Yogesh T. Jasrai

The effect of various atomic partial charge schemes to elucidate consensus activity-correlating molecular regions: a test case of diverse QSAR models

The estimation of atomic partial charges of the small molecules to calculate molecular interaction fields (MIFs) is an important process in field-based quantitative structure–activity relationship (QSAR). Several studies showed the influence of partial charge schemes that drastically affects the prediction accuracy of the QSAR model and focused on the selection of appropriate charge models that provide highest cross-validated correlation coefficient ( or q2) to explain the variation in chemical structures against biological endpoints. This study shift this focus in a direction to understand the molecular regions deemed to explain SAR in various charge models and recognize a consensus picture of activity-correlating molecular regions. We selected eleven diverse dataset and developed MIF-based QSAR models using various charge schemes including Gasteiger–Marsili, Del Re, Merck Molecular Force Field, Hückel, Gasteiger–Hückel, and Pullman. The generalized resultant QSAR models were then compared with Open3DQSAR model to interpret the MIF descriptors decisively. We suggest the regions of activity contribution or optimization can be effectively determined by studying various charge-based models to understand SAR precisely.

Prioritization of active antimalarials using structural interaction profile of Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR)-triclosan derivatives

An empirical relationship between the experimental inhibitory activities of triclosan derivatives and its computationally predicted Plasmodium falciparum enoyl-acyl carrier protein (ACP) reductase (PfENR) dock poses was developed to model activities of known antimalarials. A statistical model was developed using 57 triclosan derivatives with significant measures (r = 0.849, q2 = 0.619, s = 0.481) and applied on structurally related and structurally diverse external datasets. A substructure-based search on ChEMBL malaria dataset (280 compounds) yielded only two molecules with significant docking energy, whereas eight active antimalarials (EC50 < 100 nM, tested on 3D7 strain) with better predicted activities (pIC50 ~ 7) from Open Access Malaria Box (400 compounds) were prioritized. Further, calculations on the structurally diverse rhodanine molecules (known PfENR inhibitors) distinguished actives (experimental IC50 = 0.035 μM; predicted pIC50 = 6.568) and inactives (experimental IC50 = 50 μM; predicted pIC50 = -4.078), which showed that antimalarials possessing dock poses similar to experimental interaction profiles can be used as leads to test experimentally on enzyme assays.

Effect of p-sulfonatocalix[4]resorcinarene (PSC[4]R) on the solubility and bioavailability of a poorly water soluble drug lamotrigine (LMN) and computational investigation

As a part of our research investigations to unfold the chemistry of calixresorcinarene, we studied the formation of an inclusion complex with p-sulfonatocalix[4]resorcinarene (PSC[4]R) of a poorly water soluble drug lamotrigine (LMN). The complete complexation of the drug was achieved after 48 h of stirring with PSC[4]R in water and evaporation of the water to give a solid complex. The inclusion complex between PSC[4]R and LMN was studied by different analytical techniques including FT-IR, PXRD and UV-VIS spectroscopy. The complexation was determined by thermal analysis and a phase solubility study. The prepared complexes exhibited improved in vitro dissolution profile and decreased in vivo acute oral toxicity compared to the pure drug. The results of the phase solubility experiments are in good conformity to signify the formation of 1 : 1 PSC[4]R : LMN complexes. Computational studies were performed to understand the intermolecular association of this inclusion complex using docking and short dynamic simulations. The purpose of this study was to enhance solubility resulting in high dissolution rate and bioavailability of this essentially poorly water soluble drug LMN.

Compound prioritization from inverse docking experiment using receptor‐centric and ligand‐centric methods: a case study on Plasmodium falciparum Fab enzymes

Prioritization of compounds using inverse docking approach is limited owing to potential drawbacks in its scoring functions. Classically, molecules ranked by best or lowest binding energies and clustering methods have been considered as probable hits. Mining probable hits from an inverse docking approach is very complicated given the closely related protein targets and the chemically similar ligand data set. To overcome this problem, we present here a computational approach using receptor‐centric and ligand‐centric methods to infer the reliability of the inverse docking approach and to recognize probable hits. This knowledge‐driven approach takes advantage of experimentally identified inhibitors against a particular protein target of interest to delineate shape and molecular field properties and use a multilayer perceptron model to predict the biological activity of the test molecules. The approach was validated using flavone derivatives possessing inhibitory activities against principal antimalarial molecular targets of fatty acid biosynthetic pathway, FabG, FabI and FabZ, respectively. We propose that probable hits can be retrieved by comparing the rank list of docking, quantitative‐structure activity relationship and multilayer perceptron models. Copyright

Development of pharmacophore similarity-based quantitative activity hypothesis and its applicability domain: applied on a diverse data-set of HIV-1 integrase inhibitors

Quantitative pharmacophore hypothesis combines the 3D spatial arrangement of pharmacophore features with biological activities of the ligand data-set and predicts the activities of geometrically and/or pharmacophoric similar ligands. Most pharmacophore discovery programs face difficulties in conformational flexibility, molecular alignment, pharmacophore features sampling, and feature selection to score models if the data-set constitutes diverse ligands. Towards this focus, we describe a ligand-based computational procedure to introduce flexibility in aligning the small molecules and generating a pharmacophore hypothesis without geometrical constraints to define pharmacophore space, enriched with chemical features necessary to elucidate common pharmacophore hypotheses (CPHs). Maximal common substructure (MCS)-based alignment method was adopted to guide the alignment of carbon molecules, deciphered the MCS atom connectivity to cluster molecules in bins and subsequently, calculated the pharmacophore similarity matrix with the bin-specific reference molecules. After alignment, the carbon molecules were enriched with original atoms in their respective positions and conventional pharmacophore features were perceived. Distance-based pharmacophoric descriptors were enumerated by computing the interdistance between perceived features and MCS-aligned ‘centroid’ position. The descriptor set and biological activities were used to develop support vector machine models to predict the activities of the external test set. Finally, fitness score was estimated based on pharmacophore similarity with its bin-specific reference molecules to recognize the best and poor alignments and, also with each reference molecule to predict outliers of the quantitative hypothesis model. We applied this procedure to a diverse data-set of 40 HIV-1 integrase inhibitors and discussed its effectiveness with the reported CPH model.

Green tea potentially ameliorates bisphenol a-induced oxidative stress: an in vitro and in silico study.

The present investigation was an attempt to elucidate oxidative stress induced by bisphenol A on erythrocytes and its amelioration by green tea extract. For this, venous blood samples from healthy human adults were collected in EDTA vials and used for preparation of erythrocytes suspension. When erythrocyte suspensions were treated with different concentrations of BPA/H2O2, a dose-dependent increase in hemolysis occurred. Similarly, when erythrocytes suspensions were treated with either different concentrations of H2O2 (0.05–0.25 mM) along with BPA (50 μg/mL) or 0.05 mM H2O2 along with different concentrations of BPA (50–250 μg/mL), dose-dependent significant increase in hemolysis occurred. The effect of BPA and H2O2 was found to be additive. For the confirmation, binding capacity of bisphenol A with erythrocyte proteins (hemoglobin, catalase, and glutathione peroxidase) was inspected using molecular docking tool, which showed presence of various hydrogen bonds of BPA with the proteins. The present data clearly indicates that BPA causes oxidative stress in a similar way as H2O2 . Concurrent addition of different concentrations (10–50 μg/mL) of green tea extract to reaction mixture containing high dose of bisphenol A (250 μg/mL) caused concentration-dependent amelioration in bisphenol A-induced hemolysis. The effect was significant (P < 0.05). It is concluded that BPA-induced oxidative stress could be significantly mitigated by green tea extract.

Design, Synthesis, Biological Evaluation, and Molecular Modeling of Coumarin–Piperazine Derivatives as Acetylcholinesterase Inhibitors

Acetylcholinesterase (AChE) is an important drug target for the treatment of Alzheimers disease. A novel series of coumarin–piperazine derivatives were synthesized and their potency to inhibit human AChE enzyme (hAChE) was studied. All the final compounds were characterized by infrared, 1H NMR, 13C NMR, and elemental analysis. Docking experiments of the designed coumarin–piperazine derivatives were carried out in order to compare the theoretical and experimental binding affinities toward hAChE, to delineate the inhibitory mechanism. Subsequently, a structure–activity relationship (SAR) study using the molecular field method showed that the hydrophobic field and positive charge center conferred by the coumarin and piperazine moieties demonstrated an inhibitory mechanism. Among the compounds tested, 3f, 3j, and 3m were found to be the most potent inhibitors of hAChE.

Evolutionary and molecular aspects of Indian tomato leaf curl virus coat protein.

Tomato leaf curl disease (ToLCD) is manifested by yellowing of leaf lamina with upward leaf curl, leaf distortion, shrinking of the leaf surface, and stunted plant growth caused by tomato leaf curl virus (ToLCV). In the present study, using computational methods we explored the evolutionary and molecular prospects of viral coat protein derived from an isolate of Vadodara district, Gujarat (ToLCGV-[Vad]), India. We found that the amino acids in coat protein required for systemic infection, viral particle formation, and insect transmission to host cells were conserved amongst Indian strains. Phylogenetic studies on Indian ToLCV coat proteins showed evolutionary compatibility with other viral taxa. Modeling of coat protein revealed a topology similar to characteristic Geminate viral particle consisting of antiparallel β-barrel motif with N-terminus α-helix. The molecular interaction of coat protein with the viral DNA required for encapsidation and nuclear shuttling was investigated through sequence- and structure-based approaches. We further emphasized the role of loops in coat protein structure as molecular recognition interface.

Pharmacophore-similarity-based QSAR (PS-QSAR) for group-specific biological activity predictions

Recent technological breakthroughs in medicinal chemistry arena had ameliorated the perspectives of quantitative structure–activity relationship (QSAR) methods. In this direction, we developed a group-based QSAR method based on pharmacophore-similarity concept which takes into account the 2D topological pharmacophoric descriptors and predicts the group-specific biological activities. This activity prediction may assist the contribution of certain pharmacophore features encoded by respective fragments toward activity improvement and/or detrimental effects. We termed this method as pharmacophore-similarity-based QSAR (PS-QSAR) and studied the activity contribution of fragments from 3-hydroxypyridinones derivatives possessing antimalarial activities.

Structural Insights into the Theoretical Model of Plasmodium falciparum NADH Dehydrogenase and its Interaction with Artemisinin and Derivatives: Towards Global Health Therapeutics

It is a continuing quest to uncover the principal molecular targets of malarial parasites to understand the antimalarial activity and mechanism of action of artemisinin, a potent antimalarial. A series of parasite proteins are experimentally validated as potential targets, such as translationally controlled tumor protein (TCTP) and sarco/endoplasmic reticulum membrane calcium ATP-ase (SERCA). The present study addressed the development of a theoretical model of Plasmodium falciparum NADH dehydrogenase with inference from artemisinin in vivo inhibitory activity. We report here the predicted binding modes of artemisinin and its derivatives. The modeled protein resembled the structural architecture of flavoproteins and oxidoreductases, consisting of two Rossmann folds and dedicated binding sites for its cofactors. Docked poses of the ligand dataset revealed its interactions at or near the si face, indicating being activated. This may aid in generation of reactive oxygen species, thereby disrupting the membrane potential of parasite mitochondria and leading to the clearance from the blood. These observations open up new strategies for development of novel therapeutics, or improvement of existing pharmacotherapies against malaria, a major burden for global health.