Valasani Koteswara Rao

Mitochondrial permeability transition pore is a potential drug target for neurodegeneration

Mitochondrial permeability transition pore (mPTP) plays a central role in alterations of mitochondrial structure and function leading to neuronal injury relevant to aging and neurodegenerative diseases including Alzheimers disease (AD). mPTP putatively consists of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocator (ANT) and cyclophilin D (CypD). Reactive oxygen species (ROS) increase intra-cellular calcium and enhance the formation of mPTP that leads to neuronal cell death in AD. CypD-dependent mPTP can play a crucial role in ischemia/reperfusion injury. The interaction of amyloid beta peptide (Aβ) with CypD potentiates mitochondrial and neuronal perturbation. This interaction triggers the formation of mPTP, resulting in decreased mitochondrial membrane potential, impaired mitochondrial respiration function, increased oxidative stress, release of cytochrome c, and impaired axonal mitochondrial transport. Thus, the CypD-dependent mPTP is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of AD. Designing small molecules to block this interaction would lessen the effects of Aβ neurotoxicity. This review summarizes the recent progress on mPTP and its potential therapeutic target for neurodegenerative diseases including AD.

Design, Synthesis and Anti Colon Cancer Activity Evaluation of Phosphorylated Derivatives of Lamivudine (3TC)

The novel phosphorylated derivatives of Lamivudine (5a-5l) as potential anti colon cancer agents are synthe- sized. These title compounds are designed based on the basic pyrimidine derivative lamivudine as a starting compound and reacted with various phosphorodichloridates followed by the introduction of bioactive groups at the phosphorus. Their structures were characterized by IR, 1 H, 13 C, 31 P NMR and mass spectral analyses. All the compounds were evaluated for their anti colon cancer activity against COLO-205 cell lines in vitro studies. Among them 5a and 5b emerged as lead compounds with 0.003 μM and 0.0001 μM values.

Identification of substituted (3, 2-a) pyrimidines as selective antiviral agents: Molecular modeling study

A series of novel substituted dihydropyrimidine and 5H-thiazolo [3, 2-a] pyrimidine derivatives were designed and synthesized as a potential target to discover drugs fighting against the viral diseases. The main objective of the present work is to carry out the QSAR studies for all the series of the compounds starting from 4a to 6j to find out their molecular descriptors and predict the biological properties. All of them are showing the best QSAR descriptors, hence chosen for the prediction of anti-viral activity against Newcastle disease virus (NDV). Initially their inhibitory activity was predicted by molecular docking of these compounds against haemaglutinin-neuraminidase (HN) protein using molecular operating environment (MOE) software. Based on the best affinity and highest docking scores 4b, 5b and 6b were assayed in vivo on NDV infected chicks and it was found that there is significant improvement in the survival of the chicks with the treatment (P<0.05). 4b and 6b showed better curative effect than 5b at the dose concentration of 40 mg/kg body weight of chicks. The results from molecular docking study and biological assays can be inferred to consider these molecules as potential antiviral drugs.

Comparison and correlation of binding mode of ATP in the kinase domains of Hexokinase family.

Hexokinases (HKs) are the enzymes that catalyses the ATP dependent phosphorylation of Hexose sugars to Hexose-6-Phosphate (Hex-6-P). There exist four different forms of HKs namely HK-I, HK-II, HK-III and HK-IV and all of them share a common ATP binding site core surrounded by more variable sequence that determine substrate affinities. Although they share a common binding site but they differ in their kinetic functions, hence the present study is aimed to analyze the binding mode of ATP. The analysis revealed that the four ATP binding domains are showing 13 identical, 7 similar and 6 dissimilar residues with similar structural conformation. Molecular docking of ATP into the kinase domains using Molecular Operating Environment (MOE) soft ware tool clearly showed the variation in the binding mode of ATP with variable docking scores. This probably explains the variable phosphorylation rates among hexokinases family.

In silico designing and molecular docking of a potent analog against Staphylococcus aureus porphobilinogen synthase

Background: The emergence of multidrug-resistant strains of Staphylococcus aureus, there is an urgent need for the development of new antimicrobials which are narrow and pathogen specific. Aim: In this context, the present study is aimed to have a control on the staphylococcal infections by targeting the unique and essential enzyme; porphobilinogen synthase (PBGS) catalyzes the condensation of two molecules of δ-aminolevulinic acid, an essential step in the tetrapyrrole biosynthesis. Hence developing therapeutics targeting PBGS will be the promising choice to control and manage the staphylococcal infections. 4,5-dioxovalerate (DV) is known to inhibit PBGS. Materials and Methods: In view of this, in this study, novel dioxovalerate derivatives (DVDs) molecules were designed so as to inhibit PBGS, a potential target of S. aureus and their inhibitory activity was predicted using molecular docking studies by molecular operating environment. The 3D model of PBGS was constructed using Chlorobium vibrioform (Protein Data Bank 1W1Z) as a template by homology modeling method. Results: The built structure was close to the crystal structure with Z score − 8.97. Molecular docking of DVDs into the S. aureus PBGS active site revealed that they are showing strong interaction forming H-bonds with the active sites of K248 and R217. The ligand–receptor complex of DVD13 showed a best docking score of − 14.4555 kcal/mol among DV and all its analogs while the substrate showed docking score of − 13.0392 kcal/mol showing interactions with S199, K217 indicating that DVD13 can influence structural variations on the enzyme and thereby inhibiting the enzyme. Conclusion: The substrate analog DVD13 is showing significant interactions with active site of PBGS and it may be used as a potent inhibitor to control S. aureus infections.

Comparative structural and functional analysis of staphylococcus aureus glucokinase with other bacterial glucokinases

Glucokinase is classified in bacteria based upon having ATP binding site and ‘repressor/open reading frames of unknown function/sugar kinases’ motif, the sequence of glucokinase gene (JN645812) of Staphylococcus aureus ATCC12600 showed presence of ATP binding site and ‘repressor/open reading frames of unknown function/sugar kinases’ motif. We have earlier observed glucokinase of S. aureus has higher affinity towards the substrate compared to other bacterial glucokinase and under anaerobic condition with increased glucose concentration S. aureus exhibited higher rate of biofilm formation. To establish this, 3D structure of glucokinase was built using homology modeling method, the PROCHECK and ProSA-Web analysis indicated this built glucokinase structure was close to the crystal structure. This structure was superimposed with different bacterial glucokinase structures and from the root-mean-square deviation values, it is concluded that S. aureus glucokinase exhibited very close homology with Enterococcus faecalis and Clostridium difficle while with other bacteria it showed high degree of variations both in domain and nondomain regions. Glucose docking results indicated -12.3697 kcal/mol for S. aureus glucokinase compared with other bacterial glucokinase suggesting higher affinity of glucose which correlates with enzyme kinetics and higher rate of biofilm formation.

Corrigendum to “Cloning and characterization of l-lactate dehydrogenase gene of Staphylococcus aureus” [Anaerobe 24 (2013) 43–48]

Corrigendum to “Cloning and characterization of L-lactate dehydrogenase gene of Staphylococcus aureus” [Anaerobe 24 (2013) 43e48] Sthanikam Yeswanth , Yellapu Nanda Kumar , Uppu Venkateswara Prasad , Vimjam Swarupa , Valasani Koteswara Rao , Potukuchi Venkata Gurunadha Krishna Sarma a, * a Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Tirupati 517507, Andhra Pradesh, India b Department of Zoology, Division of Animal Biotechnology, Sri Venkateswara University, Tirupati 517502, Andhra Pradesh, India c Department of Pharmacology & Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA