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Background: JAK2 inhibitors have been proposed as a new therapeutic option for thalassemia therapy. The objective of this study was to discover the key structural features for improving 2-aminopyrimidine derivatives as potential JAK2 inhibitors. Materials & methods: Quantitative structure–activity relationship (QSAR) approaches (hologram QSAR and comparative molecular similarity indices analysis), molecular dynamics simulations, binding energy calculations and pharmacokinetic predictions were employed. Results: Reliable QSAR models, binding mode and binding interactions of JAK2 inhibitors were obtained and these obtained results were used as the key information for rational design of highly potent JAK2 inhibitors. Conclusion: The concept of new potential JAK2 inhibitors integrated from the obtained results was proved, producing two newly designed compounds, D01 and D02, with potential for use as JAK2 inhibitors.

Aim: In silico screening approaches were performed to discover novel InhA inhibitors. Methods: Candidate InhA inhibitors were obtained from the combination of virtual screening and pharmacokinetic prediction. In addition, molecular mechanics Poisson–Boltzmann surface area, molecular mechanics Generalized Born surface area and WaterSwap methods were performed to investigate the binding interactions and binding energy of candidate compounds. Results: Four candidate compounds with suitable physicochemical, pharmacokinetic and antibacterial properties are proposed. The crucial interactions of the candidate compounds were H-bond, pi–pi and sigma–pi interactions observed in the InhA binding site. The binding affinity of these compounds was improved by hydrophobic interactions with hydrophobic side chains in the InhA pocket. Conclusion: The four newly identified InhA inhibitors reported in this study could serve as promising hit compounds against Mycobacterium tuberculosis and may be considered for further experimental studies.

Serine/threonine protein kinase B (PknB) is essential to Mycobacterium tuberculosis (M. tuberculosis) cell division and metabolism and a potential anti-tuberculosis drug target. Here we apply Hologram Quantitative Structure Activity Relationship (HQSAR) and three-dimensional QSAR (Comparative Molecular Similarity Indices Analysis (CoMSIA)) methods to investigate structural requirements for PknB inhibition by a series of previously described quinazoline derivatives. PknB binding of quinazolines was evaluated by molecular dynamics (MD) simulations of the catalytic domain and binding energies calculated by Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) methods. Evaluation of a training set against experimental data showed both HQSAR and CoMSIA models to reliably predict quinazoline binding to PknB, and identified the quinazoline core and overall hydrophobicity as the major contributors to affinity. Calculated binding energies also agreed with experiment, and MD simulations identified hydrogen bonds to Glu93 and Val95, and hydrophobic interactions with Gly18, Phe19, Gly20, Val25, Thr99 and Met155, as crucial to PknB binding. Based on these results, additional quinazolines were designed and evaluated in silico, with HQSAR and CoMSIA models identifying sixteen compounds, with predicted PknB binding superior to the template, whose activity spectra and physicochemical, pharmacokinetic, and anti-M. tuberculosis properties were assessed. Compound, D060, bearing additional ortho- and meta-methyl groups on its R2 substituent, was superior to template regarding PknB inhibition and % caseum fraction unbound, and equivalent in other aspects, although predictions identified hepatotoxicity as a likely issue with the quinazoline series. These data provide a structural basis for rational design of quinazoline derivatives with more potent PknB inhibitory activity as candidate anti-tuberculosis agents.

Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is an important target enzyme in malarial chemotherapy. An understanding of how novel inhibitors interact with wild-type (wtPfDHFR), quadruple-mutant (qmPfDHFR), and human (hDHFR) enzymes is required for the development of these compounds as antimalarials. This study is focused on a series of des-Cl and m-Cl phenyl analogs of pyrimethamine with various flexible 6-substituents. The interactions of these compounds with DHFR enzymes were investigated by 3 D-QSAR, MD simulations, MM-PBSA, and DFT calculations. CoMFA and CoMSIA models were developed with good predictive abilities for wtPfDHFR and qmPfDHFR. For hDHFR, CoMSIA models combined with clogP descriptor were successfully derived. Binding free energy using MM-PBSA and comparison of per residue decomposition energy analyses with the DFT method at M06-2X/6-31G ++(d,p) level of theory indicated that Asp54 and Phe58 play important roles in the binding of the most potent compound in the series (compound 27) with both wtPfDHFR and qmPfDHFR, whereas Arg59 and Arg122 were additionally found to interact with this inhibitor in qmPfDHFR. For hDHFR, the residues Glu30 and Phe34 but not Arg70, equivalent to Asp54, Phe58, and Arg122 in PfDHFR, also play role in compound 27 binding through strong hydrophobic interactions (Phe34) and hydrogen bond network with Glu30, Ile7, and Val115. From the key interactions identified in the DHFR-inhibitor complexes, a general scheme is proposed for designing new inhibitors selective for PfDHFR that is important for the development of novel antifolate antimalarials. Communicated by Ramaswamy H. Sarma

Acetylcholinesterase (AChE) is currently one of the potent targets for the treatment of Alzheimer's disease (AD). The discovery of promising new AChE inhibitors using a hybridisation method is considered as one of the effective strategies to overcome AD. In this study, potent hybrid donepezils previously reported as AChE inhibitors were investigated to gain an insight into the key binding interaction of their scaffolds, using molecular docking, molecular dynamics simulations and quantum chemical calculations. The results indicated that the key interactions found in both donepezil and the selected hybrid donepezils were the π-π interaction to Trp86 in the catalytic anionic site (CAS) and Trp286 and Tyr341 in the peripheral anionic site (PAS) in the AChE binding pocket. Moreover, the modification of the scaffolds revealed the adaptation of the orientation in the binding pocket and additional important interactions from the modified scaffold, such as H-bond and H-π interactions to Asp74, Tyr124 and Tyr337. In addition, the HOMO-LUMO prediction indicated the binding interaction by considering the electron transfer between the hybrid donepezils and key residues, such as Trp86 and Trp286. The bioavailability, drug-likeness and pharmacokinetics predictions confirmed the suitability of the hybrid donepezils for AD drug development. Most of the selected hybrid donepezils revealed good bioavailability, drug-likeness properties and pharmacokinetics; however, some need improved pharmacokinetic properties. The obtained information highlights the significance of the scaffold from the hybridisation method, which will be helpful for AD drug design and development in the future.

Biomineralization is the study of minerals produced by biomaterials or living organisms, and it has attracted considerable attention in industry and fundamental research. Here, for the first time, the roles of alkali-treated mung bean (MB) and cassava (CS) starches as templates for calcium carbonate (CaCO3) spherulite formation were investigated by bulk rheology and molecular dynamics (MD) simulations. The rheological results, including yield stress, flow behavior index, consistency coefficient, and hysteresis area of alkali-treated MB and CS starch suspensions containing Ca2+, revealed that the Ca2+ induced the folding of starch chains via Ca2+ crosslinking, leading to aggregation of starch–Ca2+ complexes. After the starch films were fabricated from the suspensions, CaCO3 spherulites were observed inside the films. The size and number of the spherulites increased with increasing concentration of Ca2+ in the suspensions as a result of an increase in nucleation sites needed for spherulite growth. Moreover, to gain a deeper understanding of the interactions between Ca2+ and starch and of the formation of the nucleation sites for spherulite growth, MD simulations were performed. Our findings pave the way for the design of new biomaterial-based templates, which can efficiently control crystal shape and size of CaCO3.

Acetylcholinesterase (AChE) plays a vital role in Alzheimer's disease (AD), which is one of the most common causes of dementia. Discovering new effective inhibitors against AChE activity is seen to be one of the effective approaches to reduce the suffering from AD. Protoberberine alkaloids isolated from natural resources have previously been reported as potent AChE inhibitors. In order to gain insights into how these alkaloids could inhibit AChE, berberine, palmatine, and cyclanoline were selected to investigate in terms of binding orientation and their key interactions with AChE using molecular docking and molecular dynamics simulations and quantum chemical calculations. The results revealed that the molecular dynamics structures of palmatine and berberine indicated that their equilibrated structures did not occupy the gorge but they slightly moved away from the catalytic site (CAS). For cyclanoline, the binding mode was quite different from those of donepezil and the other protoberberine alkaloids: it preferred to stay deeper in the CAS site. Interaction energies and residual interaction energies confirmed that the key interactions for palmatine and berberine were π-π interactions with Trp286 and Tyr341 and H-bond interactions with Tyr124. Cyclanoline formed π-π interactions with Trp86 and H-bonds to the amino acids in the CAS site. The results suggested the importance of aromaticity in the core structure and the flexibility of the core structure or the substituents in order to fit into the narrow gorge. The HOMO, LUMO, bioavailability, drug-likeness and pharmacokinetics were also predicted. The results obtained will be useful for further AD drug development.

Human serum albumin (HSA) is abundant in blood. HSA binds a wide range of drugs, metabolites, and nutrients. A glycated HSA is also a potential diabetes biomarker. Recently, crystal structures of glucose- and fructose-bound HSA have been reported. Both cyclic and acyclic sugar forms are trapped in Sudlow site I. Galactose can also bind HSA, but no atomic detail is available. Thus, molecular dynamics simulations were employed to study the structural and dynamic properties of fructose- and galactose-bound HSA in comparison to glucose-bound HSA from previous studies. Both bound sugars promote different degrees of domain motions which can affect a drug/solute binding affinity at Sudlow site I. A large and highly water-exposed Sudlow site I allows high mobility of bound sugars. Nonetheless, more protein contacts imply a tighter binding of fructose than galactose. Although galactose and glucose are epimers, galactose forms a different interaction network which disrupts a formation of interactions with K195 and K199 resulting in the escape of galactose. In contrast, fructose molecules are anchored inside by a number of protein interactions and sugar dimer structure. These highlights the importance of protein–sugar and sugar–sugar interactions for ligand binding in large and highly water-exposed cavity.

Conformational adaptation of non-nucleoside reverse transcriptase inhibitor (NNRTI) via torsional flexibility is found to be very significant for targeting human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) mutants. Catechol diether derivative including flexible torsions is new potent NNRTI with picomolar activity. Moreover, this derivative also reveals the good solubility, low toxicity and potent inhibition for HIV-1 mutants. In this study, torsional flexibility of an undecorated catechol diether compound in the binding pocket of wild type and mutants (Y181C and K103N/Y181C) HIV-1 RT is investigated by using QM/MM calculations. From the results, the uracil ring is found to exhibit more flexibility in the NNIBP. On the contrary, potential energy surfaces show that high energy is encountered by changing of the corresponding torsion of the cyanovinyl aryl ring indicating the limitation for torsional flexibility. For pointing out the key interaction for the binding, the residual interaction energies are performed by means of QM calculations. Important attractive interactions through hydrogen bonds between the inhibitor and K102, K/N103, V106, and Y188 are observed. The catechol ring is proposed to be modified in order to strengthen interactions with surrounding amino acids. The results may help for the designing of new potent NNRTIs.

The nondiscriminating aspartyl-tRNA synthetase (ND-AspRS), found in many archaea and bacteria, covalently attaches aspartic acid to tRNAAsp and tRNAAsn generating a correctly charged Asp-tRNAAsp and an erroneous Asp-tRNAAsn . This relaxed tRNA specificity is governed by interactions between the tRNA and the enzyme. In an effort to assess the contributions of the anticodon-binding domain to tRNA specificity, we constructed two chimeric enzymes, Chimera-D and Chimera-N, by replacing the native anticodon-binding domain in the Helicobacter pylori ND-AspRS with that of a discriminating AspRS (Chimera-D) and an asparaginyl-tRNA synthetase (AsnRS, Chimera-N), both from Escherichia coli. Both chimeric enzymes showed similar secondary structure compared to wild-type (WT) ND-AspRS and maintained the ability to form dimeric complexes in solution. Although less catalytically active than WT, Chimera-D was more discriminating as it aspartylated tRNAAsp over tRNAAsn with a specificity ratio of 7.0 compared to 2.9 for the WT enzyme. In contrast, Chimera-N exhibited low catalytic activity toward tRNAAsp and was unable to aspartylate tRNAAsn . The observed catalytic activities for the two chimeras correlate with their heterologous toxicity when expressed in E. coli. Molecular dynamics simulations show a reduced hydrogen bond network at the interface between the anticodon-binding domain and the catalytic domain in Chimera-N compared to Chimera-D or WT, explaining its lower stability and catalytic activity.

Four meroterpenoids, 1-hydroxychevalone C, 1-acetoxychevalone C, 1,11-dihydroxychevalone C, and 11-hydroxychevalone C and two ester epimers, 2 S ,4 S -spinosate and 2 S ,4 R -spinosate, together with seven known compounds, chevalones B, C, and E, tryptoquivaline, nortryptoquivaline, tryptoquivaline L, and quinadoline A were isolated from the fungus Neosartorya spinosa . Their structures were established based on spectroscopic data analyses. The theoretical ECD spectra of epimers, 2 S ,4 S -spinosate and 2 S ,4 R -spinosate were calculated to support the experimental results of their CD spectra. 1-hydroxychevalone C exhibited antimycobacterial activity against Mycobacterium tuberculosis with a MIC value of 26.4 μM. 1-Acetoxychevalone C and tryptoquivaline showed antimalarial activity against Plasmodium falciparum with IC 50 values of 6.67 and 2.65 μM, respectively. In addition, 1-hydroxychevalone C, 1-acetoxychevalone C, 1,11-dihydroxychevalone C and quinadoline A showed cytotoxicity against KB and NCI-H187 cancer cell lines with IC 50 values in the range of 32.7–103.3 μM.

Investigation of the fungus Phoma herbarum PSU-H256 isolated from a leaf of Hevea brasiliensis resulted in the isolation of eight terezine derivatives (E-L) together with four known compounds. Their structures were established by analysis of spectroscopic evidence. For terezines E and H, their structures were confirmed by single-crystal X-ray diffraction crystallography. In addition, the absolute configuration at C-7 in terezine E was established by Mosher's method. Terezines K and L were tested for antibacterial, antimalarial, antimycobacterial and cytotoxic activities, but were inactive.

A 2-trans enoyl-acyl carrier protein (ACP) reductase or InhA of M. tuberculosis is a drug target of isoniazid (INH), the first-line drug for tuberculosis treatment. Many series of compounds have been developed as novel inhibitors of this enzyme. However, they lack good potency against purified InhA and activity against intact M. tuberculosis cells. Benzofuran pyrrolidin pyrazole derivatives are potent direct InhA inhibitors. These compounds show high potency for InhA inhibition with IC50 values at nanomolar levels. However, their activities against M. tuberculosis cells in terms of MIC90 were about one-thousand fold than IC50. Accordingly, in this work, IC50 and MIC90 values of benzofuran pyrrolidin pyrazole derivatives were subjected to CoMFA and CoMSIA studies in order to investigate the structural basis required for good activity against both purified InhA and M. tuberculosis cells. Moreover, MD simulations were employed to evaluate key interactions for binding benzofuran pyrrolidin pyrazole derivatives in InhA. Based on MD results, the core structure of these compounds is the key portion for binding in the InhA pocket. Alternatively, R substituents showed weak interactions with the InhA pockets. Interpretation of IC50 and MIC90 CoMSIA contour maps revealed the structural requirements in terms of steric, electrostatic, hydrophobic and hydrogen donor and acceptor for IC50 and MIC90 values of InhA inhibitors. Finally, the integrated results obtained from MD simulations and graphic interpretation of CoMSIA models provided a structural concept for rational design of novel InhA inhibitors with better potency against both the InhA enzyme and intact M. tuberculosis cells.

Overstimulation of CFTR-mediated Cl− secretion plays an important role in the pathogenesis of secretory diarrheas, which remain an important global health problem. This study aimed to identify inhibitors of CFTR-mediated Cl− secretion from a library of fungus-derived compounds and to evaluate their pharmacological properties and anti-diarrheal utility. We identified zearalenone, 7′-dehydrozearalenone and 8′-hydroxyzearalenone isolated from the seagrass-derived fungus Fusarium sp. PSU-ES123 as inhibitors of CFTR-mediated Cl− secretion in human intestinal epithelial (T84) cells. Being the most potent fungal metabolite capable of inhibiting CFTR-mediated Cl− secretion, zearalenone reversibly inhibited CFTR Cl− channel activity in T84 cells with an IC50 of ∼0.5 μM. Functional and biochemical analyses and molecular docking studies indicate that zearalenone binds to the β-estradiol binding sites in the ATP-binding pockets on NBD1 and NBD2 of CFTR. Mechanisms of CFTR inhibition by zearalenone do not involve activation of phosphodiesterases, protein phosphatases, multidrug-resistance protein 4 and AMP-activated protein kinases. Importantly, zearalenone significantly inhibited cholera toxin (CT)-induced Cl− secretion in T84 cells and blocked CT-induced intestinal fluid secretion in mice. Collectively, our study indicates that zearalenone represents the first class of fungus-derived CFTR inhibitors. Further development of this class of compounds may provide an effective treatment of secretory diarrheas.

In late 2012, an outbreak of acute gastroenteritis due to norovirus variant Sydney_2012 occurred and have been reported from many counties. In this study, we described surveillance study of the incidence of norovirus infections among Japanese pediatric patients in association with gastroenteritis and investigated the antigenic change of the new variant Sydney_2012 circulated in Japanese populations. A total of 2381 fecal specimens collected from children with acute gastroenteritis in Hokkaido, Tokyo, Shizuoka, Kyoto, Osaka, and Saga from 2009 to 2013 were examined for norovirus and further analyzed molecularly. A high proportion (39.3%) of norovirus positive samples and several genotypes were detected. Norovirus GII.4 dominated over other genotypes (71.4%). The Den_Haag_2006b (43.2%) was detected as the predominant variant and co-circulated with New_Orleans_2009 (17.8%) until March 2012. Subsequently, they were displaced by Sydney_2012. The Sydney_2012 variant has been responsible for the majority of norovirus infections in 2012-2013 (85.7%). Although Sydney_2012 variant has a common ancestor with New_Orleans_2009 variant, analysis of P2 sub-domain showed a high level of diversity in comparison with other variants in four amino acid changes at the antigenic sites. The change in particular residue 393 of new variant may affect HBGA recognition. Analysis of noroviruses circulating in the past 4years revealed a change of predominant variant of norovirus GII.4 in each epidemic season. The change of amino acid in putative epitopes may have led the virus escape from the existing herd immunity and explain the increase of new variant outbreaks.

PicoGreen (PG) is used as a probe to selectively quantitate double-stranded (ds-) DNA because it shows unique fluorescence enhancement when complexed with DNA. By binding to ds- and single-stranded...

Azanaphthoquinone annelated pyrrole derivatives have been developed and synthesized with a continuous attempt to develop novel DNA intercalating agents as anti-cancer compounds with lower organ toxicity. With the remarkable antiproliferative activity of synthesized azanaphthoquinone annelated pyrrole derivatives, a structurally novel scaffold of these compounds is appropriated for further development of novel anti-cancer agents. Therefore, in the present study, 3D QSAR study (CoMSIA) was applied on 28 azanaphthoquinone annelated pyrrole derivatives to evaluate the structural requirement of these compounds. The resulting CoMSIA model is satisfied with r(2) of 0.99 and q(2) of 0.65. The interpretation of CoMSIA contours reveals the significant importance of steric, electrostatic, hydrophobic and hydrogen acceptor descriptors on the activities of azanaphthoquinone annelated pyrrole derivatives. Remarkably, the structural requirement of six substituent positions on the azanaphthoquinone annelated pyrrole scaffold was elucidated here. This result is the useful concept for design of new and more active azanaphthoquinone annelated pyrrole derivatives. Moreover, MD simulations using AMBER program were performed to model the binding of azanaphthoquinone annelated pyrrole derivatives in the intercalation site of the DNA duplex. Based on MD simulations, the information in terms of ligand-DNA interaction, complex structure and binding free energy was provided in this work. Therefore, the integrated results are informative for further modification of azanaphthoquinone annelated pyrrole scaffold leading to gain novel azanaphthoquinone annelated pyrrole derivatives possessing better antiproliferative activity.

An effective tripeptide inhibitor, 2-naphthoyl–Lys–Lys–Arg–H (Naph-KKR-H), acts as an inhibitor against West Nile Virus (WNV) NS3 protease (NS3pro). Two conformations of Naph-KKR-H were found in th...

The azanaphthoquinone annelated pyrrole derivatives were synthesized and characterized with an effort to develop novel DNA intercalating agents as anticancer compounds. To model the binding of these compounds in the intercalation site of the DNA duplex, molecular dynamics (MD) simulations using AMBER program were performed. Moreover, molecular mechanics/Poisson–Boltzmann surface area method was used to calculate the binding free energy of azanaphthoquinone annelated pyrrole derivatives in the intercalation site of the DNA duplex. On the basis of MD simulations, the π–π stacking interaction of azanaphthoquinone annelated pyrrole derivatives with base pairs of C and G is the crucial interaction for binding of these DNA intercalating agents. Moreover, the hydrogen bond interaction of side chain could enhance the binding affinity of azanaphthoquinone annelated pyrrole derivatives in the intercalation site. Therefore, the obtained results should be helpful for better understanding the binding of azanaphthoquinone annelated pyrrole derivatives in the intercalation site. © 2012 Wiley Periodicals, Inc.

The interactions between ligands and the surrounding binding site depend on the different contributions of individual amino acids. The determination of these particular interaction energies is sensitive to the model used, i.e., which part of the amino acids is taken into account and which terminating procedure is applied. In this study, the subtle interaction between individual residues from the HIV-1 reverse transcriptase allosteric binding site and an inhibitor, isopropyl (S)-2-ethyl-7-fluoro-3,4-dihydro-3-oxoquinoxalin-1(2H)-carboxylate (GW420867X), was investigated by using high-level quantum chemical calculations (MP2, M06-2X, and B3LYP) with the following basis sets: 6-31G(d), 6-31G(d,p), 6-311G(d), and 6-311G(d,p). The results obtained indicate that the interaction between the inhibitor and Lys101 is the most important one for the binding. We have calculated this interaction using various models to evaluate the effect of neighboring residues. Electrostatic interactions induced by the terminating substituents were also studied using natural population analysis. The results show that even systems where the amide bond is cut and capped with hydrogen atoms can be used as reliable models for estimating the individual interaction energies. Furthermore, the interaction energies of GW420867X in wild-type and Lys101Glu mutant are also investigated to explain the loss of GW420867X’s activity in the Lys101Glu mutant.

The common structural requirements for cytotoxicity of lamellarins against two human breast cancer cell lines were determined using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Twenty lamellarins were selected to serve as the training set, whereas another group of six compounds were used as the test set. The best CoMFA and CoMSIA models for both cell lines yielded satisfactory predictive ability with r cv 2 values in the range of 0.659–0.728. Additionally, the contour maps obtained from both the CoMFA and CoMSIA models agreed well with the experimental results and may be used in the design of more potent cytotoxic compounds for human breast cancers. Both analyses not only suggested structural requirements of various substituents around the lamellarin skeleton for their cytotoxic activity against both human breast cancer cell lines but also revealed the molecular basis for the differences between the saturated and unsaturated D-rings of the lamellarins.

The enoyl ACP reductase enzyme (InhA) involved in the type II fatty acid biosynthesis pathway of Mycobacterium tuberculosis is an attractive target enzyme for antitubercular drug development. Arylamide derivatives are a novel class of InhA inhibitors used to overcome the drug-resistance problem of isoniazid, the frontline drug for tuberculosis treatment. Their remarkable property of inhibiting the InhA enzyme directly without requiring any coenzyme, makes them especially appropriate for the design of new antibacterials. In order to find a sound binding conformation for the different arylamide analogs, molecular docking experiments were performed with subsequent QSAR investigations. The X-ray conformation of one arylamide within its cocrystallized complex with InhA was used as a starting conformation for the docking experiments. The results thus obtained are perfectly consistent (rmsd = 0.73 A) with the results from X-ray analysis. A thorough investigation of the arylamide binding modes with InhA provided ample information about structural requirements for appropriate inhibitor–enzyme interactions. Three different QSAR models were established using two three-dimensional (CoMFA and CoMSIA) and one two-dimensional (HQSAR) techniques. With statistically ensured models, the QSAR results obtained had high correlation coefficients between molecular structure properties of 28 arylamide derivatives and their biological activity. Molecular fragment contributions to the biological activity of arylamides could be obtained from the HQSAR model. Finally, a graphic interpretation designed in different contour maps provided coincident information about the ligand–receptor interaction thus offering guidelines for syntheses of novel analogs with enhanced biological activity.

Reverse transcriptase (RT), an essential enzyme for HIV-1 (human immunodeficiency virus type-1) life cycle, is a key target in drug discovery efforts against HIV-1 infection. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are very specific to HIV-1 RT and have relatively less toxicity than the nucleoside reverse transcriptase inhibitors (NRTIs). However, the rapid emergence of drug-resistant viral strains has limited the therapeutic efficacy of these inhibitors. In this review, recent advances in computer-aided drug design (CADD) for design of new compounds against HIV-1 RT based on ligand-based drug design (LBDD) using 2D-and 3D-QSAR approaches, structure-based drug design (SBDD) with the combination of molecular docking, virtual screening and de novo drug design, molecular simulations and particular interaction calculated from quantum chemical calculations are discussed. Their successful applications are also highlighted.

The ethanolic extract from seed kernels of Thai mango (MSKE) ( Mangifera indica L. cv. ‘Fahlun’) (Anacardiaceae) and its major phenolic principle (pentagalloyl glucopyranose) exhibited dose-dependent inhibitory effects on enzymatic activities of phospholipase A 2 (PLA 2 ), hyaluronidase and L -amino acid oxidase (LAAO) of Calloselasma rhodostoma (CR) and Naja naja kaouthia (NK) venoms by in vitro tests. The anti-hemorrhagic and anti-dermonecrotic activities of MSKE against both venoms were clearly supported by in vivo tests. Molecular docking studies indicated that the phenolic molecules of the MSKE could selectively bind to the active sites or their proximity, or modify conserved residues that are critical for the catalysis of PLA 2 , and selectively bind to the LAAO binding pocket of both CR and NK venoms and thereby inhibit their enzymatic activities. The results imply a potential use of MSKE against snake venoms. Keywords: Calloselasma rhodostoma ; Mangifera indica L.; Molecular docking study

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on the docked conformation were performed for 24 pyrazinone derivatives. All compounds were docked into the wild-type HIV-1 RT binding pocket and the lowest-energy docked configurations were used to construct the 3D QSAR models. The CoMFA and CoMSIA models enable good prediction of inhibition by the pyrazinones, with [FORMULA] = 0.703 and 0.735. Results obtained from CoMFA and CoMSIA based on the docking conformation of the pyrazinones are, therefore, powerful means of elucidating the mode of binding of pyrazinones and suggesting the design of new potent NNRTIs.Graphical Abstract[IMAGE]

Comparative molecular field analysis (CoMFA) was performed on twenty-three pyrimethamine (pyr) derivatives active against quadruple mutant type (Asn51Ile, Cys59Arg, Ser108Asn, Ile164Leu) dihydrofolate reductase of Plasmodium falcipaarum (PfDHFR). The represented CoMFA models were evaluated based on the various three different probe atoms, C(sp3) (+1), O(sp3) (-1) and H (+1), resulting in the best model with combined three types of probe atoms. The statistical results were r(2)(cv) = 0.702, S(press) = 0.608, r(2)(nv) = 0.980, s = 0.156, and r(2)(test-set) = 0.698 which can explain steric contribution of about 50%. In addition, an understanding of particular interaction energy between inhibitor and surrounding residues in the binding pocket was performed by using MP2/6-31G(d,p) quantum chemical calculations. The obtained results clearly demonstrate that Asn108 is the cause of pyr resistance with the highest repulsive interaction energy. Therefore, CoMFA and particular interaction energy analyses can be useful for identifying the structural features of potent pyr derivatives active against quadruple mutant type PfDHFR.

Human serum albumin (HSA) is the most abundant protein found in blood serum. It carries essential metabolites and many drugs. The glycation of HSA causes abnormal biological effects. Importantly, glycated HSA (GHSA) is of interest as a biomarker for diabetes. Recently, the first HSA structure with bound pyranose (GLC) and open-chain (GLO) glucose at Sudlow site I has been crystallised. We therefore employed molecular dynamics (MD) simulations and ONIOM calculations to study the dynamic nature of two bound glucose in a pre-glycated HSA (pGHSA) and observe how those sugars alter a protein structure comparing to wild type (Apo) and fatty acid-bound HSA (FA). Our analyses show that the overall structural stability of pGHSA is similar to Apo and FA, except Sudlow site II. Having glucose induces large protein flexibility at Sudlow site II. Besides, the presence of glucose causes W214 to reorient resulting in a change in W214 microenvironment. Considering sugars, both sugars are exposed to water, but GLO is more solvent-accessible. ONIOM results show that glucose binding is favoured for HSA (−115.04 kcal/mol) and GLO (−85.10 kcal/mol) is more preferable for Sudlow site I over GLC (−29.94 kcal/mol). GLO can strongly react with K195 and K199, whereas K195 and K199 provide slightly repulsive forces for GLC. This can confirm that an open-chain GLO is more favourable inside a pocket.

A series of scopoletin derivatives incorporated with the pyridinium moiety was synthesized and evaluated for their acetylcholinesterase (AChE) inhibitory activity by the colorimetric Ellman's method. A 2-fluorobenzylpyridinium derivative was the most potent among the tested compounds, with an IC50 value of 0.215±0.015μM, which was greatly improved from that of scopoletin. Docking studies revealed that the scopoletin portion of the mentioned compound was bound to the peripheral anionic site of the AChE, whereas the N-benzylpyridinium residue to the catalytic anionic site.

The Mycobacterium tuberculosis protein kinase B (PknB) is critical for growth and survival of M. tuberculosis within the host. The series of aminopyrimidine derivatives show impressive activity against PknB (IC50 .5 μM). However, most of them show weak or no cellular activity against M. tuberculosis (MIC 63 μM). Consequently, the key structural features related to activity against of both PknB and M. tuberculosis need to be investigated. Here, two- and three-dimensional quantitative structure-activity relationship (2D and 3D QSAR) analyses combined with molecular dynamics (MD) simulations were employed with the aim to evaluate these key structural features of aminopyrimidine derivatives. Hologram quantitative structure-activity relationship (HQSAR) and CoMSIA models constructed from IC50 and MIC values of aminopyrimidine compounds could establish the structural requirements for better activity against of both PknB and M. tuberculosis. The NH linker and the R1 substituent of the template compound are not only crucial for the biological activity against PknB but also for the biological activity against M. tuberculosis. Moreover, the results obtained from MD simulations show that these moieties are the key fragments for binding of aminopyrimidine compounds in PknB. The combination of QSAR analysis and MD simulations helps us to provide a structural concept that could guide future design of PknB inhibitors with improved potency against both the purified enzyme and whole M. tuberculosis cells.