Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies

Summary We have performed docking studies with the SYSDOC program on acetylcholinesterase (AChE) to predict the binding sites in AChE of huperzine A (HA), which is a potent and selective, reversible inhibitor of AChE. The unique aspects of our docking studies include the following: (i) Molecular flexibility of the guest and the host is taken into account, which permits both to change their conformations upon binding. (ii) The binding energy is evaluated by a sum of energies of steric, electrostatic and hydrogen bonding interactions. In the energy calculation no grid approximation is used, and all hydrogen atoms of the system are treated explicitly. (iii) The energy of cation- interactions between the guest and the host, which is important in the binding of AChE, is included in the calculated binding energy. (iv) Docking is performed in all regions of the host's binding cavity. Based on our docking studies and the pharmacological results reported for HA and its analogs, we predict that HA binds to the bottom of the binding cavity of AChE (the gorge) with its ammonium group interacting with Trp⁸⁴, Phe³³⁰, Glu¹⁹⁹ and Asp⁷² (catalytic site). At the the opening of the gorge with its ammonium group partially interacting with Trp²⁷⁹ (peripheral site). At the catalytic site, three partially overlapping subsites of HA were identified which might provide a dynamic view of binding of HA to the catalytic site.     

Modeling effects of oxyanion hole on the ester hydrolysis catalyzed by human cholinesterases

Molecular dynamics (MD) simulations and hydrogen bonding energy (HBE) calculations have been performed on the prereactive enzyme-substrate complexes (ES), transition states (TS1), and intermediates (INT1) for acetylcholinesterase (AChE)-catalyzed hydrolysis of acetylcholine (ACh), butyrylcholinesterase (BChE)-catalyzed hydrolysis of ACh, and BChE-catalyzed hydrolysis of (+)/(-)-cocaine to examine the protein environmental effects on the catalytic reactions. The hydrogen bonding of cocaine with the oxyanion hole of BChE is found to be remarkably different from that of ACh with AChE/BChE. Whereas G121/G116, G122/G117, and A204/A199 of AChE/BChE all can form hydrogen bonds with ACh to stabilize the transition state during the ACh hydrolysis, BChE only uses G117 and A199 to form hydrogen bonds with cocaine. The change of the estimated total HBE from ES to TS1 is ca. -5.4/-4.4 kcal/mol for AChE/BChE-catalyzed hydrolysis of ACh and ca. -1.7/-0.8 kcal/mol for BChE-catalyzed hydrolysis of (+)/(-)-cocaine. The remarkable difference of approximately 3 to 5 kcal/mol reveals that the oxyanion hole of AChE/BChE can lower the energy barrier of the ACh hydrolysis significantly more than that of BChE for the cocaine hydrolysis. These results help to understand why the catalytic activity of AChE against ACh is considerably higher than that of BChE against cocaine and provides valuable clues on how to improve the catalytic activity of BChE against cocaine.     

Homology modeling and molecular dynamic simulation of UDP-N-acetylmuramoyl-l-alanine-d-glutamate ligase (MurD) from Mycobacterium tuberculosis H37Rv using in silico approach

The present study aimed to identify the prospective inhibitors of MurD, a cytoplasmic enzyme that catalyzes the addition of d-glutamate to the UDP-N-acetylmuramoyl-l-alanine nucleotide precursor in Mycobacterium tuberculosis (MTB), using virtual screening, docking studies, pharmacokinetic analysis, Molecular Dynamic (MD) simulation, and Molecular Mechanics Generalized Born and Surface Area (MM-GBSA) analyses. The three dimensional (3D) structure was determined based on the homology technique using a template from Streptococcus agalactiae. The modeled structure had three binding sites, namely; substrate binding site (Val18, Thr19, Asp39, Asp40, Gly75, Asn147, Gln171 and His192), the ATP binding site (Gly123, Lys124, Thr125, Thr126, Glu166, Asp283, and Arg314) and the glutamic acid binding site (Arg382, Ser463, and Tyr470). These residues mentioned above play a critical role in the catalytic activity of the enzyme, and their inhibition could serve as a stumbling block to the normal function of the enzyme. A total of 10,344 obtained from virtual screened of Zinc and PubChem databases. These compounds further screened for Lipinski rule of five, docking studies and pharmacokinetic analysis. Four compounds with good binding energies (ZINC11881196 = −10.33 kcal/mol, ZINC12247644 = −8.90 kcal/mol, ZINC14995379 =−8.42 kcal/mol, and PubChem6185 = −8.20 kcal/mol), better than the binding energies of the ATP (−2.31 kcal/mol) and the ligand with known IC₅₀, Aminothiazole (−7.11 kcal/mol) were selected for the MD simulation and MM-GBSA analyses. The result of the analyses showed that all the four ligands formed a stable complex and had the binding free energies better than the binding energy of ATP. Therefore, these ligands considered as suitable prospective inhibitors of the MurD after experimental validation.     

Revealing the importance of linkers in K-series oxime reactivators for tabun-inhibited AChE using quantum chemical,docking and SMD studies

Inhibition of acetylcholinesterase (AChE) with organophosphorus compounds has a detrimental effect on human life. Oxime K203 seems to be one of the promising reactivators for tabun-inhibited AChE than (K027, K127, and K628). These reactivators differ only in the linker units between the two pyridinium rings. The conformational analyses performed with quantum chemical RHF/6-31G* level for K027, K127, K203 and K628 showed that the minimum energy conformers have different orientations of the active and peripheral pyridinium rings for these reactivator molecules. K203 with (–CH₂–CH=CH–CH₂–) linker unit possesses more open conformation compared to the other reactivators. Such orientation of K203 experiences favorable interaction with the surrounding residues of catalytic anionic site (CAS) and peripheral anionic site (PAS) of tabun-inhibited AChE. From the steered molecular dynamics simulations, it has been observed that the oxygen atom of the oxime group of K203 reactivator approaches nearest to the P-atom of the SUN203 (3.75 Å) at lower time scales (less than ~1000 ps) as compared to the other reactivators. K203 experiences less number of hydrophobic interaction with the PAS residues which is suggested to be an important factor for the efficient reactivation process. In addition, K203 crates large number of H-bonding with CAS residues SUN203, Phe295, Tyr337, Phe338 and His447. K203 barely changes its conformation during the SMD simulation process and hence the energy penalty to adopt any other conformation is minimal in this case as compared to the other reactivators. The molecular mechanics and Poisson–Boltzmann surface area binding energies obtained for the interaction of K203 inside the gorge of tabun inhibited AChE is substantially higher (?290.2 kcal/mol) than the corresponding K628 reactivator (?260.4 kcal/mol), which also possess unsaturated aromatic linker unit.     

Periodic density functional theory study of methane activation over La(2)O(3): activity of O(2-), O(-), O(2)(2-), oxygen point defect,and Sr(2+)-doped surface sites

Results of gradient-corrected periodic density functional theory calculations are reported for hydrogen abstraction from methane at O(s)(2-), O(s)(-), O(2)(s)(2-) point defect, and Sr(2+)-doped surface sites on La(2)O(3)(001). The results show that the anionic O(s)(-) species is the most active surface oxygen site. The overall reaction energy to activate methane at an O(s)(-) site to form a surface hydroxyl group and gas-phase (*)CH(3) radical is 8.2 kcal/mol, with an activation barrier of 10.1 kcal/mol. The binding energy of hydrogen at an site O(s)(-) is -102 kcal/mol. An oxygen site with similar activity can be generated by doping strontium into the oxide by a direct Sr(2+)/La(3+) exchange at the surface. The O(-)-like nature of the surface site is reflected in a calculated hydrogen binding energy of -109.7 kcal/mol. Calculations indicate that surface peroxide (O(2(s))(2-)) sites can be generated by adsorption of O(2) at surface oxygen vacancies, as well as by dissociative adsorption of O(2) across the closed-shell oxide surface of La(2)O(3)(001). The overall reaction energy and apparent activation barrier for the latter pathway are calculated to be only 12.1 and 33.0 kcal/mol, respectively. Irrespective of the route to peroxide formation, the O(2)(s)(2-) intermediate is characterized by a bent orientation with respect to the surface and an O-O bond length of 1.47 A; both attributes are consistent with structural features characteristic of classical peroxides. We found surface peroxide sites to be slightly less favorable for H-abstraction from methane than the O(s)(-) species, with DeltaE(rxn)(CH(4)) = 39.3 kcal/mol, E(act) = 47.3 kcal/mol, and DeltaE(ads)(H) = -71.5 kcal/mol. A possible mechanism for oxidative coupling of methane over La(2)O(3)(001) involving surface peroxides as the active oxygen source is suggested.     

Exploring the conformation,charge density distribution and the electrostatic properties of galanthamine molecule in the active site of AChE using DFT and AIM theory

Quantum chemical calculations and charge density analysis were carried out to understand the geometry, charge density distribution and the electrostatic properties of isolated galanthamine molecule (form I) and for the same lifted out from the active site (form II) of AChE. The optimized geometry of isolated galanthamine was obtained from a hybrid density functional theory (B3LYP/6‐311G**) calculation. A docking analysis on galanthamine with AChE was performed, and the lowest docked energy structure was selected from the active site of AChE for the further study. A single point energy quantum chemical calculation (B3LYP/6‐311G**) was carried out for the lowest energy structure, which was lifted from the galanthamine–AChE complex from molecular docking analysis. The structural comparison between (I) and (II) helps to understand the conformational modification of the galanthamine molecule in the active site. When the molecule present in the active site, the molecular geometry is seen to be significantly altered, specifically, large changes were observed in the outer core of the molecule while the inner core geometry is intact. The bond topological and electrostatic properties of (I) and (II) were calculated. The dipole moment of the galanthamine molecule also increases from 2.09 to 2.67 D in the process. A large negative electrostatic potential region is found at the vicinity of oxygen and nitrogen atoms of the molecule, which predominantly involve strong hydrophobic and electrostatic interactions with the amino acid residues TRP84, PHE330, GLY118, TYR70, and SER122 present in the active site of AChE. © 2013 Wiley Periodicals, Inc.     

Activation of orotidine 5'-monophosphate decarboxylase by phosphite dianion: the whole substrate is the sum of two parts

We report that the binding of phosphite dianion to orotidine 5'-monophosphate decarboxylase (OMPDC) results in an 80 000-fold increase in kcat/Km for decarboxylation of the truncated substrate, 1-(beta-d-erythrofuranosyl)orotic acid (EO), which lacks a 5'-phosphodianion moiety. The intrinsic binding energy (IBE) of phosphite dianion in the transition state is 7.8 kcal/mol, which represents a very large fraction of the 11.8 kcal/mol IBE of the phosphodianion group of the natural substrate orotidine 5'-monophosphate (OMP). The data give kcat = 160 +/- 70 s-1 for turnover of EO in the active site of OMPDC containing phosphite dianion, which is significantly larger than kcat = 15 s-1 for turnover of OMP. Despite the weaker binding of the individual EO and HPO32- "parts" (KmKd = 0.014 M2) than of OMP (Km = 1.6 x 10-6 M), once bound, OMPDC provides a slightly greater stabilization of the transition state for reaction of the parts than of the whole substrate. Thus, the covalent connection between the reacting portion of the substrate and the nonreacting phosphodianion group is not necessary for efficient catalysis. This implies that a major role of the phosphodianion group of OMP is to provide binding interactions that are used to drive an enzyme conformational change, resulting in formation of an active site environment optimized for transition state stabilization.     

Identification of novel PI3Kδ inhibitors by docking,ADMET prediction and molecular dynamics simulations

BackgroundPhosphoinositide-3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ is confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Virtual screening techniques have been used to discover new molecules for developing novel PI3Kδ inhibitors with little side effects.MethodComputer aided drug design method were used to rapidly screen optimal PI3Kδ inhibitors from the Asinex database. Virtual screening based molecular docking was performed to find novel and potential lead compound targeting PI3Kδ, at first. Subsequently, drug likeness studies were carried out on the retrieved hits to evaluate and analyze their drug like properties such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) for toxicity prediction. Three least toxic compounds were selected for the molecular dynamics (MD) simulations for 30 ns in order to validate its stability inside the active site of PI3Kδ receptor.ResultsBased on the present in silico analysis, two molecules have been identified which occupied the same binding pocket confirming the selection of active site. ASN 16296138 (Glide score: −12.175 kcal/mol, cdocker binding energy: −42.975 kcal/mol and ΔG_bind value: −90.457 kcal/mol) and BAS 00227397 (Glide score: −10.988 kcal/mol, cdocker binding energy: −39.3376 kcal/mol and ΔG_bind value: −81.953 kcal/mol) showed docking affinities comparatively much stronger than those of already reported known inhibitors against PI3Kδ. These two ligand’s behaviors also showed consistency during the simulation of protein-ligand complexes for 30000 ps respectively, which is indicative of its stability in the receptor pocket.ConclusionCompound ASN 16296138 and BAS 00227397 are potential candidates for experimental validation of biological activity against PI3Kδ in future drug discovery studies. This study smoothes the path for the development of novel leads with improved binding properties, high drug likeness, and low toxicity to humans for the treatment of cancer.     

Mapping of the active site of proteases in the 1960s and rational design of inhibitors/drugs in the 1990s

For several decades the specificity of proteases has been presented as an active site divided into subsites, using the nomenclature of Schechter & Berger from 1967 (S1, S2... for subsites of the active site; P1, P2... for residues of the substrate occupying the corresponding subsites). At early stages of the research (1960s) it was realized that the size of the active site was larger than expected and important interactions occur in regions remote from the catalytic site. Since the active site was found to be large it was divided into subsites, and a procedure to map it up was developed. The map provides information on the size of the active site (number of subsites), the properties of each subsite (free energy of ligand binding, nature of binding forces, etc.), and it enables rational design of new substrates and inhibitors. Already in 1968 inhibitors with binding constants ten thousand fold higher than available inhibitors, were prepared. The model of a large active site was initially met with strong opposition. Before long, however, predictions of the model (size of the active site, interactions in subsites remote from the catalytic site) were confirmed by X-ray crystallography (1970). During the 1990s proteolytic enzymes received renewed attention in biology and medicine, they became therapeutic targets, and protease inhibitors were successfully applied in the treatment of AIDS and hypertension. The model of large active site divided into subsites, proposed 38 years ago, stood the test of time. This model is still in use in basic research to evaluate enzyme activity, and in pharmaceutical research for the development of inhibitors/drugs.     

Free-energy barriers in MbCO rebinding

The rebinding of CO to myoglobin (Mb) from locations around the active site is studied using a combination of molecular dynamics and stochastic simulations for native and L29F mutant Mb. The interaction between the dissociated ligand and the protein environment is described by the recently developed fluctuating three-point charge model for the CO molecule. Umbrella sampling along trajectories, previously found to sample the binding site (B) and the Xe4 pocket, is used to construct free-energy profiles for the ligand escape. On the basis of the Smoluchowski equation, the relaxation of different initial population distributions is followed in space and time. For native Mb at room temperature, the calculated rebinding times are in good agreement with experimental values and give an inner barrier of 4.3 kcal/mol between the docking site B (Mb...CO) and the A state (bound MbCO), compared to an effective barrier, Heff, of 4.5 kcal/mol and barriers into the majority conformation A1 and the minority conformation A3 of 2.4 and 4.3 kcal/mol, respectively. In the case of the L29F mutant, the free-energy surface is flatter and the dynamics is much more rapid. As was found in experiment, escape to the Xe4 pocket is facile for L29F whereas, for native Mb, the barriers to this site are larger. At lower temperatures, the rebinding dynamics is delayed by orders of magnitude also due to increased barriers between the docking sites.     

Ab initio model study on acetylcholinesterase catalysis: potential energy surfaces of the proton transfer reactions

Ab initio molecular orbital (MO) and hybrid density functional theory (DFT) calculations have been applied to the initial step of the acylation reaction catalyzed by acetylcholinesterase (AChE), which is the nucleophiric addition of Ser200 in catalytic triads to a neurotransmitter acetylcholine (ACh). We focus our attention mainly on the effects of oxyanion hole and Glu327 on the potential energy surfaces (PESs) for the proton transfer reactions in the catalytic triad Ser200-His440-Glu327. The activation barrier for the addition reaction of Ser200 to ACh was calculated to be 23.4 kcal/mol at the B3LYP/6-31G(d)//HF/3-21G(d) level of theory. The barrier height under the existence of oxyanion hole, namely, Ser200-His440-Glu327-ACh-(oxyanion hole) system, decreased significantly to 14.2 kcal/mol, which is in reasonable agreement with recent experimental value (12.0 kcal/mol). Removal of Glu327 from the catalytic triad caused destabilization of both energy of transition state for the reaction and tetrahedral intermediate (product). PESs calculated for the proton transfer reactions showed that the first proton transfer process is the most important in the stabilization of tetrahedral intermediate complex. The mechanism of addition reaction of ACh was discussed on the basis of theoretical results.     

Identification and energetic ranking of possible docking sites for pterin on dihydrofolate reductase

The reliability of new methodology for detecting sites for ligand binding on the surfaces of proteins has been tested using a range of dihydrofolate reductase (DHFR) crystal structures. Docking of the pterin molecule to ten such DHFR structures has been examined. Initial docking sites were selected using the VDW-FFT method we have developed recently. This procedure was followed by rigid geometry optimization and solvation energy calculations using our parametrized reaction field multipoles (PRFM) method and the finite difference solution of the Poisson equation (FDPB) method. Two different sets of MM parameters, from the OPLS and Amber94 force fields, have been used. In eight cases the energy of the complexes with pterin bound at the active site was the lowest with the recent Amber94 parameters. In one case the spurious first-ranked site was only 1.8 kcal/mol lower in energy compared with the active site. The other failure of the method may, in fact, represent a valid initial binding site. The calculations with the old OPLS parameters gave slightly worse results.     

A novel class of 1,4-disubstituted 1,2,3-triazoles: Regioselective synthesis,antimicrobial activity and molecular docking studies

A Novel class of 1,4-disubstituted 1,2,3-triazoles have been synthesized in good to excellent yields via Cu(I) accelerated azide-alkyne click chemistry reaction strategy. The newly synthesized compounds were assessed for their in vitro antimicrobial activity against five Gram-positive, seven Gram-negative bacteria and three fungi. Most of the synthesized compounds displayed significant activity against the tested Gram-positive and Gram-negative bacteria. Molecular docking study revealed that all docked compounds are bound efficiently with the active site of Topoisomerase IV (4EMV) receptor with the observed the free energy of binding from −7.79 to −9.44 kcal/mol. Interestingly, compound 13a forms four hydrogen bonds and displayed high binding energy (−9.44 kcal/mol) with the Topoisomerase IV (4EMV) receptor which correlated with their in vitro antimicrobial assays.     

Kinetics and Computational Docking Studies on the Inhibition of Tyrosinase Induced by Oxymatrine

A combination of enzymatic inhibition kinetics and computational prediction was employed to search for an effective inhibitor of tyrosinase. We found that oxymatrine significantly inhibited tyrosinase, and that this reaction was not accompanied by detectable conformational changes. Kinetic analysis showed that oxymatrine reversibly inhibited tyrosinase in a mixed-type manner. Measurements of intrinsic and ANS-binding fluorescences showed that oxymatrine did not induce any conspicuous changes in the tertiary structure. We also conducted a docking simulation between tyrosinase and oxymatrine using two docking programs, Dock6.3 and AutoDock4.2 (binding energy was ?118.81 kcal/mol for Dock6 and ?8.04 kcal/mol for AutoDock4). The results also suggested that oxymatrine interacts mostly with the residues of CYS83 and HIS263 in the active site of tyrosinase. This strategy of predicting tyrosinase inhibition by simulation of docking coupling with kinetics may prove useful in screening for potential tyrosinase inhibitors. Knowledge of tyrosinase inhibition can provide medical, cosmetic, and agricultural applications. Our study suggests that oxymatrine is an important agent for various applications related to pigment formation.     

Antibiotic deactivation by a dizinc beta-lactamase: mechanistic insights from QM/MM and DFT studies

Hybrid quantum mechanical/molecular mechanical (QM/MM) methods and density functional theory (DFT) were used to investigate the initial ring-opening step in the hydrolysis of moxalactam catalyzed by the dizinc L1 beta-lactamase from Stenotrophomonas maltophilia. Anchored at the enzyme active site via direct metal binding as suggested by a recent X-ray structure of an enzyme-product complex (Spencer, J.; et al. J. Am. Chem. Soc. 2005, 127, 14439), the substrate is well aligned with the nucleophilic hydroxide that bridges the two zinc ions. Both QM/MM and DFT results indicate that the addition of the hydroxide nucleophile to the carbonyl carbon in the substrate lactam ring leads to a metastable intermediate via a dominant nucleophilic addition barrier. The potential of mean force obtained by SCC-DFTB/MM simulations and corrected by DFT/MM calculations yields a reaction free energy barrier of 23.5 kcal/mol, in reasonable agreement with the experimental value of 18.5 kcal/mol derived from kcat of 0.15 s(-1). It is further shown that zinc-bound Asp120 plays an important role in aligning the nucleophile, but accepts the hydroxide proton only after the nucleophilic addition. The two zinc ions are found to participate intimately in the catalysis, consistent with the proposed mechanism. In particular, the Zn(1) ion is likely to serve as an "oxyanion hole" in stabilizing the carbonyl oxygen, while the Zn(2) ion acts as an electrophilic catalyst to stabilize the anionic nitrogen leaving group.     

New insights into the mechanism of the Schiff base formation catalyzed by type I dehydroquinate dehydratase from <Emphasis Type="Italic">S. enterica</Emphasis>

The Schiff base formation catalyzed by type I dehydroquinate dehydratase (DHQD) from Salmonella enterica has been studied by molecular docking, molecular dynamics simulation, and quantum chemical calculations. The substrate locates stably a similar position as the Schiff base intermediate observed in the crystal structure and forms strong hydrogen bonds with several active site residues. This binding mode is different from that of several other Schiff base enzymes. Then, the quantum chemical model has been constructed and the fundamental reaction pathways have been explored by performing quantum chemical calculation. The energy barrier of the previously proposed reaction pathway is calculated to be 30.7 kcal/mol, which is much higher than the experimental value of 14.3 kcal/mol of the whole dehydration reaction by type I DHQD from S. enterica. It means that this pathway is not favorable in energy. Therefore, a new and unexpected reaction pathway has been investigated with the favorable and reasonable energy barrier of 12.1 kcal/mol. The complicated role of catalytic His143 residue has also been elucidated that it mediates two proton transfers to facilitate the reaction. Moreover, the similarity and the difference between these two reaction pathways have been analyzed in detail. The new structural and mechanistic insights may direct the design of the inhibitors of type I dehydroquinate dehydratase as non-toxic antimicrobials, antifungals, and herbicides.     

Rational in silico design of aptamers for organophosphates based on the example of paraoxon

Poisoning by organophosphates (OPs) takes one of the leading places in the total number of exotoxicoses. Detoxication of OPs at the first stage of the poison entering the body could be achieved with the help of DNA- or RNA-aptamers, which are able to bind poisons in the bloodstream. The aim of the research was to develop an approach to rational in silico design of aptamers for OPs based on the example of paraoxon. From the published sequence of an aptamer binding organophosphorus pesticides, its three-dimensional model has been constructed. The most probable binding site for paraoxon was determined by molecular docking and molecular dynamics (MD) methods. Then the nucleotides of the binding site were mutated consequently and the values of free binding energy have been calculated using MD trajectories and MM-PBSA approach. On the basis of the energy values, two sequences that bind paraoxon most efficiently have been selected. The value of free binding energy of paraoxon with peripheral anionic site of acetylcholinesterase (AChE) has been calculated as well. It has been revealed that the aptamers found bind paraoxon more effectively than AChE. The peculiarities of paraoxon interaction with the aptamers nucleotides have been analyzed. The possibility of improving in silico approach for aptamer selection is discussed.     

Molecular Docking and Design of Novel Heterodimers of Donepezil and Huperzine Fragments as Acetylcholinesterase Inhibitors

To provide hints for the design of new acetylcholinesterase(ACh E) inhibitors with higher potency and specificity, the binding modes of novel heterodimers comprised of donepezil and huperzine A fragments with ACh E were explored by employing the docking simulations. The results show that the binding mode of S-17b(the most potent inhibitor in Ref. 2, i.e., Bioorg. Med. Chem. 2013, 21, 676-683) is clearly different from that of donepezil, while the binding modes of other heterodimers in Ref. 2 are the same as that of donepezil. In addition, based on the binding mode and structure modification of S-17 b, two novel inhibitors(S-17b1 and S-17bb1) with much higher inhibitory potency than S-17 b were obtained. Our design strategy was to replace the hupyridone moiety of S-17 b with the bulky group, and to replace the dimethoxyindanone moiety of S-17 b with more hydrophobic and bulky group with a highly positive charge, which would result in generating potent and selective AChE inhibitors.     

Rational design of biologically important chemosensors: a novel receptor for selective recognition of acetylcholine over ammonium cations

[structure: see text] In consideration of competition between cation-pi and hydrogen bond interaction forces, we designed a novel receptor, 1,3,5-tris(pyrrolyl)benzene, which shows high selectivity for acetylcholine (ACh). The selectivity of the receptor for ACh over other ammonium cations is demonstrated by the ion-selective electrode (ISE) method in buffer solution. The binding free energy of the receptor with ACh in chloroform solution is measured to be 3.65 kcal/mol in the presence of chloride anion by nuclear magnetic resonance spectroscopy, and that in water is estimated to be much greater ( approximately 6 kcal/mol).     

A molecular docking study of potential inhibitors and repurposed drugs against SARS-CoV-2 main protease enzyme

COVID-19 has affected millions of people. Although many drugs are in use to combat disease, there is not any sufficient treatment yet. Having critical role in propagation of the novel coronavirus (SARS-CoV-2) works Main Protease up into a significant drug target. We have performed a molecular docking study to define possible inhibitor candidates against SARS-CoV-2 Main Protease enzyme. Besides docking Remdesivir, Ribavirin, Chloroquine and 28 other antiviral inhibitors (totally 31 inhibitors) to Main Protease enzyme, we have also performed a molecular docking study of 2177 ligands, which are used against Main Protease for the first time by using molecular docking program Autodock4. All ligands were successfully docked into Main Protease enzyme binding site. Among all ligands, EY16 coded ligand which previously used as EBNA1-DNA binding blocker candidate showed the best score for Main Protease with a binding free energy of −10.83 ​kcal/mol which was also lower than re-docking score of N3 ligand (−10.72 ​kcal/mol) contained in crystal structure of Main Protease. After analyzing the docking modes and docking scores we have found that our ligands have better binding free energy values than the inhibitors in use of treatment. We believe that further studies such as molecular dynamics or Molecular Mechanic Poisson Boltzmann Surface Area studies can make contribution that is more exhaustive to the docking results.