleton in the tachyzoites, while it transiently becomes a part of the cyst wall in the early bradyzoites, followed by a cytosolic and peripheral localization in late bradyzoites. TgELD is phosphorylated by a casein kinase 2-like protein, which has potential implications for its localization and function in the parasite.

Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease.

The recent pandemic of severe acute respiratory syndrome-coronavirus2 (SARS-CoV-2) infection (COVID-19) has put the world on serious alert. The main protease of SARS-CoV-2 (SARS-CoV-2-MPro) cleaves the long polyprotein chains to release functional proteins required for replication of the virus and thus is a potential drug target to design new chemical entities in order to inhibit the viral replication in human cells. The current study employs state of art computational methods to design novel molecules by linking molecular fragments which specifically bind to different constituent sub-pockets of the SARS-CoV-2-MPro binding site. A huge library of 191678 fragments was screened against the binding cavity of SARS-CoV-2-MPro and high affinity fragments binding to adjacent sub-pockets were tailored to generate new molecules. These newly formed molecules were further subjected to molecular docking, ADMET filters and MM-GBSA binding energy calculations to select 17 best molecules (named as MP-In1 to MP-In17), which showed comparable binding affinities and interactions with the key binding site residues as the reference ligand. The complexes of these 17 molecules and the reference molecule with SARS-CoV-2-MPro, were subjected to molecular dynamics simulations, which assessed the stabilities of their binding with SARS-CoV-2-MPro. Fifteen molecules were found to form stable complexes with SARS-CoV-2-MPro. These novel chemical entities designed specifically according to the pharmacophoric requirements of SARS-CoV-2-MPro binding pockets showed good synthetic feasibility and returned no exact match when searched against chemical databases. Considering their interactions, binding efficiencies and novel chemotypes, they can be further evaluated as potential starting points for SARS-CoV-2 drug discovery.

Identification of unique subtype-specific interaction features in Class II zinc-dependent HDAC subtype binding pockets: A computational study.

Zinc-dependent HDAC subtypes (ZnHDACs) exhibit differential expression in various cancer types and significantly contribute to oncogenic cell transformation, and hence are interesting anticancer drug targets. The approved pan HDAC inhibitors (PHIs) lack subtype specificity and inhibit all ZnHDACs, causing severe sideeffects. Considering the distinct tissue distribution and roles of individual ZnHDACs in specific cancer types, it is crucial to rationally design subtype-specific inhibitors (SSIs) for enhanced efficacy and reduced side-effects. There are numerous approaches already conducted for designing SSIs, especially Class I ZnHDACs, whereas Class II and III ZnHDACs are relatively unexplored and equally important in disease pathogenesis. This study attempts to decipher the specificity rendering interaction features of six different ZnHDACs by robust analyses of reported experimental data employing sophisticated computational methods like homology modelling, docking, pharmacophore analysis, and molecular dynamic (MD) simulations. Experimentally validated SSIs (activity<1000 nM) of different ZnHDACs and 8 approved PHIs were docked to 40 MD generated conformations of each ZnHDACs followed by MM-GBSA binding energy estimations. Sequences, structures, physicochemical properties, and interaction patterns of the binding sites obtained from docking were exhaustively compared to identify unique subtype-specific interaction features for each Class II ZnHDACs. To further validate the stabilities of these features, 20 ns MD simulations were performed on 12 complexes (each Class II ZnHDACs bound to one SSI and one PHI) in explicit water models. Distinct pharmacophoric patterns were observed in the binding pockets of each subtype despite high sequence similarities. Presence of amides, ketone, hydroxyl, carboxyl groups, and moieties occupying additional sub-pockets and interacting with Zn 2+, etc., in the SSIs affect the orientations of the binding site residues (BSRs) owing to subtype-specific protein- ligand interactions. Stable and unique residue interactions specific for a HDAC subtype are, e.g. E329 for HDAC4, S904 for HDAC5, W496 S563 I569 for HDAC6, M793 for HDAC9, and E302 for HDAC10. Such unique interaction features and pharmacophoric patterns can be utilized for subtype-specific ZnHDAC inhibitor design.

Molecular chaperone function of stress inducible Hsp70 is critical for intracellular multiplication of Toxoplasma gondii.

Intracellular pathogens like Toxoplasma gondii often target proteins and pathways critical for host cell survival and stress response. Molecular chaperones encoded by the evolutionary conserved Heat shock proteins (Hsps) maintain proteostasis and are vital to cell survival following exposure to any form of stress. A key protein of this family is Hsp70, an ATP-driven molecular chaperone, which is stress inducible and often indiscernible in normal cells. Role of this protein with respect to intracellular survival and multiplication of protozoan parasite like T. gondii remains to be examined. We find that T. gondii infection upregulates expression of host Hsp70. Hsp70 selective inhibitor 2-phenylethynesulfonamide (PES) attenuates intracellular T. gondii multiplication. Biotinylated PES confirms selective interaction of this small molecule inhibitor with Hsp70. We show that PES acts by disrupting Hsp70 chaperone function which leads to dysregulation of host autophagy. Silencing of host Hsp70 underscores its importance for intracellular multiplication of T. gondii, however, attenuation achieved using PES is not completely attributable to host Hsp70 indicating the presence of other intracellular targets of PES in infected host cells. We find that PES is also able to target T. gondii Hsp70 homologue which was shown using PES binding assay. Detailed molecular docking analysis substantiates PES targeting of TgHsp70 in addition to host Hsp70. While establishing the importance of protein quality control in infection, this study brings to the fore a unique opportunity of dual targeting of host and parasite Hsp70 demonstrating how structural conservation of these proteins may be exploited for therapeutic design.

Hybrid Dynamic Pharmacophore Models as Effective Tools to Identify Novel Chemotypes for Anti-TB Inhibitor Design: A Case Study With Mtb-DapB.

Antimicrobial resistance (AMR) is one of the most serious global public health threats as it compromises the successful treatment of deadly infectious diseases like tuberculosis. New therapeutics are constantly needed but it takes a long time and is expensive to explore new biochemical space. One way to address this issue is to repurpose the validated targets and identify novel chemotypes that can simultaneously bind to multiple binding pockets of these targets as a new lead generation strategy. This study reports such a strategy, dynamic hybrid pharmacophore model (DHPM), which represents the combined interaction features of different binding pockets contrary to the conventional approaches, where pharmacophore models are generated from single binding sites. We have considered Mtb-DapB, a validated mycobacterial drug target, as our model system to explore the effectiveness of DHPMs to screen novel unexplored compounds. Mtb-DapB has a cofactor binding site (CBS) and an adjacent substrate binding site (SBS). Four different model systems of Mtb-DapB were designed where, either NADPH/NADH occupies CBS in presence/absence of an inhibitor 2, 6-PDC in the adjacent SBS. Two more model systems were designed, where 2, 6-PDC was linked to NADPH and NADH to form hybrid molecules. The six model systems were subjected to 200 ns molecular dynamics simulations and trajectories were analyzed to identify stable ligand-receptor interaction features. Based on these interactions, conventional pharmacophore models (CPM) were generated from the individual binding sites while DHPMs were created from hybrid-molecules occupying both binding sites. A huge library of 1,563,764 publicly available molecules were screened by CPMs and DHPMs. The screened hits obtained from both types of models were compared based on their Hashed binary molecular fingerprints and 4-point pharmacophore fingerprints using Tanimoto, Cosine, Dice and Tversky similarity matrices. Molecules screened by DHPM exhibited significant structural diversity, better binding strength and drug like properties as compared to the compounds screened by CPMs indicating the efficiency of DHPM to explore new chemical space for anti-TB drug discovery. The idea of DHPM can be applied for a wide range of mycobacterial or other pathogen targets to venture into unexplored chemical space.

Structural and Functional Diversities of the Hexadecahydro-1H-cyclopenta[a]phenanthrene Framework, a Ubiquitous Scaffold in Steroidal Hormones.

Hexadecahydro-1H-cyclopenta[a]phenanthrene framework (HHCPF) has been considered as one of the privileged scaffolds due to its versatile presence in many biologically essential molecules. In our quest to unravel the privileged nature of this framework, we undertook a systematic analysis of target binding and Absorption, Distribution, Metabolism, Elimination, Toxicity (ADMET)/physicochemical properties of 110 drugs containing HHCPF reported in DrugBank. Effect of number and positions of double bonds in the framework and substitutions at each carbon position on the target selectivity as well as drug like properties of these drugs were studied. Fifteen different scaffolds based on the numbers and positions of double bonds in the HHCPF were identified among these drugs. The optimum number of double bonds present in the HHCPF scaffolds was observed to be one to three, and one particular positional isomer is predominant among many scaffolds with same numbers of double bonds. Docking studies reveal the role of substituents at different positions to make specific interactions with their respective targets. Based on the docking interactions, we proposed structure based e-Pharmacophore models for seven important targets of HHCPF drugs. Good correlations were observed between the substitutions carbon positions 3 and 17 of the scaffolds and ADMET properties of the HHCPF drugs. This work enables preliminary prediction of the target selectivity and ADMET properties of a new HHCPF molecule based on the scaffold, substituents and the pharmacophoric features.

The efficacy of conceptual DFT descriptors and docking scores on the QSAR models of HIV protease inhibitors.

This study critically examines the role of conceptual DFT descriptors and docking scores on a diverse set of 156 inhibitors of HIV proteases. Five QSAR models were developed on the basis of available experimental IC(50) values (HIV-I and HIV-IIIB infected MT4 and CEMSS cells and HIV-I infected C8166 cells) and sixth QSAR model was generated by combining the inhibitors of all five models. B3LYP/6-31G(d) optimizations were carried out on all considered inhibitors, and the results are compared with more economic semi-empirical SCF AM1 results in order to find out the best and efficient way of descriptor calculations. Interestingly semi-empirical results appear to be satisfactory for this class of inhibitors. Selected QSAR models were validated by taking about 20% of inhibitors in the test sets. The effect of the number of descriptors on the R(2) and R(2)(cv) values was tested and three to four orthogonal descriptors based models were selected to be the optimum ones to avoid over correlation.