The nucleotide, inhibitor and cation binding sites of P-type II ATPases

P-type ATPases constitute a ubiquitous superfamily of cation transport enzymes, responsible for carrying out actions of paramount importance in biology such as ion transport and expulsion of toxic ions from cells. The harmonized toggling of gates in the extra- and intracellular domains explain the phenomenon of specific cation binding in selective physiological states. A quantitative understanding of the fundamental aspects of ion transport mechanism and regulation of P-type ATPases requires detailed knowledge of thermodynamical, structural, and functional properties. Computational studies have made significant contributions to our understanding of biological ion pumps. Various 3D structures of Ca2+-ATPase between E1 and E2 transition states have given a impetus to the theorists to work on the Na+K+- and H+K+-ATPase to address important questions about their function. The current review delineates the importance of cation, nucleotide, and inhibitor binding domains, with a focus on the therapeutic potential and biological relevance of the three P-type II ATPases. This will give an insight into the ion selectivity and their conduction across the transmembrane helices of P-type II ATPases, which may pave the way to a range of fundamental questions about the mechanism and aid in the efforts of structure- and analog-based drug design

Proton binding sites and conformational analysis of H<SUP>+</SUP>K<SUP>+</SUP>-ATPase

It is proposed that the hydronium ion, H<SUB>3</SUB>O<SUP>+</SUP>, binds to the E1 conformation of the α-subunit of gastric proton pump. The H<SUB>3</SUB>O<SUP>+</SUP> binding cavities are characterized parametrically based on valence, sequence, geometry, and size considerations from comparative modeling. The cavities have scope for accommodating monovalent cations of different ionic radii. The H3O+ transport is proposed to be aided by arenes which are arranged regularly along the pump starting from N-domain through the transmembrane region. Step-by-step structural changes accompanying H<SUB>3</SUB>O<SUP>+</SUP> occlusion are studied in detail. The observations corroborate well with earlier experimental studies

EGCG, a Green Tea Catechin, as a Potential Therapeutic Agent for Symptomatic and Asymptomatic SARS-CoV-2 Infection

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged to be the greatest threat to humanity in the modern world and has claimed nearly 2.2 million lives worldwide. The United States alone accounts for more than one fourth of 100 million COVID-19 cases across the globe. Although vaccination against SARS-CoV-2 has begun, its efficacy in preventing a new or repeat COVID-19 infection in immunized individuals is yet to be determined. Calls for repurposing of existing, approved, drugs that target the inflammatory condition in COVID-19 are growing. Our initial gene ontology analysis predicts a similarity between SARS-CoV-2 induced inflammatory and immune dysregulation and the pathophysiology of rheumatoid arthritis. Interestingly, many of the drugs related to rheumatoid arthritis have been found to be lifesaving and contribute to lower COVID-19 morbidity. We also performed in silico investigation of binding of epigallocatechin gallate (EGCG), a well-known catechin, and other catechins on viral proteins and identified papain-like protease protein (PLPro) as a binding partner. Catechins bind to the S1 ubiquitin-binding site of PLPro, which might inhibit its protease function and abrogate SARS-CoV-2 inhibitory function on ubiquitin proteasome system and interferon stimulated gene system. In the realms of addressing inflammation and how to effectively target SARS-CoV-2 mediated respiratory distress syndrome, we review in this article the available knowledge on the strategic placement of EGCG in curbing inflammatory signals and how it may serve as a broad spectrum therapeutic in asymptomatic and symptomatic COVID-19 patients

Comparison of computational methods to model DNA minor groove binders

There has been a profound interest in designing small molecules that interact in sequence-selective fashion with DNA minor grooves. However, most in silico approaches have not been parametrized for DNA ligand interaction. In this regard, a systematic computational analysis of 57 available PDB structures of noncovalent DNA minor groove binders has been undertaken. The study starts with a rigorous benchmarking of GOLD, GLIDE, CDOCKER, and AUTODOCK docking protocols followed by developing QSSR models and finally molecular dynamics simulations. In GOLD and GLIDE, the orientation of the best score pose is closer to the lowest rmsd pose, and the deviation in the conformation of various poses is also smaller compared to other docking protocols. Efficient QSSR models were developed with constitutional, topological, and quantum chemical descriptors on the basis of B3LYP/6-31G* optimized geometries, and with this &#x0394;T<SUB>m</SUB> values of 46 ligands were predicted. Molecular dynamics simulations of the 14 DNA−ligand complexes with Amber 8.0 show that the complexes are stable in aqueous conditions and do not undergo noticeable fluctuations during the 5 ns production run, with respect to their initial placement in the minor groove region

International Journal of Pharma and Bio Sciences REVIEW ARTICLE BIO PHARMACEUTICS HONEY AS COMPLEMENTARY MEDICINE:- A REVIEW

Honey is a natural sweetener, but it is not just a sweetener it’s a nature’s gift to mankind. Natural honey has various ingredients in it, that contribute to its incredible properties. It’s antimicrobial properties have attracted researchers towards itself and now we can find many research papers published on this topic. Honey is normally used in our daily life for treatment of hearing loss, bad breath, fatigue, weight loss, pimples, influenza, ingestion, heart diseases, toothache, hair loss, bladder infections, infertility etc. Honey is used as a mixture with many natural products such as lemon, clover, milk, cinnamon and water for treatment of various ailments and other health disorders. Beside this, honey is now used in various industries that exploit nature’s wonderful gift (honey). Commercially honey is used as moisturizer, hair conditioner, laxative, aphrodisiac, rooting hormone, cleansers etc. Honey mixed with ground almonds makes an excellent facial cleansing scrub. This article can be downloaded from www.ijpbs.ne

A Single-Site Mutation (F429H) Converts the Enzyme CYP 2B4 into a Heme Oxygenase: A QM/MM Study

The intriguing deactivation of the cytochrome P450 (CYP) 2B4 enzyme induced by mutation of a single residue, Phe429 to His, is explored by quantum mechanical/molecular mechanical calculations of the O–OH bond activation of the (Fe³⁺OOH)⁻ intermediate. It is found that the F429H mutant of CYP 2B4 undergoes <i>homolytic instead of heterolytic</i> O–OH bond cleavage. Thus, the mutant acquires the following characteristics of a heme oxygenase enzyme: (a) donation by His429 of an additional NH---S H-bond to the cysteine ligand combined with the presence of the substrate retards the heterolytic cleavage and gives rise to homolytic O–OH cleavage, and (b) the Thr302/water cluster orients nascent OH^• and ensures efficient meso hydroxylation

Fenchone Derivatives as a Novel Class of CB2 Selective Ligands: Design, Synthesis, X-ray Structure and Therapeutic Potential

A series of novel cannabinoid-type derivatives were synthesized by the coupling of (1S,4R)-(+) and (1R,4S)-(&minus;)-fenchones with various resorcinols/phenols. The fenchone-resorcinol derivatives were fluorinated using Selectfluor and demethylated using sodium ethanethiolate in dimethylformamide (DMF). The absolute configurations of four compounds were determined by X-ray single crystal diffraction. The fenchone-resorcinol analogs possessed high affinity and selectivity for the CB2 cannabinoid receptor. One of the analogues synthesized, 2-(2&prime;,6&prime;-dimethoxy-4&prime;-(2&Prime;-methyloctan-2&Prime;-yl)phenyl)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol (1d), had a high affinity (Ki = 3.51 nM) and selectivity for the human CB2 receptor (hCB2). In the [35S]GTP&gamma;S binding assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC50 = 2.59 nM, E(max) = 89.6%). Two of the fenchone derivatives were found to possess anti-inflammatory and analgesic properties. Molecular-modeling studies elucidated the binding interactions of 1d within the CB2 binding site