Non-covalent binding interaction of bioactive coumarin esculetin with calf thymus DNA and yeast transfer RNA: A detailed investigation to decipher the binding affinities, binding location, interacting forces and structural alterations at a molecular level.

Esculetin is a well-known coumarin derivative found abundantly in nature possessing an extensive array of pharmacological and therapeutic properties. Consequently, to comprehend its molecular recognition mechanism, our objective is to conduct a complete investigation of its interactions with the nucleic acid, specifically ct-DNA, and t-RNA, using spectroscopic and computational techniques. The intrinsic fluorescence of esculetin is quenched when it interacts with ct-DNA and t-RNA, and this occurs through a static quenching mechanism. The thermodynamic parameters demonstrated that the interaction is influenced by hydrogen bonding and weak van der Waals forces. CD and FT-IR results revealed no conformational changes in ct-DNA and t-RNA structure on binding with esculetin. Furthermore, competitive displacement assay with ethidium bromide, melting temperature, viscosity measurement, and potassium iodide quenching experiments, reflected that esculetin probably binds to the minor groove of ct-DNA. The molecular docking results provided further confirmation for the spectroscopic findings, including the binding location of esculetin and binding energies of esculetin complexes with ct-DNA and t-RNA. Molecular dynamics simulation studies demonstrated the conformational stability and flexibility of nucleic acids.

Interactions of Turmeric- and Curcumin-Functionalized Gold Nanoparticles with Human Serum Albumin: Exploration of Protein Corona Formation, Binding, Thermodynamics, and Antifibrillation Studies.

In order to better understand the bioavailability and biocompatibility of polyphenol-assisted surface-modified bioengineered nanoparticles in nanomedicine applications, here, we address a series of photophysical experiments to quantify the binding affinity of serum albumin toward polyphenol-capped gold nanoparticles. For this, two different gold nanoparticles (AuNPs) were synthesized via the green synthesis approach, where curcumin and turmeric extract act as reducing as well as capping agents. The size, surface charge, and surface plasmon bands of the AuNPs were highly affected by the adsorption of human serum albumin (HSA) during protein corona formation, which was investigated using dynamic light scattering (DLS), ξ-potential, ultraviolet-visible (UV-vis) spectroscopy, and transmission electron microscopy (TEM) measurements. Fluorescence-based methods, absorbance, and SERS experiments were carried out to evaluate the binding aspects of AuNPs with HSA. We found that the AuNPs show moderate binding affinity toward HSA (Kb ∼ 104 M-1), irrespective of the capping agents on the surface. Hydrophobic association, along with some contribution of electrostatic interaction, played a key role in the binding process. The binding interaction was more toward the subdomain IIA region of HSA, as indicated by the competitive displacement studies using site-specific binders (warfarin and flufenamic acid). Because of the large surface curvature of small-sized AuNPs, the secondary structural conformations of HSA were slightly altered, as revealed by circular dichroism (CD), Fourier transform infrared (FT-IR) spectroscopy, and surface-enhanced Raman scattering (SERS) measurements. Additionally, the findings of the binding interactions were re-evaluated using molecular dynamics (MD) simulation studies by determining the root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), and changes in the binding energy of HSA upon complexation with AuNPs. To determine the tentative evidence for pharmacokinetic administration, these biocompatible AuNPs were applied to inhibit the amyloid fibril formation of HSA and monitored by using the thioflavin T (ThT) assay, ANS fluorescence assay, fluorescence microscopic imaging, and FESEM. AuNPs were found to show better resistance toward fibrillation of the adsorbed protein.

Review on the Drug Intolerance and Vaccine Development for the Leishmaniasis.

Leishmaniasis is one of the Neglected Tropical Diseases (NTDs), a zoonotic disease of vector-borne nature that is caused by a protozoan parasite Leishmania. This parasite is transmitted by the vector sandfly into the human via a bite. Visceral leishmaniasis (VL), also called kala-azar, is the most fatal among the types of leishmaniasis, with high mortality mostly spread in the East Africa and South Asia regions. WHO report stated that approximately 3.3 million disabilities occur every year due to the disease along with approximately 50,000 annual deaths. The real matter of concern is that there is no particular effective medicine/vaccine available against leishmaniasis to date except a few approved drugs and chemotherapy for the infected patient. The current selection of small compounds was constrained, and their growing drug resistance had been a major worry. Additionally, the serious side effects on humans of the available therapy or drugs have made it essential to discover efficient and low-cost methods to speed up the development of new drugs against leishmaniasis. Ideally, the vaccine could be a low risk and effective alternative for both CL and VL and elicit long-lasting immunity against the disease. There are a number of vaccine candidates at various stages of clinical development and preclinical stage. However, none has successfully passed all clinical trials. But, the successful development and approval of commercially available vaccines for dogs against canine leishmaniasis (CanL) provides evidence that it can be possible for humans in distant future. In the present article, the approaches used for the development of vaccines for leishmaniasis are discussed and the progress being made is briefly reviewed.

A small molecule potent IRAK4 inhibitor abrogates lipopolysaccharide-induced macrophage inflammation in-vitro and in-vivo.

Increasing evidence supports vanillin and its analogs as potent toll-like receptor signaling inhibitors that strongly attenuate inflammation, though, the underlying molecular mechanism remains elusive. Here, we report that vanillin inhibits lipopolysaccharide (LPS)-induced toll-like receptor 4 activation in macrophages by targeting the myeloid differentiation primary-response gene 88 (MyD88)-dependent pathway through direct interaction and suppression of interleukin-1 receptor-associated kinase 4 (IRAK4) activity. Moreover, incubation of vanillin in cells expressing constitutively active forms of different toll-like receptor 4 signaling molecules revealed that vanillin could only able to block the ligand-independent constitutively activated IRAK4/1 or its upstream molecules-associated NF-κB activation and NF-κB transactivation along with the expression of various proinflammatory cytokines. A significant inhibition of LPS-induced IRAK4/MyD88, IRAK4/IRAK1, and IRAK1/TRAF6 association was evinced in response to vanillin treatment. Furthermore, mutations at Tyr262 and Asp329 residues in IRAK4 or modifications of 3-OMe and 4-OH side groups in vanillin, significantly reduced IRAK4 activity and vanillin function, respectively. Mice pretreated with vanillin followed by LPS challenge markedly impaired LPS-induced IRAK4 activation and inflammation in peritoneal macrophages. Thus, the present study posits vanillin as a novel and potent IRAK4 inhibitor and thus providing an opportunity for its therapeutic application in managing various inflammatory diseases.

Deciphering the interactions of phytochemicals with ovalbumin, the major food allergen from egg white: spectroscopic and computational studies.

Ovalbumin (OVA), the major component of egg white, has been used as a model carrier protein to study the interaction of four bioactive phytochemicals 6-hydroxyflavone, chrysin, naringin, and naringenin. A static quenching mechanism was primarily associated with the complexation of the flavonoids with OVA. Hydrophobic forces play a major part in the stability of the complexes. The structural changes within the protein in response to flavonoid binding revealed a decrease in OVA's α-helical content. The hypothesized binding site for flavonoids in OVA overlaps with one or more immunoglobulin E-binding epitopes that may have some effect in the immunoglobulin E response pathway. The flavonoids remain in the same binding site throughout the simulation time and impart protein stability by forming different noncovalent interactions. This study presents comprehensive information about the interaction of the flavonoids with OVA and the associated structural variations after the binding, which might help researchers better comprehend similar medication pharmacodynamics and provide critical information for future therapeutic development.

Quorum Quenching: A Drug Discovery Approach Against Pseudomonas aeruginosa.

Pseudomonas aeruginosa, a ubiquitous opportunistic and nosocomial biofilm-forming pathogen with complex, interconnected and hierarchical nature of QS systems (Las, Rhl, PQS, and IQS), is posing the biggest challenge to the healthcare sector and have made current chemotherapies incapable. Conventional antibiotics designed to intercept the biochemical or physiological processes precisely of planktonic microorganisms exert extreme selective pressure and develop resistance against them thereby emphasizing the development of alternative therapeutic approaches. Additionally, quorum sensing induced pathogenic microbial biofilms and production of virulence factors have intensified the pathogenicity, drug resistance, recurrence of infections, hospital visits, morbidity, and mortality many-folds. In this regard, QS could be a potential druggable target and the discovery of QS inhibiting agents as an anti-virulent measure could serve as an alternative therapeutic approach to conventional antibiotics. Quorum quenching (QQ) is a preferred strategy to combat microbial infections since it attenuates the pathogenicity of microbes and enhances the microbial biofilm susceptibility to antibiotics, thus qualifying as a suitable target for drug discovery. This review discusses the QS-induced pathogenicity of P. aeruginosa, the hierarchical QS systems, and QS inhibition as a drug discovery approach to complement classical antibiotic strategy.

Interaction of Nanomaterials with Protein-Peptide.

Nanomaterials have undergone rapid development in the last few decades, galvanized by the versatility of their functional attributes and many inherent advantages over bulk materials. The state of art experimental techniques to synthesize nanoparticles (NPs) from varied sources offers unprecedented opportunities for utilization and exploration of multifaceted biological activities. Such formulations demand a preliminary understanding of the interaction between NPs and biomolecules. Most of these interactions depend on the external morphology of the NPs, like the shape, size, charge and surface chemistry. In addition, most experimental techniques are limited to cellular-level data, without the atomistic details of mechanisms that lead to these interactions. Consequently, recent studies have determined these atomistic events through in-silico techniques, which provide a better understanding and integrative details of interactions between biomolecules and different NPs. Therefore, while delineating the protein-NPs interaction, it is imperative to define the consequences of nanomaterial's introduction and derive data for the formulation of better therapeutic interventions. This review briefly discusses varied types of NPs, their potential applications and interactions with peptides and proteins.

In silico analysis of antiviral phytochemicals efficacy against Epstein-Barr virus glycoprotein H.

Epstein-Barr virus is a tumor-associated, enveloped virus with glycoprotein receptor gHgL on its surface. gH attaches to epithelial or B cells and mediates internalization. Till date, no specific anti-EBV FDA approved drug is available. Targeting gH may aid in designing virus-specific therapeutics and reducing the drug induced complications in host. We investigated the influence of antiviral phytochemicals on gH using computational approaches. Through molecular docking, we performed binding energy analysis of cellocidin, bruceantin, EGCG, formononetin and sesquiterpene lactones with gH DII/DIII interface, crucial for gH functions. Further, to cause any perturbations in the protein function, the molecules must bind stably to gH. Bruceantin and EGCG interacted with high affinities to gH. Simulation of these two molecules revealed stable binding with gH throughout 100 ns moreover, van der Waal interactions stabilized overall binding. Mutation of amino acids like V265, L269, L315, I423, I459, L474 and F475 involved in stable binding to gH was predicted deleterious to protein function. We obtained no difference in RMSD between these two ligands and minor deviations in the RMSF were noticed compared to gH. Conclusively, our study provided insights into the potential of bruceantin and EGCG to target gH. Different amino acids are involved in binding of each ligand to gH, engagement of certain amino acids may affect the virus binding with epithelial or B cells. The interaction of the ligand with gH may trap it in its native conformation or induce structural flexibility thereby inhibiting the interaction with host receptors or other glycoproteins.Communicated by Ramaswamy H. Sarma.

Photosystem I P700 chlorophyll a apoprotein A1 as PCR marker to identify diatoms and their associated lineage.

The morphological characteristics of diatoms are useful for studying their taxonomy. However, the distinction between closely related diatom taxa can be very difficult, especially when the morphological characters are modified by environmental constraints. In the present study, 13 fresh water diatoms were identified morphologically and cultured under axenic conditions. To check this, PCR primers specific for multilocus genes were designed to amplify and screen 13 fresh water diatom monocultures. Multilocus PCR primers (DRR3, scfcpA, Lhcf11, SIT1, SIT3, SIT4, LOC101218388, COI-5P, rbcL, rbcL-3P, LSU D2/D3, UPA, psaA, and 18S rRNA) were tested. It was found that psaA gene, a plant pigment chlorophyll-based PCR marker, amplified in all the diatoms. Out of 13 diatom amplicons, only two fresh water diatoms DNA were sequenced. This included Cyclotella meneghiniana and Sellaphora pupula. The Sanger sequencing results thus established that morphologically identified diatom, Sellaphora pupula, exhibited close phylogeny to Sellaphora whereas fresh water Cyclotella meneghiniana has close lineage to marine diatom Thallosiosira.

Exploring the interaction of bioactive kaempferol with serum albumin, lysozyme and hemoglobin: A biophysical investigation using multi-spectroscopic, docking and molecular dynamics simulation studies.

In recent years research based on kaempferol (KMP) has shown its potential therapeutic applications in medicinal chemistry and clinical biology. Therefore, to understand its molecular recognition mechanism, we studied its interactions with the carrier proteins, namely, human serum albumin (HSA), bovine hemoglobin (BHb) and hen egg white lysozyme (HEWL). The ligand, KMP was able to quench the intrinsic fluorescence of these three proteins efficiently through static quenching mode. The binding constant (Kb) for the interactions of KMP with these three proteins were found in the following order: HSA-KMP > BHb-KMP > HEWL-KMP. Different non-covalent forces such as hydrogen bonding and hydrophobic forces played a major role in the binding of KMP with HSA and HEWL, whereas hydrogen bonding and van der Waals forces contribute to the complexation of BHb with KMP. KMP was able to alter the micro-environment near the Trp fluorophore of the proteins. KMP altered the secondary structural component of all three proteins. The putative binding sites and the residues surrounding the KMP molecule within the respective protein matrix were determined through molecular docking and molecular dynamics (MD) simulation studies. The conformational flexibility of the ligand KMP and the three individual proteins were also evident from the MD simulation studies.

In silico Metabolic Pathway Analysis Identifying Target Against Leishmaniasis - A Kinetic Modeling Approach.

The protozoan Leishmania donovani, from trypanosomatids family is a deadly human pathogen responsible for causing Visceral Leishmaniasis. Unavailability of proper treatment in the developing countries has served as a major threat to the people. The absence of vaccines has made treatment possibilities to rely solely over chemotherapy. Also, reduced drug efficacy due to emerging resistant strains magnifies the threat. Despite years of formulations for an effective drug therapy, complexity of the disease is also unfortunately increasing. Absence of potential drug targets has worsened the scenario. Therefore exploring new therapeutic approach is a priority for the scientific community to combat the disease. One of the most reliable ways to alter the adversities of the infection is finding new biological targets for designing potential drugs. An era of computational biology allows identifying targets, assisting experimental studies. It includes sorting the parasite's metabolic pathways that pins out proteins essential for its survival. We have directed our study towards a computational methodology for determining targets against L. donovani from the "purine salvage" pathway. This is a mainstay pathway towards the maintenance of purine amounts in the parasitic pool of nutrients proving to be mandatory for its survival. This study represents an integration of metabolic pathway and Protein-Protein Interactions analysis. It consists of incorporating the available experimental data to the theoretical methods with a prospective to develop a kinetic model of Purine salvage pathway. Simulation data revealed the time course mechanism of the enzymes involved in the synthesis of the metabolites. Modeling of the metabolic pathway helped in marking of crucial enzymes. Additionally, the PPI analysis of the pathway assisted in building a static interaction network for the proteins. Topological analysis of the PPI network through centrality measures (MCC and Closeness) detected targets found common with Dynamic Modeling. Therefore our analysis reveals the enzymes ADSL (Adenylosuccinate lyase) and IMPDH (Inosine-5'-monophosphate dehydrogenase) to be important having a central role in the modeled network based on PPI and kinetic modeling techniques. Further the available three dimensional structure of the enzyme "ADSL" aided towards the search for potential inhibitors against the protein. Hence, the study presented the significance of integrating methods to identify key proteins which might be putative targets against the treatment of Visceral Leishmaniasis and their potential inhibitors.

Computational Analysis of the Silver Nanoparticle-Human Serum Albumin Complex.

Drug delivery in excess concentrations and at not-specified sites inside the human body adversely affects the body and gives rise to other diseases. Several methods have been developed to deliver the drugs in required amounts and at specific targets. Nanoparticle-mediated drug delivery is one such approach and has gained success at primary levels. The effect of nanoparticles on the human body needs important apprehension, and it has been unraveled by assessing the protein-nanoparticle interactions. Here, we have measured the impact of silver nanoparticles (AgNPs) on the human serum albumin (HSA) structure and function with the help of all-atom molecular dynamics simulations (MDS). HSA is a transport protein, and any change in the structure may obstruct its function. The post MD analyses showed that the NP interacts with HSA and the conjugated system got stabilized with time evolution of trajectories. The present investigation confirms that the AgNP interacts with HSA without affecting its tertiary and secondary structures and in turn the protein function as well. AgNP application is recommended in transporting conjugated drug molecules as it has no adverse effect on serum proteins. Since HSA is present in the circulatory system, it may open various applications of AgNPs in the biomedical field.

Targeting the heme protein hemoglobin by (-)-epigallocatechin gallate and the study of polyphenol-protein association using multi-spectroscopic and computational methods.

In this work, the interaction of a bioactive tea polyphenol (-)-epigallocatechin gallate (EGCG) with bovine hemoglobin (BHb) along with its anti-oxidative behavior and the anti-glycation property have been explored using multi-spectroscopic and computational techniques. The binding affinity for EGCG towards BHb was observed to be moderate in nature with an order of 104 M-1, and the fluorescence quenching mechanism was characterized by an unusual static quenching mechanism. The binding constant (Kb) showed a continuous enhancement with temperature from 3.468 ± 0.380 × 104 M-1 at 288 K to 6.017 ± 0.601 × 104 M-1 at 310 K. The fluorescence emission measurements along with molecular docking studies indicated that EGCG binds near the most dominant fluorophore of BHb (ß2-Trp37, at the interface of α1 and ß2 chains) within the pocket formed by the α1, α2 and ß2 chains. The sign and magnitude of the thermodynamic parameters, changes in enthalpy (ΔH = +17.004 ± 1.007 kJ mol-1) and in entropy (ΔS = +146.213 ± 2.390 J K-1 mol-1), indicate that hydrophobic forces play a major role in stabilizing the BHb-EGCG complex. The micro-environment around the EGCG binding site showed an increase in hydrophobicity upon ligand binding. The binding of EGCG with BHb leads to a decrease in the α-helical content, whereas that of the ß-sheet increased. FTIR studies also indicated that the secondary structure of BHb changed upon binding with EGCG, along with providing further support for the presence of hydrophobic forces in the complexation process. Molecular docking studies indicated that EGCG binds within the cavity of α1, α2, and ß2 chains surrounded by residues such as α1- Lys99, α1-Thr134, α1-Thr137, α1-Tyr140, α2-Lys127 and ß2-Trp37. Molecular dynamics simulation studies indicated that EGCG conferred additional stability to BHb. Furthermore, moving away from the binding studies, EGCG was found to prevent the glyoxal (GO)-mediated glycation process of BHb, and it was also found to act as a potent antioxidant against the photo-oxidative damage of BHb.

A novel small molecule A2A adenosine receptor agonist, indirubin-3'-monoxime, alleviates lipid-induced inflammation and insulin resistance in 3T3-L1 adipocytes.

Saturated free fatty acid-induced adipocyte inflammation plays a pivotal role in implementing insulin resistance and type 2 diabetes. Recent reports suggest A2A adenosine receptor (A2AAR) could be an attractive choice to counteract adipocyte inflammation and insulin resistance. Thus, an effective A2AAR agonist devoid of any toxicity is highly appealing. Here, we report that indirubin-3'-monoxime (I3M), a derivative of the bisindole alkaloid indirubin, efficiently binds and activates A2AAR which leads to the attenuation of lipid-induced adipocyte inflammation and insulin resistance. Using a combination of in silico virtual screening of potential anti-diabetic candidates and in vitro study on insulin-resistant model of 3T3-L1 adipocytes, we determined I3M through A2AAR activation markedly prevents lipid-induced impairment of the insulin signaling pathway in adipocytes without any toxic effects. While I3M restrains lipid-induced adipocyte inflammation by inhibiting NF-κB dependent pro-inflammatory cytokines expression, it also augments cAMP-mediated CREB activation and anti-inflammatory state in adipocytes. However, these attributes were compromised when cells were pretreated with the A2AAR antagonist, SCH 58261 or siRNA mediated knockdown of A2AAR. I3M, therefore, could be a valuable option to intervene adipocyte inflammation and thus showing promise for the management of insulin resistance and type 2 diabetes.

Identification and analysis of structurally critical fragments in HopS2.

BACKGROUND: Among the diverse roles of the Type III secretion-system (T3SS), one of the notable functions is that it serves as unique nano machineries in gram-negative bacteria that facilitate the translocation of effector proteins from bacteria into their host. These effector proteins serve as potential targets to control the pathogenicity conferred to the bacteria. Despite being ideal choices to disrupt bacterial systems, it has been quite an ordeal in the recent times to experimentally reveal and establish a concrete sequence-structure-function relationship for these effector proteins. This work focuses on the disease-causing spectrum of an effector protein, HopS2 secreted by the phytopathogen Pseudomonas syringae pv. tomato DC3000. RESULTS: The study addresses the structural attributes of HopS2 via a bioinformatics approach to by-pass some of the experimental shortcomings resulting in mining some critical regions in the effector protein. We have elucidated the functionally important regions of HopS2 with the assistance of sequence and structural analyses. The sequence based data supports the presence of important regions in HopS2 that are present in the other functional parts of Hop family proteins. Furthermore, these regions have been validated by an ab-initio structure prediction of the protein followed by 100 ns long molecular dynamics (MD) simulation. The assessment of these secondary structural regions has revealed the stability and importance of these regions in the protein structure. CONCLUSIONS: The analysis has provided insights on important functional regions that may be vital to the effector functioning. In dearth of ample experimental evidence, such a bioinformatics approach has helped in the revelation of a few structural regions which will aid in future experiments to attain and evaluate the structural and functional aspects of this protein family.

Insulin adsorption onto zinc oxide nanoparticle mediates conformational rearrangement into amyloid-prone structure with enhanced cytotoxic propensity.

BACKGROUND: Injection localized amyloidosis is one of the most prevalent disorders in type II diabetes mellitus (TIIDM) patients relying on insulin injections. Previous studies have reported that nanoparticles can play a role in the amyloidogenic process of proteins. Hence, the present study deals with the effect of zinc oxide nanoparticles (ZnONP) on the amyloidogenicity and cytotoxicity of insulin. METHODS: ZnONP is synthesised and characterized using XRD, Zeta Sizer, UV-Visible spectroscope and TEM. The characterization is followed by ZnONP interaction with insulin, which is studied employing fluorescence spectroscopes, isothermal titration calorimetry and molecular dynamics simulations. The interaction leads insulin conformational rearrangement into amyloid-like fibril, which is studied using thioflavin T dye binding assay, circular dichroism spectroscopy and TEM, followed by cytotoxicity propensity using Alamar Blue dye reduction assay. RESULTS: Insulin has very weak interaction with ZnONP interface. Insulin at studied concentration forms amorphous aggregates at physiological pH, whereas in presence of ZnONP interface amyloid-like fibrils are formed. While the amyloid-like fibrils are cytotoxic to MIN6 and THP-1 cell lines, insulin and ZnONP individual solutions and their fresh mixtures enhance the cells proliferation. CONCLUSIONS: The presence of ZnONP interface enhances insulin fibrillation at physiological pH by providing a favourable template for the nucleation and growth of insulin amyloids. GENERAL SIGNIFICANCE: The studied protein-nanoparticle system from protein conformational dynamics point of view throws caution over nanoparticle use in biological applications, especially in vivo applications, considering the amyloidosis a very slow but non-curable degenerative disease.

Molecular recognition of bio-active flavonoids quercetin and rutin by bovine hemoglobin: an overview of the binding mechanism, thermodynamics and structural aspects through multi-spectroscopic and molecular dynamics simulation studies.

The binding of two bio-active flavonoids, quercetin and rutin, with bovine hemoglobin (BHb) was investigated by multi-spectroscopic and computational (molecular docking and molecular dynamics simulation) studies. The two flavonoids were found to quench the intrinsic fluorescence of BHb through a static quenching mechanism. The binding constants at 288 K were observed to be (14.023 ± 0.73) × 104 M-1 and (7.848 ± 0.20) × 104 M-1, respectively for quercetin and rutin binding with BHb. Both rutin and quercetin were observed to increase the polarity around the Trp residues of BHb as indicated by synchronous and 3D spectral studies. No significant alterations in the secondary structural components of the protein were caused during the binding of the flavonoids as studied by CD and FTIR studies. The negative molar Gibbs free energies indicated the spontaneity of the interaction processes while the binding processes were characterized by a negative enthalpy change (ΔH) and a positive entropy change (ΔS). The possibility of energy transfer from the donor (BHb) to the acceptor molecules (flavonoids) was indicated by the FRET studies. According to the fluorescence studies, the flavonoids interact near to the ß2-Trp37 residue of BHb. Excellent correlations with the experimental studies were observed from the molecular docking and molecular dynamics (MD) simulation studies. Further investigations established that these flavonoids are efficient in the inhibition of glucose mediated glycation of BHb.

Anti-tubercular drug development: computational strategies to identify potential compounds.

InhA is an attractive target to combat tuberculosis (TB), which is targeted by many pro-drugs (isoniazid, etc.) and drugs such as triclosan. However, triclosan is less useful as an antitubercular drug due to its low bioavailability and therefore, in order to overcome this difficulty, many derivatives of triclosan were prepared. Here, we have combined various computational techniques to virtually screen out four potential triclosan derivatives. Molecular docking methods have been employed to screen out 32 out of 62 triclosan derivatives considering the mode of binding and the top re-rank scores. A comparative study on the chemical properties of triclosan and some of its derivatives has been performed using density functional theory (DFT) calculations. DFT based global reactivity descriptors (GRD), such as hardness, chemical potential, chemical softness, electrophilicity index, Fukui function, and local philicity calculated at the optimized geometries were used to investigate the usefulness of these descriptors for understanding the reactive nature and sites of the molecules. QSAR equations were built using these descriptors considering these 32 compounds. Four common compounds showing the best correlation and the best docking scores were considered for the ADMET property calculations and their dynamical movements have been studied using molecular dynamics simulations. Our results showed that these four compounds are chemically more active than triclosan and have the potential to inhibit the Mycobacterium tuberculosis enoyl acyl carrier protein reductase. This work shows that combination of different computational techniques may help to screen out potential drug candidates from a list of possible ones.

Amino acid interaction preferences in helical membrane proteins.

Membrane proteins are involved in a number of important biological functions. Yet, they are poorly understood from the structure and folding point of view. The external environment being drastically different from that of globular proteins, the intra-protein interactions in membrane proteins are also expected to be different. Hence, statistical potentials representing the features of inter-residue interactions based exclusively on the structures of membrane proteins are much needed. Currently, a reasonable number of structures are available, making it possible to undertake such an analysis on membrane proteins. In this study we have examined the inter-residue interaction propensities of amino acids in the membrane spanning regions of the alpha-helical membrane (HM) proteins. Recently we have shown that valuable information can be obtained on globular proteins by the evaluation of the pair-wise interactions of amino acids by classifying them into different structural environments, based on factors such as the secondary structure or the number of contacts that a residue can make. Here we have explored the possible ways of classifying the intra-protein environment of HM proteins and have developed scoring functions based on different classification schemes. On evaluation of different schemes, we find that the scheme which classifies amino acids to different intra-contact environment is the most promising one. Based on this classification scheme, we also redefine the hydrophobicity scale of amino acids in HM proteins.