R. S. Rathore

Free energy calculations to estimate ligand-binding affinities in structure-based drug design.

Post-genomic era has led to the discovery of several new targets posing challenges for structure-based drug design efforts to identify lead compounds. Multiple computational methodologies exist to predict the high ranking hit/lead compounds. Among them, free energy methods provide the most accurate estimate of predicted binding affinity. Pathway-based Free Energy Perturbation (FEP), Thermodynamic Integration (TI) and Slow Growth (SG) as well as less rigorous end-point methods such as Linear interaction energy (LIE), Molecular Mechanics-Poisson Boltzmann./Generalized Born Surface Area (MM-PBSA/GBSA) and λ-dynamics have been applied to a variety of biologically relevant problems. The recent advances in free energy methods and their applications including the prediction of protein-ligand binding affinity for some of the important drug targets have been elaborated. Results using a recently developed Quantum Mechanics (QM)/Molecular Mechanics (MM) based Free Energy Perturbation (FEP) method, which has the potential to provide a very accurate estimation of binding affinities to date has been discussed. A case study for the optimization of inhibitors for the fructose 1,6- bisphosphatase inhibitors has been described.

Synthesis of green light emitting fused pyrazolinopiperidines - photophysical and electrochemical studies

We have synthesized the new, green light emitting pyrazolinopiperidines (PyP) derivatives with extended π-conjugation pathway by simple, two step reactions and are characterized using spectral and single crystal X-ray analysis. The electronic properties of PyP were studied using steady state, and time resolved spectral techniques, theoretical and electrochemical methods. PyP derivatives exhibit intense green fluorescence both in the solid and solution state with the quantum yield of 0.29 in acetonitrile. Importantly, PyP shows non-overlapping absorption and emission spectrum with the large Stokes shift value of ∼8000 cm−1. Solvent polarity dependent photophysical properties and theoretical HOMO–LUMO calculation reveal that the singlet excited state possesses significant charge transfer character. The substitution of electron donating/withdrawing substituents show negligible or little influence on the photophysical properties except the trifluoromethyl and 2,4-dichloro phenyl substituent. The electrochemical first oxidation potentials were not influenced by the substituent; however the first reduction potential becomes sensitive towards nature and position of the aryl substituent. Further, photophysical properties of PyP become sensitive to the nature of substituent (ortho/para) positions. The enhanced non-radiative decay for the 2,4-dichlorophenyl substituted PyP as compared to 2- and 4-chlorophenyl substituents (by a factor of two and seven times, respectively) emphasize the necessity for multiple electron withdrawing aryl substituents to induce the measurable charge transfer interactions. The enhanced non-radiative rate constant of trifluoromethyl substituent by eight times than methyl substituent is due to the strong intramolecular charge transfer from pyrazoline to styryl moiety.

Advances in Binding Free Energies Calculations: QM/MM-Based Free Energy Perturbation Method for Drug Design

Multiple approaches have been devised and evaluated to computationally estimate binding free energies. Results using a recently developed Quantum Mechanics (QM)/Molecular Mechanics (MM) based Free Energy Perturbation (FEP) method suggest that this method has the potential to provide the most accurate estimation of binding affinities to date. The method treats ligands/inhibitors using QM while using MM for the rest of the system. The method has been applied and validated for a structurally diverse set of fructose 1,6- bisphosphatase (FBPase) inhibitors suggesting that the approach has the potential to be used as an integral part of drug discovery for both lead identification lead optimization, where there is a structure available. In addition, this QM/MM-based FEP method was shown to accurately replicate the anomalous hydration behavior exhibited by simple amines and amides suggesting that the method may also prove useful in predicting physical properties of molecules. While the method is about 5-fold more computationally demanding than conventional FEP, it has the potential to be less demanding on the end user since it avoids development of MM force field parameters for novel ligands and thereby eliminates this time-consuming step that often contributes significantly to the inaccuracy of binding affinity predictions using conventional FEP methods. The QM/MM-based FEP method has been extensively tested with respect to important considerations such as the length of the simulation required to obtain satisfactory convergence in the calculated relative solvation and binding free energies for both small and large structural changes between ligands. Future automation of the method and parallelization of the code is expected to enhance the speed and increase its use for drug design and lead optimization.

Four component domino reaction for the synthesis of highly functionalized dimeric tetracyclic dilactam fluorophores: H-bond aided self-assembly

A series of new dimeric tetracyclic dilactam fluorophores (DTDF) consisting of diazabicyclooctane-dione (DBOD) fused to tetrahydronaphthalene (THP) was designed and synthesized from a simple precursor. The monomers showed enhanced emission in THF–water solvent and also benzene-dimer like absorption and fluorescence, originating from the hydrogen-bonding aided self-assembly of dilactams. The crystal structures revealed water-mediated molecular aggregates with several hydrogen-bond bridges formed by water.

A green approach for the one-pot multi-component synthesis of N-substituted γ, δ and ε-lactams involving C–N bond formation catalyzed by FeCl3

A green trend and efficient method for the synthesis of N-substituted γ, δ and e-lactam derivatives has been developed through one pot multi-component reaction under environmentally benign reaction conditions using FeCl3 as a green catalyst with high atom economy. The present green synthetic protocol shows fascinating properties such as enhanced yield in solvent-free conditions, with high reaction rate, easy workup and absence of column chromatography and also avoids the use of ligands or additives. The versatility of the reaction has been ascertained by using various substituted benzaldehydes, anilines and homologues of lactams.

Direct anti and regio-specific aldol reactions of cyclododecanone catalyzed by alkali metal hydroxides: implications for supramolecular helical design

The direct aldol condensation of benzaldehyde to cyclododecanone (CDD), catalyzed by NaOH is expected to yield bis-benzylidene cyclododecanone, but we interestingly ended up with novel β-hydroxy carbonyl compounds and monobenzylidene cyclododecanone derivatives in the cases of 2-halo substituted benzaldehydes. This exceptional behaviour is due to the capability of the CDD ring to exist in the zwitter ionic form. The formation of monobenzylidine derivatives can be due to less stable hydrogen bonds between –OH and –CO groups, electrostatic interaction between aldehyde substituents and metal enolates and the bulkiness of the benzaldehyde ring substituents. We extensively optimized the reaction conditions using different solvents and alkali metal hydroxide catalysts and we are getting high yield, regio-specificity and high diastereoselectivity (anti-aldol) in β-hydroxy carbonyl compounds. The representative crystal structures were examined and they suggest the tendency of anti-aldol compounds to form supramolecular helical motifs. The β-hydroxyl carbonyl derivatives form supramolecular helices via O–H⋯O hydrogen bonds with two anti-aldol units per turn and a pitch of ∼6 A. The cyclododecanone ring adopts the minimum energy [3333] square conformation. The nucleophile will attack only from the less hindered side of the carbonyl group in the CDD ring.

NeMedPlant: a database of therapeutic applications and chemical constituents of medicinal plants from north-east region of India.

The North-East region of India is one of the twelve mega biodiversity region, containing many rare and endangered species. A curated database of medicinal and aromatic plants from the regions called NeMedPlant is developed. The database contains traditional, scientific and medicinal information about plants and their active constituents, obtained from scholarly literature and local sources. The database is cross-linked with major biochemical databases and analytical tools. The integrated database provides resource for investigations into hitherto unexplored medicinal plants and serves to speed up the discovery of natural productsbased drugs. Availability The database is available for free at http://bif.uohyd.ac.in/nemedplant/orhttp://202.41.85.11/nemedplant/

1-Meth­oxy-4-({[(4-meth­oxy­phen­yl)­sulfan­yl](phen­yl)meth­yl}sulfan­yl)benzene

The title compound, C21H20O2S2, forms a propeller-shaped structure with the tetrahedral C atom as the central hub and methoxybenzene and phenyl residues as radiating blades. Short C—H⋯π contacts are observed.

Statistical descriptors to measure the effectiveness of hydrogen bonding groups and an example of ether oxygen

To quantify the effectiveness of hydrogen-bonding donors and acceptors for forming interactions, we here introduce the concept of statistical competitiveness, defined in terms of three numerical parameters namely, absolute, relative and exclusive statistical competitiveness. The concept can be applied to evaluate the effectiveness of a donor or acceptor in any chemical context. We have evaluated the efficacy of ether oxygen for hydrogen-bonding with respect to carbonyl oxygen and nitrogen acceptors. The quantification in terms of statistical parameters reveals a striking result that the population of hydrogen-bonding groups predominately dictates their effectiveness irrespective of their acidic or basic strengths. The quantification of the competitiveness serves to estimate better the outcome of crystal structure prediction and engineering methodologies, and molecular docking.

Dual Behavior of Ammonium Acetate for the Synthesis of Diverse Symmetrical/Unsymmetrical Bis[1,3]oxazines Possessing Anticancer Activity

Abstract A simple and efficient approach was developed to synthesize symmetrical/unsymmetrical bis[1,3]oxazines using ammonium acetate with controllable substitution patterns in a one-pot fashion. In a representative crystal structure, the [1,3]oxazine ring is in a distorted semichair conformation with C2-carbon and nitrogen atoms residing above and below the naphthalene plane, leading to strain in the ring that allows ring-opening polymerization to take place. A few of the derivatives were found to possess anticancer activity. This current modest protocol affords numerous advantages such as mild reaction condition, shorter reaction time, operational simplicity, and excellent yield. GRAPHICAL ABSTRACT