BITS Faculty Publications
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Item Structure-based virtual screening of FDA-approved drugs to discover potential inhibitors of phosphoinositide kinase, PIKfyve(Taylor & Francis, 2024-05) Jadhav, Hemant R.The phosphoinositide kinase, PIKfyve is a lipid kinase that plays a vital role in membrane trafficking, endosomal transport, retroviral budding, and toll-like receptor signaling. Thus, it has emerged as a potential therapeutic target for several diseases, including, cancer, viral infections, and autoimmune diseases. However, a limited number of PIKfyve inhibitors have been reported so far. Herein, we report a structure-based virtual screening-driven identification of new PIKfyve inhibitors from a library of FDA-approved small molecule drugs. Labetalol, capsaicin and ibrutinib occupy the ATP pocket of PIKfyve with dock scores of −10.3, −10.6 and −12.24 kcal/mol, and MMGBSA binding energy of −57.3, −53.7 and −66.4 kcal/mol, respectively. These drugs inhibit PIKfyve with IC50 values of 0.292, 0.965 and 0.678 µM, respectively, in an in vitro ADP-Glo kinase assay. Among the top hits from SBVS, labetalol as well as capsaicin display a stable interaction with the critical amino acid, LEU 119 of the hinge region during the 100 ns MD simulation. The results obtained herein warrant the exploration of these new inhibitors in preclinical disease models.Item New Patchy Particle Model with Anisotropic Patches for Molecular Dynamics Simulations: Application to a Coarse-Grained Model of Cellulose Nanocrystal(ACS, 2020-05) Garg, MohitSelf-assembly is ubiquitous in nature and underlies the formation of many complex systems from the molecular to the macroscopic scale. Kern–Frenkel-like patchy particles are powerful models to investigate this phenomenon by computational methods such as Monte Carlo or molecular dynamics simulations. However, in these models the interactions are mediated by circular patches at the particle surface, which can be hardly mapped to realistic systems, containing for instance faceted particles with rectangular surfaces. In this paper we extend the model to take into account such geometries, and we use it to build a supra coarse-grained model of the cellulose nanocrystal where the interactions are parametrized against all-atomistic molecular dynamics simulations. The formation of cholesteric ribbons and defects in cholesteric droplets of the cellulose nanocrystal are investigated and confirm experimental behavior reported in the literature. The flexibility of this new patchy particle model makes it a powerful tool to develop supra coarse-grained models of self-assembly for large space and time scales and should find a broad range of applications for self-assembly in chemical and biological systems.Item Dynamics and Rheology of Polymer Melts via Hierarchical Atomistic, Coarse-Grained, and Slip-Spring Simulations(ACS, 2021-02) Jana, Pritam KumarA hierarchical (triple scale) simulation methodology is presented for the prediction of the dynamical and rheological properties of high molecular-weight entangled polymer melts. The methodology consists of atomistic, moderately coarse-grained (mCG), and highly coarse-grained slip-spring (SLSP) simulations. At the mCG level, a few chemically bonded atoms are lumped into one coarse-grained bead. At this level, the chemical identity of the underlying atomistic system and the interchain topological constraints (entanglements) are preserved. The mCG interaction potentials are derived by matching local structural distributions of the mCG model to those of the atomistic model through iterative Boltzmann inversion. For matching mCG and atomistic dynamics, the mCG time is scaled by a time scaling factor, which compensates for the lower monomeric friction coefficient of the mCG model than that of the atomistic one. At the SLSP level, multiple Kuhn segments of a polymer chain are represented by one coarse-grained bead. The very soft nonbonded interactions between beads do not prevent chain crossing and, hence, can not capture entanglements. The topological constraints are represented by slip-springs, restricting the lateral motion of polymer chains. A compensating pair potential is used in the SLSP model to keep the static macromolecular properties unaltered upon the introduction of slip-springs. The static and kinetic parameters of the SLSP model are determined based on the lower-level simulation models. Particularly, matching the orientational autocorrelation of the end-to-end vector, we determine the number of slip-springs and calibrate the timescale of the SLSP model. As a test case, the hierarchical methodology is applied to cis-1,4-polybutadiene (cPB) at 413 K. Dynamical single-chain and linear viscoelastic properties of cPB melts are calculated for a broad range of molecular weights, ranging from unentangled to well-entangled chains. The calculations are compared, and found in good agreement, with experimental data from the literature.Item Dynamics of Long Entangled Polyisoprene Melts via Multiscale Modeling(ACS, 2021-09) Jana, Pritam KumarA recently proposed hierarchical triple-scale simulation methodology (Behbahani et al., Macromolecules, 2021,54, 2740–2762) is applied to cis-1,4 polyisoprene melts of a broad range of molecular weights, from oligomers to commercial-grade entangled materials. Dynamics are systematically probed over 12 orders of magnitude in time using a combination of atomistic and bottom-up parameterized coarse-grained and slip-spring simulations. Following calibration of the slip-spring simulations using the end-to-end autocorrelation function, generated data are contrasted to dielectric relaxation spectroscopy experiments and rheological measurements in the literature. A good agreement is found, particularly for highly entangled polymer melts, supporting the ability of the scheme to provide bottom-up parameter-free predictions on the dynamics of polymeric materials. Finally, we systematically examine the application of theoretical models to our strictly monodisperse cis-1,4 polyisoprene melts and provide estimates of the phenomenological parameters employed.Item Molecular Interactions at Interfaces(Intechopen, 2012-02) Manjuladevi, V.; Gupta, Raj KumarThe study on molecular organization and structure formation at the nanometer length scale is important due to its vast application in the field of nanoscience and nanotechnology. Molecular interactions play a pivotal role in the process of molecular assembly. The properties of materials can be maneuvered precisely by manipulating the structures at the nanometer length scale. The field of thin films science and technology has been growing remarkably due to its enormous industrial applications. The properties of thin films depend on the nature of the adsorbate and the structures on the surface. The structures of the thin films on a surface leads to the growth of bulk material, and hence the material properties can be controlled by manipulating the structures of the thin films. The form of such structures depends on the molecule-substrate and intermolecular interactions. The development of thin films science and technology has influenced the field of nanoscience and nanotechnology significantly. In this chapter, we discuss the role of molecular interactions in ultrathin films at air-water (A-W) and air-solid (A-S) interfaces. We form monomolecular thick films on the surface of water and study the film stability, surface phases, and other thermodynamical parameters. We found that the stability of the films at the A-W interface primarily depends on the molecular-surface and intermolecular interaction. Amphiphilic molecules, when spread on the water surface, form a monomolecular thick film at A-W interface. Such monomolecular thick film is known as Langmuir monolayer. An amphiphilic molecule has two parts : hydrophilic (water loving) and hydrophobic (water hating) part. When such molecules with a proper balance between hydrophilic and hydrophobic parts are dispersed on water surface, the hydrophilic part gets anchored to the water surface whereas the hydrophobic part stays away from the water surface. Under such condition, the anchored molecules are constrained to move on the two dimensional smooth water surface. The surface density can be varied and a corresponding change in surface tension is recorded. A Langmuir monolayer has proved to be an ideal two dimensional system not only for studying the thermodynamics but also for depositing the films on different types of substrates by vertical deposition mechanism in a highly controlled manner. Such films at A-S interface are known as Langmuir-Blodgett (LB) filmsItem 2-Substituted 4,5-dihydrothiazole-4-carboxylic acids are novel inhibitors of metallo-β-lactamases(Elsevier, 2022-10) Sundriyal, SandeepBacterial resistance to β-lactam antibiotics caused by class B metallo-β-lactamases (MBL), especially for certain hospital-acquired, Gram-negative pathogens, poses a significant threat to public health. We report several 2-substituted 4,5-dihydrothiazole-4-carboxylic acids to be novel MBL inhibitors. Structure activity relationship (SAR) and molecular modeling studies were performed and implications for further inhibitor design are discussed.Item Modeling and Informatics in Designing Anti-Diabetic Agents(Bentham Science, 2007) Sundriyal, SandeepDiabetes mellitus is a chronic metabolic disorder, characterized by glucose overproduction and glucose underutilization. Current therapy for T2DM includes drugs, like metformin, glitazones, sulphonyl ureas, etc. Extensive research has been carried out world wide on molecular targets for T2DM like PPARγ, PTP1B, DPP-IV, GSK-3, cannabinoid receptor, fructose-bisphosphatases, β3 adrenoceptor, etc. in the development of newer anti-diabetic agents. These therapeutic targets are quite important and most of them are suitable for in silico analysis. Hence, many molecular modeling and informatics studies like, molecular docking, pharmacophore mapping, 3DQSAR, virtual screening, quantum chemical studies, and pharmacoinformatics like bioinformatics and chemoinformatics studies have been performed on the drugs / leads / targets associated with T2DM. Several of these in silico efforts are exemplary studies; the methodologies adopted in these studies can be emulated in many other therapeutic areas. A review of the rational approaches reported in designing anti-diabetic agents is presented in this article.Item Discovery of Novel Coumarin-Schiff Base Hybrids as Potential Acetylcholinesterase Inhibitors: Design, Synthesis, Enzyme Inhibition, and Computational Studies(MDPI, 2023-07) Murugesan, SankaranarayananTo discover anti-acetylcholinesterase agents for the treatment of Alzheimer’s disease (AD), a series of novel Schiff base-coumarin hybrids was rationally designed, synthesized successfully, and structurally characterized using Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR), and High-Resolution Mass Spectrometry (HRMS) analyses. These hybrids were evaluated for their potential inhibitory effect on acetylcholinesterase (AChE). All of them exhibited excellent inhibitory activity against AChE. The IC50 values ranged from 87.84 to 515.59 μg/mL; hybrids 13c and 13d with IC50 values of 0.232 ± 0.011 and 0.190 ± 0.004 µM, respectively, showed the most potent activity as acetylcholinesterase inhibitors (AChEIs). The reference drug, Galantamine, yielded an IC50 of 1.142 ± 0.027 µM. Reactivity descriptors, including chemical potential (μ), chemical hardness (η), electrophilicity (ω), condensed Fukui function, and dual descriptors are calculated at wB97XD/6-311++ G (d,p) to identify reactivity changes of the designed compounds. An in-depth investigation of the natural charge pattern of the studied compounds led to a deep understanding of the important interaction centers between these compounds and the biological receptors of AChE. The molecular electrostatic surface potential (MESP) of the most active site in these derivatives was determined using high-quality information and visualization. Molecular docking analysis was performed to predict binding sites and binding energies. The structure-activity-property relationship studies indicated that the proposed compounds exhibit good oral bioavailability properties. To explore the stability and dynamic behavior of the ligand-receptor complexes, molecular dynamics simulations (MDS) were performed for 100 ns on the two best docked derivatives, 13c and 13d, with the AChE (4EY7) receptor. A popular method for determining the free binding energies (MM/GBSA) is performed using snapshots taken from the systems’ trajectories at 100 ns. These results revealed that the complex system of compound 13d acquired a relatively more stable conformation and exhibited better descriptors than the complex system of compound 13c and the Galantamine drug, suggesting its potential as an effective inhibiting drug. The binding free energy analysis revealed that the 13d-4EY7 complex exhibited greater stability with AChE receptors compared to other complexesItem 2-Amino Thiazole Derivatives as Prospective Aurora Kinase Inhibitors against Breast Cancer: QSAR, ADMET Prediction, Molecular Docking, and Molecular Dynamic Simulation Studies(ACS, 2023-11) Murugesan, SankaranarayananThe aurora kinase is a key enzyme that is implicated in tumor growth. Research revealed that small molecules that target aurora kinase have beneficial effects as anticancer agents. In the present study, in order to identify potential antibreast cancer agents with aurora kinase inhibitory activity, we employed QSARINS software to perform the quantitative structure–activity relationship (QSAR). The statistical values resulted from the study include R2 = 0.8902, CCCtr = 0.7580, Q2 LOO = 0.7875, Q2LMO = 0.7624, CCCcv = 0.7535, R2ext = 0.8735, and CCCext = 0.8783. Among the four generated models, the two best models encompass five important variables, including PSA, EstateVSA5, MoRSEP3, MATSp5, and RDFC24. The parameters including the atomic volume, atomic charges, and Sanderson’s electronegativity played an important role in designing newer lead compounds. Based on the above data, we have designed six series of compounds including 1a–e, 2a–e, 3a–e, 4a–e, 5a–e, and 6a–e. All these compounds were subjected to molecular docking studies by using AutoDock v4.2.6 against the aurora kinase protein (1MQ4). Among the above 30 compounds, the 2-amino thiazole derivatives 1a, 2a, 3e, 4d, 5d, and 6d have excellent binding interactions with the active site of 1MQ4. Compound 1a had the highest docking score (−9.67) and hence was additionally subjected to molecular dynamic simulation investigations for 100 ns. The stable binding of compound 1a with 1MQ4 was verified by RMSD, RMSF, RoG, H-bond, molecular mechanics-generalized Born surface area (MM-GBSA), free binding energy calculations, and solvent-accessible surface area (SASA) analyses. Furthermore, newly designed compound 1a exhibited excellent ADMET properties. Based on the above findings, we propose that the designed compound 1a may be utilized as the best theoretical lead for future experimental research of selective inhibition of aurora kinase, therefore assisting in the creation of new antibreast cancer drugs.Item Novel 4-substituted-N,N-dimethyltetrahydronaphthalen-2-amines: synthesis, affinity, and in silico docking studies at serotonin 5-HT2-type and histamine H1 G protein-coupled receptors(Elsiever, 2015-04-01) Sakhuja, RajeevSyntheses were undertaken of derivatives of (2S,4R)-(−)-trans-4-phenyl-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (4-phenyl-2-dimethylaminotetralin, PAT), a stereospecific agonist at the serotonin 5-HT2C G protein-coupled receptor (GPCR), with inverse agonist activity at 5-HT2A and 5-HT2B GPCRs. Molecular changes were made at the PAT C(4)-position, while preserving N,N-dimethyl substitution at the 2-position as well as trans-stereochemistry, structural features previously shown to be optimal for 5-HT2 binding. Affinities of analogs were determined at recombinant human 5-HT2 GPCRs in comparison to the phylogenetically closely-related histamine H1 GPCR, and in silico ligand docking studies were conducted at receptor molecular models to help interpret pharmacological results and guide future ligand design. In most cases, C(4)-substituted PAT analogs exhibited the same stereoselectivity ([−]-trans > [+]-trans) as the parent PAT across 5-HT2 and H1 GPCRs, albeit, with variable receptor selectivity. 4-(4′-substituted)-PAT analogs, however, demonstrated reversed stereoselectivity ([2S,4R]-[+]-trans > [2S,4R]-[−]-trans), with absolute configuration confirmed by single X-ray crystallographic data for the 4-(4′-Cl)-PAT analog. Pharmacological affinity results and computational results herein support further PAT drug development studies and provide a basis for predicting and interpreting translational results, including, for (+)-trans-4-(4′-Cl)-PAT and (−)-trans-4-(3′-Br)-PAT that were previously shown to be more potent and efficacious than their corresponding enantiomers in rodent models of psychoses, psychostimulant-induced behaviors, and compulsive feeding (‘binge-eating’).