M. Kannan

Insight into residues involved in the structure and function of the breast cancer associated protein human gamma synuclein

Aberrantly expressed human gamma synuclein (SNCG) interacts with BubR1 and heat shock protein 70 (Hsp70) in late stages of breast and ovarian cancer. This interaction is essential for progression, development and survival of cancer cells. A short, synthetically designed ankyrin-repeat-containing peptide (ANK peptide) was proven to inhibit the activity of SNCG. However, the potential binding site residues of SNCG responsible for its oncogenic function have not been reported so far. The objectives of this study were to generate a three-dimensional model of SNCG and to identify the key residues involved in interaction with BubR1, ANK peptide and Hsp70. Our study is the first attempt to report the specific binding of SNCG with the TPR motif of BubR1 and the 18kDa region of Hsp70. Our findings provide novel insights into the mechanism of interaction of SNCG, and can act as a basis for the ongoing drug design and discovery process aimed at treating breast and ovarian cancer.

Interacting mechanism of ID3 HLH domain towards E2A/E12 transcription factor – An Insight through molecular dynamics and docking approach

Inhibitor of DNA binding protein 3 (ID3) has long been characterized as an oncogene that implicates its functional role through its Helix–Loop–Helix (HLH) domain upon protein–protein interaction. An insight into the dimerization brought by this domain helps in identifying the key residues that favor the mechanism behind it. Molecular dynamics (MD) simulations were performed for the HLH proteins ID3 and Transcription factor E2-alpha (E2A/E12) and their ensemble complex (ID3-E2A/E12) to gather information about the HLH domain region and its role in the interaction process. Further evaluation of the results by Principal Component Analysis (PCA) and Free Energy Landscape (FEL) helped in revealing residues of E2A/E12: Lys570, Ala595, Val598, and Ile599 and ID3: Glu53, Gln63, and Gln66 buried in their HLH motifs imparting key roles in dimerization process. Furthermore the T-pad analysis results helped in identifying the key fluctuations and conformational transitions using the intrinsic properties of the residues present in the domain region of the proteins thus specifying their crucial role towards molecular recognition. The study provides an insight into the interacting mechanism of the ID3-E2A/E12 complex and maps the structural transitions arising in the essential conformational space indicating the key structural changes within the helical regions of the motif. It thereby describes how the internal dynamics of the proteins might regulate their intrinsic structural features and its subsequent functionality.

Synthesis and in silico evaluation of 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives against Alzheimer disease: to understand their interacting mechanism with acetylcholinesterase

Anomalous action of human acetylcholinesterase (hAChE) in Alzheimer’s disease (AD) was restrained by various AChE inhibitors, of which the specific and potent lead candidate Donepezil is used for treating the disease AD. Besides the specificity, the observed undesirable side effects caused by Donepezil invoked the quest for new lead molecules with the increased potency and specificity for AChE. The present study elucidates the potency of six 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives to form a specific interaction with the peripheral anionic site and catalytic anionic subsite residues of hAChE. The NMSMs were prepared in good yield from 1,1-di(methylsulfanyl)-2-nitroethylene and primary amine (or) amino acid esters. In silico interaction analysis reveals specific and potent interactions between hAChE and selected ligand molecules. The site-specific interactions formed between these molecules also results in a conformational change in the orientation of active site residues of hAChE, which prevents them from being accessed by beta-amyloid protein (Aβ), which is a causative agent for amyloid plaque formation and acetylcholine (ACh). In silico interaction analysis between the ligand-bounded hAChE with Aß and ACh confirms this observation. The variation in the conformation of hAChE associated with the decreased ability of Aβ and ACh to access the respective functional residues of hAChE induced by the novel NMSMs favors their selection for in vivo analysis to present themselves as new members of hAChE inhibitors.

6-Amino-3,4-dimethyl-4-phenyl-2H,4H-pyrano[2,3-c]pyrazole-5-carbonitrile.

In the title compound, C15H14N4O, the pyrazole ring is aligned at 88.23 (4)° with respect to the aromatic ring and at 3.75 (4)° with respect to the pyran ring. In the crystal, N—H⋯N hydrogen bonds link adjacent molecules into a linear chain motif. C—H⋯N interactions are also observed.

6,8-Dichloro-N-methyl-3-nitro-4-nitro­methyl-4H-chromen-2-amine

In the title compound, C11H9Cl2N3O5, the dihydropyran ring adopts a near-half-chair conformation. The benzene ring makes a torsion angle of 5.02 (5)° with the dihydropyran ring. Adjacent molecules are interlinked through intermolecular C—H⋯O, N—H⋯O and C—Cl⋯π [3.4743 (9) Å] interactions. The intermolecular N—H⋯O hydrogen bond generates an R 2 2(12) motif, which is observed to contribute to the crystal packing stability. Moreover, the molecular structure displays an S(6) motif formed by intramolecular N—H⋯O hydrogen bonding.

Ethyl 2-(6-amino-5-cyano-3,4-dimethyl-2H,4H-pyrano[2,3-c]pyrazol-4-yl)acetate

In he title compound, C13H16N4O3, the pyrazole ring is planar (r.m.s. deviation = 0.054 Å). The pyran ring is not planar; the mean plane makes a dihedral angle of 1.9 (1)° with the pyrazole ring. In the crystal structure, intermolecular N—H⋯N and N—H⋯O interactions lead to a linear chain motif.

N-(4-Chloro­phen­yl)-1-(5-{[(2-phenyl­ethen­yl)sulfon­yl]meth­yl}-1,3,4-oxadiazol-2-yl)methane­sulfonamide

In the title compound, C18H16ClN3O5S2, the dihedral angles between the oxadiazole ring and the phenyl and chlorobenzene rings are 23.4 (2) and 45.4 (2)°, respectively. The C—S—N—C and Cox—C—S—C (ox = oxadiazole) torsion angles are 89.3 (5) and −69.1 (3)°, respectively. A short intramolecular C—H⋯O contact closes an S(6) ring. In the crystal, molecules are linked by N—H⋯O hydrogen bonds, generating C(10) chains propagating in [001]. The packing is consolidated by C—H⋯O, C—H⋯π and very weak aromatic π–π stacking interactions [centroid–centroid separation = 4.085 (2) Å].

Bis(μ-phenyl­tellurido-κ2Te:Te)bis­[tetra­carbonyl­rhenium(I)]

The title compound, [Re2(C6H5Te)2(CO)8], crystallizes with two molecules in the asymmetric unit, in which two Re atoms are coordinated in a slightly distorted octahedral environment and are bridged by two Te atoms, which show a distorted trigonal-pyramidal geometry. The torsion angles for the Te—Re—Te—Re sequence of atoms are 19.29 (18) and 16.54 (16)° in the two molecules. Thus, the Re—Te four-membered rings in the two molecules deviate significantly from planarity. Two intramolecular C—H⋯O interactions occur in one of the molecules. Te—Te [4.0551 (10) Å] interactions between the two molecules and weak intermolecular C—H⋯O interactions stabilize the crystal packing.

Ethyl 6-amino-5-cyano-2,4-bis­(4-methyl­phen­yl)-4H-pyran-3-carboxyl­ate

In the title compound, C23H22N2O3, the pyran ring adopts a twisted boat conformation. The tolyl rings and carboxylate group are attached to the pyran ring with torsion angles of −77.1 (2), 59.5 (3) and 17.8 (3)°, respectively. The ethyl group is disordered over two orientations with a site-occupancy ratio of 0.508 (5):0.492 (5). In the crystal, molecules are linked by N—H⋯N and N—H⋯O hydrogen bonds, generating a chain running the a axis. Weak C—H⋯O, C—H⋯N and C—H⋯π interactions are also observed.

3-Benzyl-6-benzyl­amino-1-methyl-5-nitro-1,2,3,4-tetra­hydro­pyrimidine

In the title compound, C19H22N4O2, the tetrahydropyrimidine ring adopts an envelope conformation (with the N atom connected to the benzyl group representing the flap). This benzyl group occupies a quasi-axial position. The two benzyl groups lie over the tetrahydropyridimidine ring. The amino group is a hydrogen-bond donor to the nitro group.