A-kinase anchoring proteins are enriched in the central pair microtubules of motile cilia in Chlamydomonas reinhardtii.

Cilia are microtubule-based sensory organelles present in a number of eukaryotic cells. Mutations in the genes encoding ciliary proteins cause ciliopathies in humans. A-kinase anchoring proteins (AKAPs) tether ciliary signaling proteins such as protein kinase A (PKA). The dimerization and docking domain (D/D) on the RIIα subunit of PKA interacts with AKAPs. Here, we show that AKAP240 from the central-pair microtubules of Chlamydomonas reinhardtii cilia uses two C-terminal amphipathic helices to bind to its partner FAP174, an RIIα-like protein with a D/D domain at the N-terminus. Co-immunoprecipitation using anti-FAP174 antibody with an enriched central-pair microtubule fraction isolated seven interactors whose mass spectrometry analysis revealed proteins from the C2a (FAP65, FAP70, and FAP147) and C1b (CPC1, HSP70A, and FAP42) microtubule projections and FAP75, a protein whose sub-ciliary localization is unknown. Using RII D/D and FAP174 as baits, we identified two additional AKAPs (CPC1 and FAP297) in the central-pair microtubules.

Prediction of QcrB Inhibition as a Measure of Antitubercular Activity with Machine Learning Protocols.

It has always been a challenge to develop interventional therapies for Mycobacterium tuberculosis. Over the years, several attempts at developing such therapies have hit a dead-end owing to rapid mutation rates of the tubercular bacilli and their ability to lay dormant for years. Recently, cytochrome bcc complex (QcrB) has shown some promise as a novel target against the tubercular bacilli, with Q203 being the first molecule acting on this target. In this paper, we report the deployment of several ML-based approaches to design molecules against QcrB. Machine learning (ML) models were developed based on a data set of 350 molecules using three different sets of molecular features, i.e., MACCS keys, ECFP6 fingerprints, and Mordred descriptors. Each feature set was trained on eight ML classifier algorithms and optimized to classify molecules accurately. The support vector machine-based classifier using the ECFP6 feature set was found to be the best classifier in this study. Further, screening of the known imidazopyridine amide inhibitors demonstrated that the model correctly classified the most potent molecules as actives, hence validating the model for future applications.

Amalgamation of comparative protein modeling with quantitative structure-retention relationship for prediction of the chromatographic behavior of peptides.

Peptide therapeutics plays a prominent role in medical practice. Both peptides and proteins have been used in several disease conditions like diabetes, cancer, bacterial infections etc. The optimization of a peptide library is a time consuming and expensive chore. The tools of computational chemistry offer a way to optimize the properties of peptides. Quantitative Structure Retention (Chromatographic) Relationships (QSRR) is a powerful tool which statistically derives relationships between chromatographic parameters and descriptors that characterize the molecular structure of analytes. In this paper, we show how Comparative Protein ModelingQuantitative Structure Retention Relationship (acronym ComProM-QSRR) can be used to predict the retention time of peptide sequences. This formalism is founded on our earlier published QSAR methodology HomoSAR. ComProM-QSRR can recognize and distinguish the contribution of amino acids at specific positions in the peptide sequences to the retention phenomena through their related physicochemical properties. This study firmly establishes the fact that this approach can be pragmatically used to predict the retention time to all classes of peptides regardless of size or sequence.

Design, synthesis and SAR of antitubercular benzylpiperazine ureas.

N-furfuryl piperazine ureas disclosed by scientists at GSK Tres Cantos were chosen as antimycobacterial hits from a phenotypic whole-cell screen. Bioisosteric replacement of the furan ring in the GSK Tres Cantos molecules with a phenyl ring led to molecule (I) with an MIC of 1 µM against Mtb H37Rv, low cellular toxicity (HepG2 IC50 ~ 80 µM), good DMPK properties and specificity for Mtb. With the aim of delineating the SAR associated with (I), fifty-five analogs were synthesized and screened against Mtb. The SAR suggests that the piperazine ring, benzyl urea and piperonyl moieties are essential signatures of this series. Active compounds in this series are metabolically stable, have low cellular toxicity and are valuable leads for optimization. Molecular docking suggests these molecules occupy the Q0 site of QcrB like Q203. Bioisosteric replacement of N-furfuryl piperazine-1-carboxamides yielded molecule (I) a novel lead with satisfactory PD, metabolism, and toxicity profiles.

Identification of potential antileishmanial 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-ones, in vitro metabolic stability, cytotoxicity and molecular modeling studies.

We report the synthesis and in vitro evaluation of 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one derivatives against Leishmania donovani. Amongst the compound library synthesized, molecules 3d, 3f, 3h, 3i, 3l, and 3m demonstrated substantial dose-dependent killing of the promastigotes. Their IC50 values range from 55.0 to 77.0 µg/ml, with 3m (IC50 55.75 µg/ml) being equipotent with amphotericin B (IC50 50.0 µg/ml, used as standard). The most active compound 3m, is metabolically stable in rat liver microsomes. Furthermore, the molecules are highly specific against leishmania as shown by their weak antibacterial and antifungal activity. In vitro cytotoxicity studies show the compounds lack any cytotoxicity. Furthermore, molecular modeling studies show plausibility of binding to Leishmania donovani topoisomerase 1 (LdTop1). Structure activity relationships reveal bulky substitutions on the pyridone nitrogen are well-tolerated, and such compounds have better binding affinity. Intramolecular hydrogen bonds confer some rigidity to the molecules, rendering a degree of planarity akin to topotecan. Taken together, we emphasis the merits of molecules possessing the 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one skeleton as potential antileishmanial agents warranting further investigation.

Novel p-Functionalized Chromen-4-on-3-yl Chalcones Bearing Astonishing Boronic Acid Moiety as MDM2 Inhibitor: Synthesis, Cytotoxic Evaluation and Simulation Studies.

BACKGROUND: Novel 4-[3-(6/7/8-Substituted 4-Oxo-4H-chromen-3-yl)acryloyl]phenylboronic acid derivatives (5a-h) as well as other 6/7/8-substituted-3-(3-oxo-3-(4-substitutedphenyl) prop-1-enyl)-4H-chromen-4-one derivatives (3a-u) have been designed as p53-MDM2 pathway inhibitors and reported to possess significant cytotoxic properties against several cancer cell lines. OBJECTIVES: The current project aims to frame the structure-anticancer activity relationship of chromen-4-on-3-yl chalcones (3a-u/5a-h). In addition, docking studies were performed on these chromeno-chalcones in order to have an insight into their interaction possibilities with MDM2 protein. METHODS: Twenty-nine chromen-4-on-3-yl chalcone derivatives (3a-u/5a-h) were prepared by utilizing silica supported-HClO4 (green route with magnificent yield) and tested against four cancer cell lines (HCT116, MCF-7, THP-1, NCIH322). RESULTS: Among the series 3a-u, compound 3b exhibited the highest anticancer activity (with IC50 values ranging from 8.6 to 28.4 µM) overall against tested cancer cell lines. Interestingly, para- Boronic acid derivative (5b) showed selective inhibition against colon cancer cell line, HCT-116 with an IC50 value of 2.35 µM. Besides the emblematic hydrophobic interactions of MDM2 inhibitors, derivative 5b was found to exhibit extra hydrogen bonding with GLN59 and GLN72 residues of MDM2 in molecular dynamics (MD) simulation. All the compounds were virtually nontoxic against normal fibroblast cells. CONCLUSION: Novel compounds were obtained with good anticancer activity especially 6- Chlorochromen-4-one substituted boronic acid derivative 5b. The molecular docking study proposed good activity as a MDM-2 inhibitor suggesting hydrophobic as well as hydrogen bonding interactions with MDM2.

4-Hydroxy-2-pyridone Derivatives and the δ-pyrone Isostere as Novel Agents Against Mycobacterium smegmatis Biofilm Inhibitors.

BACKGROUND: The treatment of a bacterial infection when the bacterium is growing in a biofilm is a vexed issue. This is because the bacteria in a biofilm behaves differently compared to the individual planktonic free-form. As a result, traditional antibacterial agents lose their activity. OBJECTIVE: Presently, there are not many drugs that are effective against bacteria growing in biofilms. Based on literature reports, we have sought to develop novel derivatives of 4-hydroxy-2- pyridone as both antimycobacterial and antibiofilm agents. METHODS: The pyridone derivatives were synthesized by reacting 4-hydroxy-6-methyl-2H-pyran-2- one with appropriate amines and followed by reaction with substituted phenyl isocyanates as reported in the literature. RESULTS: Four compounds in this series significantly inhibit the growth and formation of biofilm by Mycobacterium smegmatis (mc2 155 strain) at 50 µg/ml. Further, in silico evaluation of the ADME parameters shows that these compounds possess good drug-like properties and have the potential to be developed both as antibiofilm and as oral antimycobacterial agents. CONCLUSION: This finding is of significance as presently very few small molecules are known to inhibit biofilm formation in mycobacteria. These compounds are unique in the sense that they are more potent against Mycobacterium smegmatis in the biofilm state compared to the planktonic form.

Preferential Formulation of Second Generation Antipsychotic Asenapine as Inclusion Complex with Sulphobutylether-ßCD (Captisol): In vitro and In vivo Evaluation.

BACKGROUND: Asenapine is an anti-psychotic agent approved by the US-FDA for treatment of acute schizophrenia and manic or bipolar I disorder in adults. It is poorly absorbed when administered orally, hence exhibits poor oral bioavailability, which limits its use in clinical practice. OBJECTIVE: Enhancement in solubility of asenapine through complexation with three different cyclodextrins, viz. ßCD, HPßCD and sulphobutylether-ßCD (Captisol®) was attempted and compared due to its poor bioavailability. METHOD: Kneading method was used for preparation of inclusion complexes which were characterized by FTIR, DSC, and XRD methods. Extent of binding and stability of the 1:1 inclusion complexes were evaluated by molecular modelling and phase solubility studies. Pharmacokinetic studies were also carried out of these inclusion complexes. RESULTS: Captisol® complex was the most stable amongst all complexes showing 4.9 times solubility enhancement of asenapine and 96% drug release at the end of 60 min, whereas asenapine maleate (uncomplexed drug) was released completely at the end of 120min. The Cmax and AUC values of Captisol® asenapine complex (AS-Captisol complex) were 2.8 and 2.3 times higher than the uncomplexed drug. CONCLUSION: This study thus demonstrated that Captisol® inclusion complex is an effective strategy for solubility and bioavailability enhancement of asenapine.

Discovery of new leads against Mycobacterium tuberculosis using scaffold hopping and shape based similarity.

BM212 [1,5-diaryl-2-methyl-3-(4-methylpiperazin-1-yl)-methyl-pyrrole] is a pyrrole derivative with strong inhibitory activity against drug resistant Mycobacterium tuberculosis and mycobacteria residing in macrophages. However, it was not pursued because of its poor pharmacokinetics and toxicity profile. Our goal was to design and synthesize new antimycobacterial BM212 analogs with lower toxicity and better pharmacokinetic profile. Using the scaffold hopping approach, three structurally diverse heterocycles - 2,3-disubstituted imidazopyridines, 2,3-disubstituted benzimidazoles and 1,2,4-trisubstituted imidazoles emerged as promising antitubercular agents. All compounds were synthesized through easy and convenient methods and their structures confirmed by IR, 1H NMR, 13C NMR and MS. In-vitro cytotoxicity studies on normal kidney monkey cell lines and HepG2 cell lines, as well as metabolic stability studies on rat liver microsomes for some of the most active compounds, established that these compounds have negligible cytotoxicity and are metabolically stable. Interestingly the benzimidazole compound (4a) is as potent as the parent molecule BM212 (MIC 2.3µg/ml vs 0.7-1.5µg/ml), but is devoid of the toxicity against HepG2 cell lines (IC50 203.10µM vs 7.8µM).

Soluble curcumin amalgamated chitosan microspheres augmented drug delivery and cytotoxicity in colon cancer cells: In vitro and in vivo study.

In present investigation, initially curcumin was complexed with 2-HP-ß-CD (curcumin-2-HP-ß-CD-complex) in 1:1 ratio and later amalgamated with chitosan microspheres (curcumin-2-HP-ß-CD-CMs) for selective delivery in colon only through oral route of administration. Various analytical, spectral and in-silico docking techniques revealed that the curcumin was deeply inserted in the 2-HP-ß-CD cavity with apparent stability constant of 3.35×10-3M. Furthermore, the mean particle size of 6.8±2.6µm and +39.2±4.1mV surface charge of curcumin-2-HP-ß-CD-complex-CMs in addition to encapsulation efficiency of about 79.8±6.3% exhibited that the tailored microspheres were optimum for colon delivery of curcumin. This was also demonstrated in dissolution testing and standard cell proliferation assay in which curcumin-2-HP-ß-CD-complex-CMs exhibited maximum release in simulated colonic fluid (SCF, pH ∼7.0-8.0, almond emulsion-ß-glucosidase) with improved therapeutic index in HT-29 cells. Consistently, curcumin-2-HP-ß-CD-complex-CMs successively enhanced the colonic bio-distribution of curcumin by ∼8.36 folds as compared to curcumin suspension in preclinical pharmacokinetic studies. In conclusion, curcumin-2-HP-ß-CD-complex-CMs warrant further in vivo tumor regression study to establish its therapeutic efficacy in experimental colon cancer.

A Computational Model for Docking of Noncompetitive Neuraminidase Inhibitors and Probing their Binding Interactions with Neuraminidase of Influenza Virus H5N1.

BACKGROUND: With cases of emergence of drug resistance to the current competitive inhibitors of neuraminidase (NA) such as oseltamivir and zanamavir, there is a present need for an alternative approach in the treatment of avian influenza. With this in view, some flavones and chalcones were designed based on quercetin, the most active naturally occurring noncompetitive inhibitor. OBJECTIVE: We attempt to understand the binding of quercetin to H5N1-NA, and synthetic analogs of quercetin namely flavones and its precursors the chalcones using computational tools. METHODS: Molecular docking was done using Libdock. Molecular dynamics (MD) simulations were performed using Amber14. We synthesized the two compounds; their structures were confirmed by infrared spectroscopy, 1H-NMR, and mass spectrometry. These molecules were then tested for H5N1-NA inhibition and kinetics of inhibition. RESULTS: Molecular docking studies yielded two compounds i.e., 4'-methoxyflavone and 2'-hydroxy-4-methoxychalcone, as promising leads which identified them as binders of the 150-cavity of NA. Furthermore, MD simulation studies revealed that quercetin and the two compounds bind and hold the 150 loop in its open conformation, which ultimately perturbs the binding of sialic acid in the catalytic site. Estimation of the free energy of binding by MM-PBSA portrays quercetin as more potent than chalcone and flavone. These molecules were then determined as non-competitive inhibitors from the Lineweaver-Burk plots rendered from the enzyme kinetic studies. CONCLUSION: We conclude that non-competitive type of inhibition, as shown in this study, can serve as an effective method to block NA and evade the currently seen drug resistance.

Characterization of pioglitazone cyclodextrin complexes: Molecular modeling to in vivo evaluation.

AIMS: The objective of present study was to study the influence of different ß-cyclodextrin derivatives and different methods of complexation on aqueous solubility and consequent translation in in vivo performance of Pioglitazone (PE). MATERIAL AND METHODS: Three cyclodextrins: ß-cyclodextrin (BCD), hydroxypropyl-ß-cyclodextrin (HPBCD) and Sulfobutylether-7-ß-cyclodextrin (SBEBCD) were employed in preparation of 1:1 Pioglitazone complexes by three methods viz. co-grinding, kneading and co-evaporation. Complexation was confirmed by phase solubility, proton NMR, Fourier Transform Infrared spectroscopy, Differential Scanning Calorimetry (DSC) and X-Ray diffraction (XRD). Mode of complexation was investigated by molecular dynamic studies. Pharmacodynamic study of blood glucose lowering activity of PE complexes was performed in Alloxan induced diabetic rat model. RESULTS: Aqueous solubility of PE was significantly improved in presence of cyclodextrin. Apparent solubility constants were observed to be 254.33 M(-1) for BCD-PE, 737.48 M(-1) for HPBCD-PE and 5959.06 M(-1) for SBEBCD-PE. The in silico predictions of mode of inclusion were in close agreement with the experimental proton NMR observation. DSC and XRD demonstrated complete amorphization of crystalline PE upon inclusion. All complexes exhibited >95% dissolution within 10 min compared to drug powder that showed <40% at the same time. Marked lowering of blood glucose was recorded for all complexes. CONCLUSION: Complexation of PE with different BCD significantly influenced its aqueous solubility, improved in vitro dissolution and consequently translated into enhanced pharmacodynamic activity in rats.

Evaluation of risedronate as an antibiofilm agent.

Escherichia coli cra null mutants have been reported in the literature to be impaired in biofilm formation. To develop E. coli biofilm-inhibiting agents for prevention and control of adherent behaviour, analogues of a natural Cra ligand, fructose-1,6-bisphosphate, were identified based on two-dimensional similarity to the natural ligand. Of the analogues identified, those belonging to the bisphosphonate class of drug molecules were selected for study, as these are approved for clinical use in humans and their safety has been established. Computational and in vitro studies with purified Cra protein showed that risedronate sodium interacted with residues in the fructose-1,6-bisphosphate-binding site. Using a quantitative biofilm assay, risedronate sodium, at a concentration of 300-400 µM, was found to decrease E. coli and Salmonella pullorum biofilm formation by >60 %. Risedronate drastically reduced the adherence of E. coli cells to a rubber Foley urinary catheter, demonstrating its utility in preventing the formation of biofilm communities on medical implant surfaces. The use of risedronate, either alone or in combination with other agents, to prevent the formation of biofilms on surfaces is a novel finding that can easily be translated into practical applications.

Design, synthesis and evaluation of benzotriazole derivatives as novel antifungal agents.

Considering the need for discovery of new antifungal drugs with greater potency and broader spectrum of activity, a new series of 5-substituted benzotriazole derivatives were designed, through structure based design, as inhibitors of fungal cytochrome P450 lanosterol 14-α demethylase. These were further optimized by a combination of iterative medicinal chemistry principles and molecular docking. Based on the best docking scores, some benzotriazole derivatives were synthesized and characterized by IR, (1)H NMR and MS/MS. The molecules were evaluated for their antifungal action against Candida albicans by cup plate method and ergosterol quantification method by UV spectroscopy. Reasonably good correlation between docking scores and antifungal activity were observed. The computational predictions were in consensus with the experimental results.

Drug-DNA Interaction Studies of Acridone-Based Derivatives.

N10-alkylated 2-bromoacridones are a novel series of potent antitumor compounds. DNA binding studies of these compounds were carried out using spectrophotometric titrations, Circular dichroism (CD) measurements using Calf Thymus DNA (CT DNA). The binding constants were identified at a range of K=0.3 to 3.9×10(5) M(-1) and the percentage of hypochromism from the spectral titrations at 28-54%. This study has identified a compound 9 with the good binding affinity of K=0.39768×10(5) M(-1) with CT DNA. Molecular dynamics (MD) simulations have investigated the changes in structural and dynamic features of native DNA on binding to the active compound 9. All the synthesized compounds have increased the uptake of Vinblastine in MDR KBChR-8-5 cells to an extent of 1.25- to1.9-fold than standard modulator Verapamil of similar concentration. These findings allowed us to draw preliminary conclusions about the structural features of 2-bromoacridones and further chemical enhancement will improve the binding affinity of the acridone derivatives to CT-DNA for better drug-DNA interaction. The molecular modeling studies have shown mechanism of action and the binding modes of the acridones to DNA.

New horizons in antimalarial drug discovery in the last decade by chemoinformatic approaches.

Antimalarial drug discovery process is progressively carried out by a combination of innovation and knowledge based methods that include computational and experimental approaches to achieve potent leads. Among the various computational approaches, chemoinformatics plays a critical role in the discovery of new leads or drug candidates. Chemoinformatics provides researchers tools to derive information on substructures, chemical space, similarity and diversity. It also helps to manage and store chemical data, study important molecular properties and filter libraries with regard to specified criteria in the database. To accomplish these ends it uses various tools amongst which are docking, 3D-QSAR, similarity search, virtual screening, database mining and pharmacophore mapping. This review is a perspective of the utility of chemoinformatic approaches in antimalarial drug design. It covers various facets such as targets that have been exploited for antimalarial drug discovery by chemoinformatic methods; potential antimalarial targets that have not yet been explored; the challenges faced in antimalarial drug discovery, and future directions for discovery of novel antimalarial agents.

How good are ensembles in improving QSAR models? The case with eCoRIA.

A conceptually new idea in quantitative structure-activity relationships (QSAR) which makes use of ensembles from molecular dynamics (MD) trajectories and information retrieved from enzyme-inhibitor binding thermodynamics is presented in this study. This new methodology, termed ensemble comparative residue interaction analysis (eCoRIA), attempts to overcome the current one chemical-one structure-one parameter value dogma in computational chemistry by modeling the biological activity as a function of molecular descriptors derived from an ensemble of conformers of enzyme-inhibitor complexes. The approach is distinctly different from the standard QSAR methodology which uses a single low-energy conformation or the properties averaged over a set of conformers to correlate with the activity. Each conformational ensemble derived from MD simulations is analyzed for the distribution of the non-bonded interaction energies (steric, electrostatic, and hydrophobic) along with solvation, strain, and entropic energy of the inhibitors with the individual amino acid residues in the receptor and these are correlated to the activity through a QSAR model. The scope of the new method is demonstrated with three diverse enzyme-inhibitor data-sets - glycogen phosphorylase b, human immunodeficiency virus-1 protease and cyclin-dependent kinase 2. The QSAR equations derived from the methodology have revealed all the structure activity relationships previously reported for these classes of molecules as well as uncovered some features that were hitherto unknown and may have a hidden role in driving the ligand-receptor-binding process. Impressive improvements in the predictions of affinity have been achieved compared to other QSAR formalisms namely CoMFA, CoMSIA (receptor-independent QSAR techniques), and CoRIA (a receptor-dependent QSAR technique). eCoRIA could provide an understanding of the thermodynamic properties influencing the ligand-receptor binding over a time scale as sampled by the MD simulation. The advantage of analyzing enzyme-inhibitor interaction energies in a statistical domain is that the noise due to inaccuracies in the potential energy functions can be reduced and mechanistically important interaction terms related to protein-ligand binding specificity can be identified which can assist the medicinal chemists in designing new molecules and biologists in studying the influence of position-specific mutations in the receptor on ligand binding.

Quantifying ligand-receptor interactions for gorge-spanning acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.

There is a need for continued development of acetylcholinesterase (AChE) inhibitors that could prolong the life of acetylcholine in the synaptic cleft and also prevent the aggregation of amyloid peptides associated with Alzheimer's disease. The lack of a 3D-QSAR model which specifically deconvulates the type of interactions and quantifies them in terms of energies has motivated us to report a CoRIA model vis-à-vis the standard 3D-QSAR methods, CoMFA and CoMSIA. The CoRIA model was found to be statistically superior to the CoMFA and CoMSIA models and it could efficiently extract key residues involved in ligand recognition and binding to AChE. These interactions were quantified to gauge the magnitude of their contribution to the biological activity. In order to validate the CoRIA model, a pharmacophore map was first constructed and then used to virtually screen public databases, from which novel scaffolds were cherry picked that were not present in the training set. The biological activities of these novel molecules were then predicted by the CoRIA, CoMFA, and CoMSIA models. The hits identified were purchased and their biological activities were measured by the Ellman's method for AChE inhibition. The predicted activities are in unison with the experimentally measured biological activities.

Targeting dormant tuberculosis bacilli: results for molecules with a novel pyrimidone scaffold.

Our inability to completely control TB has been due in part to the presence of dormant mycobacteria. This also renders drug regimens ineffective and is the prime cause of the appearance of drug-resistant strains. In continuation of our efforts to develop novel antitubercular agents that especially target dormant mycobacteria, a set of 55 new compounds belonging to the pyrimidone class were designed on the basis of CoMFA and CoMSIA studies, and these were synthesized and subsequently tested against both the dormant and virulent BCG strain of M. tuberculosis. Some novel compounds have been identified which selectively inhibit the dormant tuberculosis bacilli with significantly low IC50 values. This study reports the second molecule after TMC-207, having the ability to inhibit tuberculosis bacilli exclusively in its dormant phase. The synthesis was accomplished by a modified multicomponent Biginelli reaction. A classification model was generated using the binary QSAR approach--recursive partitioning (RP) to identify structural characteristics related to the activity. Physicochemical, structural, topological, connectivity indices, and E-state key descriptors were used for generation of the decision tree. The decision tree could provide insights into structure-activity relationships that will guide the design of more potent inhibitors.

CoRILISA: a local similarity based receptor dependent QSAR method.

Molecular similarity methods have played a crucial role in the success of structure-based and computer-assisted drug design. However, with the exception of CoMSIA, the current approaches for estimating molecular similarity yield a global picture thereby providing limited information about the local spatial molecular features responsible for the variation of activity with the 3D structure. Application of molecular similarity measures, each related to the functional "pieces" of a ligand-receptor complex, is advantageous over a composite molecular similarity alone and will provide more insights to rationally interpret the activity based on the receptor and ligand structural features. Building on the ideas of our previously published methodologies-CoRIA and LISA, we present here a local molecular similarity based receptor dependent QSAR method termed CoRILISA which is a hybrid of the two approaches. The method improves on previous techniques by inclusion of receptor attributes for the calculation and comparison of similarity between molecules. For validation studies, the CoRILISA methodology was applied on three large and diverse data sets-glycogen phosphorylase b (GPb), human immunodeficiency virus-1 protease (HIV PR), and cyclin dependent kinase 2 (CDK2) inhibitors. The statistics of the CoRILISA models were benchmarked against the standard CoRIA approach and with other published approaches. The CoRILISA models were found to be significantly better, especially in terms of the predictivity for the test set. CoRILISA is able to identify the thermodynamic properties associated with residues that define the active site and modulate the variation in the activity of the molecules. It is a useful tool in the fragment-based drug discovery approach for ligand activity prediction.