Soft versus hard metastable conformations in molecular simulations

Particle methods have become indispensible in conformation dynamics to compute transition rates in protein folding, binding processes and molecular design, to mention a few. Conformation dynamics requires at a decomposition of a molecule’s position space into metastable conformations. In this paper, we show how this decomposition can be obtained via the design of either “soft” or “hard” molecular conformations. We show, that the soft approach results in a larger metastabilitiy of the decomposition and is thus more advantegous. This is illustrated by a simulation of Alanine Dipeptide

SYNTHESIS, EVALUATION AND DOCKING STUDIES OF NOVEL FORMAZAN DERIVATIVES AS AN ENOYL-ACP REDUCTASE INHIBITORS

Objective: To synthesize, evaluate and performing the docking studies of novel formazan derivatives as enoyl-ACP reductase inhibitors.Materials: In the present investigation, a series of formazans (Ia-d) were synthesized by stirring aryl diazonium salts solution with Schiff's base at 0-5˚C for 2 h. The intermediate azomethine (Schiff base) itself was synthesized by condensation of para aminobenzoic acid with dimethylamino benzaldehyde in presence of a glacial acetic acid as a catalyst. The antimicrobial activity was done for these synthesized compounds by cup plate method. Moreover, the antimicrobial activity was further confirmed by its molecular docking approach study by using Molecular Operating Environment (MOE) 2009.10 software.Results: In the present study all the synthesized compounds (Ia-Id) showed the enhanced zone of inhibition against S. aureus, B. subtilis, E. coli and S. typhi (5±0.12 to 12±0.45) whereas, the antifungal activity against A. niger and C. albicans were showed the zone of inhibition in the range of 9±0.51 to 12±0.43 when compared to that of the standard drug.Further the docking study reveals that, only three of the formazan compounds under observation (Ia, Ib and Ic) have higher binding affinity with the receptors enzymes enoyl-ACP reductase, which is in the narrow range of binding energy for the protein PDB: 1C14 is-24.4598 to-23.9377 kcal/mol, which shows the further confirmation of these formazan compounds as better microbial inhibitor.Conclusion: Therefore our present report shows that formazans could be the potential drug candidate that inhibits the microbial activity by interacting and inhibiting the enoyl-ACP reductase enzyme which is confirmed by its both in vitro antimicrobial study and as well as from its docking study

DESIGN, SYNTHESIS, AND DOCKING OF SULFADIAZINE SCHIFF BASE SCAFFOLD FOR THEIR POTENTIAL CLAIM AS INHA ENOYL-(ACYL-CARRIER-PROTEIN) REDUCTASE INHIBITORS

Objective: An effort was made to design and synthesize the series of sulfadiazine building blocks as a targeted candidate for antimycobacterial activity.Method: The synthesized compounds were subjected to preliminary in silico screening study for testing their antimycobacterial action by doing their molecular docking study on bioinformatics software, molecular operating environment 2009.10.Result: The results obtained from this tool showed that there is a best docking affinity score of these target compounds against the enzyme InhA Enoyl-(acyl-carrier-protein) reductase from Mycobacterium tuberculosis (MTB) pathogen, which is one of the key enzymes involved in the type II fatty acid biosynthesis pathway of MTB.Conclusion: Thus, the synthesized sulfadiazine Schiff base derivatives might serve as the best drug candidate for the existence of menacing pathogen MTB.Â

Experimental and theoretical justifications for the observed discriminations between enantiomers of prochiral alcohols by chirally blind EI-MS

To all appearances, electron impact mass spectrometer (EI-MS) is considered a "chirally blind" instrument. Yet, numerous non-identical R (right) and S (left) configurations of prochiral alcohols' mass spectra alcohols have appeared in the literature with almost no justification. Such observations are often attributed to impurities, experimental circumstances, inaccurate measurements, etc. In an experimental attempt to explain this phenomenon, here we have avoided the above mentioned pitfalls by conducting control experiments using different pure enantiomers under the same circumstances. Hence, we report the mass spectra of R- and S-enantiomers of 2-octanol (1R, 1S) and 1-octyn-3-ol (2R, 2S) collected by running 20 independent experiments for each R- and S-enantiomer. Statistical analyses confirmed that the peak intensities were significant to an acceptable level of confidence. The 1R and 1S enantiomers were separated reasonably in the PC space, implying that the chirally blind EI-MS is able to discriminate between R and S prochiral alcohols. Theoretically, self-complexation through H-bonding for S (or R) appears to give a new chiral center at the H-bonded oxygen atom, producing a new dimeric pair of diastereomers SRS and SSS (or RRR and RSR) before ionization, and SRS.+ and SSS.+ (or RRR.+ and RSR.+) after ionization. The results of our calculations have explicitly shown that these hydrogen bonds formed. Interestingly, the latter four ionized diastereomers appear with different structural and thermodynamic parameters at the M06-2X/6-311++g (d,p) level of theory

A sobering assessment of small-molecule force field methods for low energy conformer predictions

We have carried out a large scale computational investigation to assess the utility of common small-molecule force fields for computational screening of low energy conformers of typical organic molecules. Using statistical analyses on the energies and relative rankings of up to 250 diverse conformers of 700 different molecular structures, we find that energies from widely used classical force fields (MMFF94, UFF, and GAFF) show unconditionally poor energy and rank correlation with semiempirical (PM7) and Kohn–Sham density functional theory (DFT) energies calculated at PM7 and DFT optimized geometries. In contrast, semiempirical PM7 calculations show significantly better correlation with DFT calculations and generally better geometries. With these results, we make recommendations to more reliably carry out conformer screening

Changes in Alprazolam Metabolism by CYP3A43 Mutants

Alprazolam is a triazolobenzodiazepine which is most commonly used in the short-term management of anxiety disorders, often in combination with antipsychotics. The four human members of the CYP3A subfamily are mainly responsible for its metabolism, which yields the main metabolites 4-hydroxyalprazolam and α-hydroxyalprazolam. We performed a comparison of alprazolam metabolism by all four CYP3A enzymes upon recombinant expression in the fission yeast Schizosaccharomyces pombe. CYP3A4 and CYP3A5 show the highest 4-hydroxyalprazolam production rates, while CYP3A5 alone is the major producer of α-hydroxyalprazolam. For both metabolites, CYP3A7 and CYP3A43 show lower activities. Computational simulations rationalize the difference in preferred oxidation sites observed between the exemplary enzymes CYP3A5 and CYP3A43. Investigations of the alprazolam metabolites formed by three previously described CYP3A43 mutants (L293P, T409R, and P340A) unexpectedly revealed that they produce 4-hydroxy-, but not α-hydroxyalprazolam. Instead, they all also make a different metabolite, which is 5-N-O alprazolam. With respect to 4-hydroxyalprazolam, the mutants showed fourfold (T409R) to sixfold (L293P and P340A) higher production rates compared to the wild-type (CYP3A43.1). In the case of 5-N-O alprazolam, the production rates were similar for the three mutants, while no formation of this metabolite was found in the wild-type incubation

QM7-X: A comprehensive dataset of quantum-mechanical properties spanning the chemical space of small organic molecules

We introduce QM7-X, a comprehensive dataset of 42 physicochemical properties for $\approx$ 4.2 M equilibrium and non-equilibrium structures of small organic molecules with up to seven non-hydrogen (C, N, O, S, Cl) atoms. To span this fundamentally important region of chemical compound space (CCS), QM7-X includes an exhaustive sampling of (meta-)stable equilibrium structures - comprised of constitutional/structural isomers and stereoisomers, e.g., enantiomers and diastereomers (including cis-/trans- and conformational isomers) - as well as 100 non-equilibrium structural variations thereof to reach a total of $\approx$ 4.2 M molecular structures. Computed at the tightly converged quantum-mechanical PBE0+MBD level of theory, QM7-X contains global (molecular) and local (atom-in-a-molecule) properties ranging from ground state quantities (such as atomization energies and dipole moments) to response quantities (such as polarizability tensors and dispersion coefficients). By providing a systematic, extensive, and tightly-converged dataset of quantum-mechanically computed physicochemical properties, we expect that QM7-X will play a critical role in the development of next-generation machine-learning based models for exploring greater swaths of CCS and performing in silico design of molecules with targeted properties

Understanding the contribution of individual amino acid residues in the binding of psychoactive substances to monoamine transporters

© 2020 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Omega, Vol 5, Iss 28, p.17223–17231, after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acsomega.0c01370.The development of point-of-care detection methodologies for biologically relevant analytes that can facilitate rapid and appropriate treatment is at the forefront of current research efforts and interests. Among the various approaches, those exploiting host–guest chemistries where the optoelectronic signals of the chemical sensor can be modulated upon interaction with the target analyte are of particular interest. In aiding their rational development, judicious selection of peripheral functional groups anchored to core motifs with desired properties is critical. Herein, we report an in-depth investigation of the binding of three psychoactive substances, MDAI, mexedrone, and phenibut, to receptors of the monoamine transporters for dopamine, norepinephrine, and serotonin, particularly focusing on the role of individual amino acid residues. We first evaluated the conformational flexibility of the ligands by comparing their experimentally determined crystal structure geometries to those optimized by means of quantum as well as molecular mechanics, observing significant changes in the case of phenibut. Molecular docking studies were employed to identify preferential binding sites by means of calculated docking scores. In all cases, irrespective of the monoamine transporter, psychoactive substances exhibited preferred interaction with the S1 or central site of the proteins, in line with previous studies. However, we observed that experimental trends for their relative potency on the three transporters were only reproduced in the case of mexedrone. Subsequently, to further understand these findings and to pave the way for the rational development of superior chemical sensors for these substances, we computed the individual contributions of each nearest neighbor amino acid residue to the binding to the target analytes. Interestingly, these results are now in agreement with those experimental potency trends. In addition, these observations were in all cases associated with key intermolecular interactions with neighboring residues, such as tyrosine and aspartic acid, in the binding of the ligands to the monoamine transporter for dopamine. As a result, we believe this work will be of interest to those engaged in the rational development of chemical sensors for small molecule analytes as well as to those interested in the use of computational approaches to further understand protein–ligand interactions.Peer reviewe