Padmaja D. Wakchaure

Bio: Padmaja D. Wakchaure is an academic researcher from Central Salt and Marine Chemicals Research Institute. The author has contributed to research in topics: Ligand (biochemistry) & Riboswitch. The author has an hindex of 3, co-authored 13 publications receiving 37 citations. Previous affiliations of Padmaja D. Wakchaure include Academy of Scientific and Innovative Research & Council of Scientific and Industrial Research.

Revealing the Inhibition Mechanism of RNA-Dependent RNA Polymerase (RdRp) of SARS-CoV-2 by Remdesivir and Nucleotide Analogues: A Molecular Dynamics Simulation Study.

Abstract: Antiviral drug therapy against SARS-CoV-2 is not yet established and posing a serious global health issue. Remdesivir is the first antiviral compound approved by the US FDA for the SARS-CoV-2 treatment for emergency use, targeting RNA-dependent RNA polymerase (RdRp) enzyme. In this work, we have examined the action of remdesivir and other two ligands screened from the library of nucleotide analogues using docking and molecular dynamics (MD) simulation studies. The MD simulations have been performed for all the ligand-bound RdRp complexes for the 30 ns time scale. This is one of the earlier reports to perform the MD simulations studies using the SARS-CoV-2 RdRp crystal structure (PDB ID 7BTF). The MD trajectories were analyzed and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations were performed to calculate the binding free energy. The binding energy data reveal that compound-17 (-59.6 kcal/mol) binds more strongly as compared to compound-8 (-46.3 kcal/mol) and remdesivir (-29.7 kcal/mol) with RdRp. The detailed analysis of trajectories shows that the remdesivir binds in the catalytic site and forms a hydrogen bond with the catalytic residues from 0 to 0.46 ns. Compound-8 binds in the catalytic site but does not form direct hydrogen bonds with catalytic residues. Compound-17 showed the formation of hydrogen bonds with catalytic residues throughout the simulation process. The MD simulation results such as hydrogen bonding, the center of mass distance analysis, snapshots at a different time interval, and binding energy suggest that compound-17 binds strongly with RdRp of SARS-CoV-2 and has the potential to develop as a new antiviral against COVID-19. Further, the frontier molecular orbital analysis and molecular electrostatic potential (MESP) iso-surface analysis using DFT calculations shed light on the superior binding of compound-17 with RdRp compared to remdesivir and compound-8. The computed as well as the experimentally reported pharmacokinetics and toxicity parameters of compound-17 is encouraging and therefore can be one of the potential candidates for the treatment of COVID-19.

A Highly Selective Turn-On Biosensor for Measuring Spermine/Spermidine in Human Urine and Blood

Abstract: Spermine and spermidine serve as the key biomarkers for early-stage cancer diagnosis. This work reports a rapid, highly selective, and noninvasive sensing platform for spermine/spermidine. The hybr...

Structure investigation, enrichment analysis and structure-based repurposing of FDA-approved drugs as inhibitors of BET-BRD4

Abstract: We report herein detailed structural insights into the ligand recognition modes guiding bromodomain selectivity, enrichment analysis and docking-based database screening for the identification of the FDA-approved drugs that have potential to be the human BRD4 inhibitors. Analysis of multiple X-ray structures prevailed that the lysine-recognition sites are highly conserved, and apparently, the dynamic ZA loop guides the specific ligand-recognition. The protein-ligand interaction profiling revealed that both BRD2 and BRD4 shared hydrophobic interaction of bound ligands with PRO-98/PRO-82, PHE-99/PHE-83, LEU-108/LEU-92 and direct H-bonding with ASN-156/ASN-140 (BRD2/BRD4), while on the other hand the water-mediated H-bonding of bound ligands with PRO-82, GLN-85, PRO-86, VAL-87, ASP-88, LEU-92, TYR-97 and MET-132, and aromatic π-π stacking with TRP-81 prevailed as unique interaction in BRD4, and were not observed in BRD2. Subsequently, through ROC curve analysis, the best enrichment was found with PDB-ID 4QZS of BRD4 structures. Finally, through docking-based database screening study, we found that several drugs have better binding affinity than the control candidate lead (+)-JQ1 (Binding affinity = -7.9 kcal/mol), a well-known BRD4 inhibitor. Among the top-ranked drugs, azelastine, a selective histamine H1 receptor antagonist, showed the best binding affinity of -9.3 kcal/mol and showed interactions with several key residues of the acetyl lysine binding pocket. Azelastine may serve as a promising template for further medicinal chemistry. These insights may serve as basis for structure-based drug design, drug repurposing and the discovery of novel BRD4 inhibitors. Communicated by Ramaswamy H. Sarma.

Revealing the cholinergic inhibition mechanism of Alzheimer's by galantamine: a metadynamics simulation study.

Abstract: Galantamine is one of the approved drugs based on the cholinergic hypothesis for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). The etiology of AD is not fully known; however, the reported cholinergic hypothesis suggests the inadequate synthesis of the neurotransmitter acetylcholine (ACh) is responsible for this disease. The crystal structure of galantamine bound human acetylcholinesterase (hAChE) has been reported; however, the inhibition mechanism of hAChE by galantamine is not well understood. A Well-tempered metadynamics (WTMtD) simulation study has been performed with the crystal structure of galantamine bound hAChE. The reported mechanism for the degradation of ACh is suggested through a proton transfer process from a carboxylic group of Glu334 to the hydroxyl group of Ser203, which attacks ACh for the degradation to acetic acid and choline. Such proton transfer process is lowered in the presence of galantamine due to the separation of catalytic triad inside the gorge of AChE as observed with WTMtD. A docking study has been performed to examine the ACh's binding with the catalytic triad of galantamine bound hAChE. The docking results reveal that the approach of ACh to the catalytic triad is interrupted due to the galantamine's presence in the gorge of the enzyme.

Molecular level insights into the inhibition of gene expression by thiamine pyrophosphate (TPP) analogs for TPP riboswitch: A well-tempered metadynamics simulations study.

Abstract: Riboswitches are metabolite sensing aptamer domains present in non-coding regions in RNA and act as gene-regulating elements. Thiamine pyrophosphate (TPP) riboswitch is evolved as a new target for developing antibiotics against many pathogenic bacteria. The earlier reports suggest that the modification of the pyrophosphate group in the ligand molecule can enhance gene expression. In this work, we have examined the binding affinity and efficacy of TPP and two recently reported ligands, CH2-TPP, and CF2-TPP, using Well-tempered metadynamics (WT-MtD) simulations. The experimental in vitro assays show that both TPP and CH2-TPP repress the gene expression to the same extent. The calculated binding energies correlate well with the experimental study and show the same trend of binding affinity of ligands for the TPP riboswitch. The root mean square fluctuation profiles suggest that the CH2-TPP and TPP trigger higher fluctuations in P1 and L3 region, and such fluctuations in the P1 region is involved in the gene regulation process. The metal ion mediated contact of TPP ligand with pyrophosphate binding helix is found to be critical in the gene regulation process. The simulation results corroborate the experimental observations that the role of conformational changes occurring in different riboswitch regions upon ligand binding is essential to repress the gene expression process. This work sheds light on the subtle change in the ligand structure that can induce a more considerable impact on binding affinity and efficacy of ligands with riboswitch.

Molecular Probes, Chemosensors, and Nanosensors for Optical Detection of Biorelevant Molecules and Ions in Aqueous Media and Biofluids

Abstract: Synthetic molecular probes, chemosensors, and nanosensors used in combination with innovative assay protocols hold great potential for the development of robust, low-cost, and fast-responding sensors that are applicable in biofluids (urine, blood, and saliva). Particularly, the development of sensors for metabolites, neurotransmitters, drugs, and inorganic ions is highly desirable due to a lack of suitable biosensors. In addition, the monitoring and analysis of metabolic and signaling networks in cells and organisms by optical probes and chemosensors is becoming increasingly important in molecular biology and medicine. Thus, new perspectives for personalized diagnostics, theranostics, and biochemical/medical research will be unlocked when standing limitations of artificial binders and receptors are overcome. In this review, we survey synthetic sensing systems that have promising (future) application potential for the detection of small molecules, cations, and anions in aqueous media and biofluids. Special attention was given to sensing systems that provide a readily measurable optical signal through dynamic covalent chemistry, supramolecular host–guest interactions, or nanoparticles featuring plasmonic effects. This review shall also enable the reader to evaluate the current performance of molecular probes, chemosensors, and nanosensors in terms of sensitivity and selectivity with respect to practical requirement, and thereby inspiring new ideas for the development of further advanced systems.

Biofunctionalized Graphene Quantum Dots Based Fluorescent Biosensor toward EfficientDetection of Small Cell Lung Cancer

Abstract: Quantitative detection of cancer biomarkers with higher accuracy and sensitivity provides an effective platform for screening, monitoring, early diagnosis, and disease surveillance. The present wor...

The Conservation of Orbital Symmetry (福井謙一とフロンティア軌導理論) -- (参考論文)

Abstract: Chemistry remains an experimental science. The theory of chemical bonding leaves much to be desired. Yet, the past 20 years have been marked by a fruitful symbiosis of organic chemistry and molecular orbital theory. Of necessity this has been a marriage of poor theory with good experiment. Tentative conclusions have been arrived a t on the basis of theories which were such a patchwork on approximations that they appeared to have no right to work; yet, in the hands of clever experimentalists, these ideas were transformed into novel molecules with unusual properties. In the same way, by utilizing the most simple but fundamental concepts of molecular orbital theory we have in the past 3 years been able to rationalize and predict the stereochemical course of virtually every concerted organic reaction.' In our work we have relied on the most basic ideas of molecular orbital theory-the concepts of symmetry, overlap, interaction, bonding, and the nodal structure of wave functions. The lack of numbers in our discussion is not a weakness-it is its greatest strength. Precise numerical values would have to result from some specific sequence of approximations. But an argument from first principles or symmetry, of necessity qualitative, is in fact much stronger than the deceptively authoritative numerical result. For, if the simple argument is true, then any approximate method, as well as the now inaccessible exact solution, must obey it. The simplest description of the electronic structure of a stable molecule is that i t is characterized by a finite band of doubly occupied electronic levels, called bonding orbitals, separated by a gap from a corresponding band of unoccupied, antiboding levels as well as a continuum of higher levels. The magnitude of the gap may range from 40 kcal/mole for highly delocalized, large aromatic systems to 250 kcal/mole for saturated hydrocarbons. It should be noted in context that socalled nonbonding electrons of heteroatoms are in fact bonding. Consider a simple reaction of two molecules to give a third species, proceeding in a nonconcerted manner through a diradical intermediate I. A + B + [I] + C

Well-tempered metadynamics: a smoothly-converging and tunable free-energy method

Abstract: We present a method for determining the free-energy dependence on a selected number of collective variables using an adaptive bias. The formalism provides a unified description which has metadynamics and canonical sampling as limiting cases. Convergence and errors can be rigorously and easily controlled. The parameters of the simulation can be tuned so as to focus the computational effort only on the physically relevant regions of the order parameter space. The algorithm is tested on the reconstruction of an alanine dipeptide free-energy landscape.

Epidrug Repurposing: Discovering New Faces of Old Acquaintances in Cancer Therapy.

Abstract: Gene mutations are strongly associated with tumor progression and are well known in cancer development. However, recently discovered epigenetic alterations have shown the potential to greatly influence tumoral response to therapy regimens. Such epigenetic alterations have proven to be dynamic, and thus could be restored. Due to their reversible nature, the promising opportunity to improve chemotherapy response using epigenetic therapy has arisen. Beyond helping to understand the biology of the disease, the use of modern clinical epigenetics is being incorporated into the management of the cancer patient. Potential epidrug candidates can be found through a process known as drug repositioning or repurposing, a promising strategy for the discovery of novel potential targets in already approved drugs. At present, novel epidrug candidates have been identified in preclinical studies and some others are currently being tested in clinical trials, ready to be repositioned. This epidrug repurposing could circumvent the classic paradigm where the main focus is the development of agents with one indication only, while giving patients lower cost therapies and a novel precision medical approach to optimize treatment efficacy and reduce toxicity. This review focuses on the main approved epidrugs, and their druggable targets, that are currently being used in cancer therapy. Also, we highlight the importance of epidrug repurposing by the rediscovery of known chemical entities that may enhance epigenetic therapy in cancer, contributing to the development of precision medicine in oncology.