Chemistry

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Shiv Nadar University

Optimization of lead structures is crucial for drug discovery. However, the accuracy of such a prediction using the traditional molecular docking approach remains a major concern. Our study demonstrates that the employment of quantum crystallographic approach-counterpoise corrected kernel energy method (KEM-CP) can improve the accuracy by and large. We select human aldose reductase at 0.66 Å, cyclin dependent kinase 2 at 2.0 Å and estrogen receptor β at 2.7 Å resolutions with active site environment ranging from highly hydrophilic to moderate to highly hydrophobic and several of their known ligands. Overall, the use of KEM-CP alongside the GoldScore resulted superior prediction than the GoldScore alone. Unlike GoldScore, the KEM-CP approach is neither environment-specific nor structural resolution dependent, which highlights its versatility. Further, the ranking of the ligands based on the KEM-CP results correlated well with that of the experimental IC50 values. This computationally inexpensive yet simple approach is expected to ease the process of virtual screening of potent ligands, and it would advance the drug discovery research. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

World University root node

(SoNS) School of Natural Sciences

Fulltext

Molecules

Predicting accurate lead structures for screening molecular libraries: A quantum crystallographic approach

Exploration of the properties of monomers by modulating their stereochemistry is not well reported in polybenzoxazines (PBzs). Isosorbide contains a rigid bicyclic (endo-exo-configuration) core that has shown promise in high-performance thermoplastic polymers. In this report, new chiral PBzs were prepared from industrially available feedstocks, carbohydrate-derived (isosorbide), and lignin- or cashew nut waste-sourced renewable phenols (cardanol and guaiacol). A fully biobased benzoxazine monomer based on a one-step condensation reaction of isosorbide diamine (isa) with phenols was carried out for 15 min under microwave and solvent- and catalyst-free conditions. Structural elucidation of monomers was achieved by two-dimensional (2D) NMR spectroscopy [heteronuclear single quantum correlation (HSQC) and COSY (correlated spectroscopy)]. The "isa"-based monomer revealed a comparable ring-opening polymerization temperature and a good processing window for the widely available bisphenol-A/aniline-based monomer. The resultant polymers showed a higher Tg, better thermomechanical properties, and adhesive strength compared to other classical petrobased PBzs. The current work extends the importance of the major component of the sugar-derived isohexide family member, isosorbide, in polybenzoxazine chemistry and suggests that stereocontrol in the monomer is another approach to affect the thermomechanical properties of this upcoming class of high-performance phenolic polymer. © 2021 American Chemical Society.

ACS Sustainable Chemistry and Engineering

Understanding the Stereochemical Effect on the Properties of Emerging Thermosets: Sustainable Polybenzoxazines

Herein we have reported a blue LED mediated reaction of aryl diazoacetate with a stoichiometric amount of 1,4-dioxane/tetrahydropyran (THP) and various heterocycles like indoles, pyrroles, phthalimides, thiazolidinediones and hydantoins in water. During the reaction, various aryl diazoacetates were converted to oxonium ylides by reacting with 1,4-dioxane and THP. These ylides generated in aqueous medium (under metal- and base-free conditions) were then used for the amino etherification of the aforementioned heterocycles in excellent yield. The ylides underwent a [1,2] shift to afford substituted 1,4-dioxepanes. Phthalimide products were also converted to 1,4,7-dioxazonan-6-ones. Reaction kinetics, Hammett's plot and DFT calculations (solvent phase) rationalize the ylide formation and subsequent reactions with the nucleophiles. The reaction was also demonstrated at the multigram scale. This amino etherification reaction of aryl diazoacetates in aqueous medium demonstrated a sustainable process of converting toxic 1,4-dioxane in functionalizing heterocycles. This journal is © The Royal Society of Chemistry.

Green Chemistry

Photolytic amino etherification reactions of aryl diazoacetates with N-heterocycles and a stoichiometric amount of dioxane/tetrahydropyran in aqueous medium: Synthesis of 1,4-dioxepane/1,4,7-dioxazonan-6-one systems

CD4-mimetic HIV-1 entry inhibitors are small sized molecules which imitate similar conformational flexibility, in gp120, to the CD4 receptor. However, the mechanism of the conformational flexibility instigated by these small sized inhibitors is little known. Likewise, the effect of the antibody on the function of these inhibitors is also less studied. In this study, we present a thorough inspection of the mechanism of the conformational flexibility induced by a CD4-mimetic inhibitor, NBD-557, using Molecular Dynamics Simulations and free energy calculations. Our result shows the functional importance of Asn425 in substrate induced conformational dynamics in gp120. The MD simulations of Asn425Gly mutant provide a less dynamic gp120 in the presence of NBD-557 without incapacitating the binding enthalpy of NBD-557. The MD simulations of complexes with the antibody clearly show the enhanced affinity of NBD-557 due to the presence of the antibody, which is in good agreement with experimental Isothermal Titration Calorimetry results (Biochemistry2006, 45, 10973-10980).

Chemical Engineering

(SoE) School of Engineering

Molecules (Basel, Switzerland)

Does Antibody Stabilize the Ligand Binding in GP120 of HIV-1 Envelope Protein? Evidence from MD Simulation

The current theoretical perception of enzymatic activity is highly reliant on the determination of the activation energy of the reactions{,} which is often calculated using computationally demanding quantum mechanical calculations. With the ever-increasing use of bioengineering techniques that produce too many variants of the same enzyme{,} a fast and accurate way to study the relative efficiency of enzymes is currently in high demand. Here{,} we propose the local electric field (LEF) of the enzyme along the reaction axis as a descriptor for the enzymatic activity using the example of chorismate mutase in its native form and several variants (R90A{,} R90G{,} and R90K/C88S). The study shows a direct correlation between the calculated enzymatic EF and the enzymatic activity for all the complexes. MD simulations of the Michaelis complex and the transition state analog (TSA) show a stabilizing force on the TSA due to the enzymatic EF. QM/MM and QM-only DFT calculations in the presence of an external electric field (EEF) oriented along the reaction axis show that the electric field can interact with the dipole moment of the TS{,} thereby stabilizing it and thus lowering the activation energy.

Phys. Chem. Chem. Phys.

Can the local electric field be a descriptor of catalytic activity? A case study on chorismate mutase

The HisA enzyme catalyzes the first step of histidine biosynthesis via Amadori rearrangement of substrate ProFAR. Since it possesses the most conserved and ancient TIM-barrel fold{,} it provides an ideal framework for bioengineering a new function from ancestral enzymes. In the present study firstly{,} the catalytic mechanism of HisA biosynthesis was elucidated using hybrid Quantum Mechanical/Molecular Mechanical calculations{,} and thereafter{,} key residues contributing towards the promiscuity for TrpF activity were revealed using several MD simulations of wild type enzyme and its variant with the native (ProFAR) and promiscuous (PRA) substrates. Our study reveals that the two loops (βα)1 and (βα)5 on the catalytic site of the HisA enzyme{,} have incredible adaptability for the native and promiscuous substrates. The conformational interplay between these two loops is substrate driven and precise bioengineering targeting these loops is key to the emergence of new functions. Furthermore{,} the study reveals a key role of Arg 15 residue which is close to the catalytic center of the enzyme in the bifunctionality of HisA enzyme by increasing the loop flexibility. Therefore{,} our study provides crucial information for future bioengineering work to use the HisA enzyme as a scaffold for new enzymatic activity.

Org. Biomol. Chem.

Simulations Reveal Key Role of Arg15 for Promiscuous Activity in HisA Enzyme

This chapter describes the use of external-electric fields (EEFs) as effectors of chemical change{,} with the aim of providing a guiding conceptual framework. As such{,} the following text intends to serve as a teaching material for readers{,} on how to conceptualize and design electric-field effects on bonds{,} structures{,} and reactions. Many of these effects can be comprehended in terms of valence bond (VB) concepts as the field-induced stabilization of ionic structures. Thus{,} orienting the field along the “bond axis” will facilitate bond breaking. Similarly{,} orienting the field along the “reaction axis”{,} the direction in which electron pairs transform from reactant-to product-like{,} will lower the reaction barrier. Flipping the field{'}s orientation along the reaction axis will cause inhibition. Orienting the field off-reaction-axis will generally control stereo-selectivity and enantioselectivity{,} and the removal of forbidden-orbital mixing. Three-directional fields will orient the reactants in space and control their reactivity and selectivity patterns. Increasing the field strength for concerted reactions{,} e.g.{,} in Diels–Alder and oxidative addition reactions{,} will cause mechanistic-switchover to stepwise mechanisms with ionic intermediates. Examples of bond breaking and control of reactivity/selectivity and mechanistic crossovers are presented and analysed from the “ionic perspective”. Textboxes and rules summarize the various effects of electric fields.

CHAPTER 2 The Impact of Electric Fields on Chemical Structure and Reactivity

To improve the power conversion efficiency (PCE) of the organic solar cells (OSCs), it is necessary to widen the absorption profile of the active layer. It is possible by using a ternary active layer consisting of either two donors (D) and one acceptor (A) or two acceptors and one donor having complementary absorption and appropriate frontier energy levels for efficient exciton generation and their dissociation into free charge carriers and subsequent charge/energy transfer. Herein, a large bandgap guaiacol-based small molecule (SMD) is used as guest donor in ternary OSCs to improve the PCE and suppress the energy loss. SMD exhibits a lager bandgap and deeper highest occupied molecular orbital (HOMO) energy level compared with conjugated polymer donor (P). Therefore, the HOMO energy level is effectively down-shifted when P is mixed with SMD, which is beneficial for attaining high open circuit voltage (VOC). OSCs based on the optimized ternary blend P:SMD:Y6 (0.8:0.2:1.2, w/w) after solvent vapor annealing attained a higher VOC of 0.85 V and low energy loss of 0.51 eV compared with the binary device P:Y6 (1:1.2, w/w) with VOC of 0.81 V and energy loss of 0.55 eV, delivering an overall PCE of 15.37%. © 2021 Wiley-VCH GmbH.

Solar RRL

Incorporation of a Guaiacol-Based Small Molecule Guest Donor Enables Efficient Nonfullerene Acceptor-Based Ternary Organic Solar Cells

This paper describes an efficient, sustainable, one-step procedure for synthesizing substituted phenazines and phenoxazinones from commercially available ortho-substituted aromatic amines with very good yield (≥80%) in water. The procedure uses eosin Y (EY) as a photoredox catalyst at room temperature (RT). The highly reactive o-quinone-diimine or o-quinone-imine intermediate was characterized by the HR-MS technique. © 2021 American Chemical Society.

Organic Letters

Visible-light-mediated synthesis of substituted phenazine and phenoxazinone using eosin y as a photoredox catalyst

The eight membered ring system with one sulfur (S) atom was reviewed in the CHEC-III (2008) 1 and the articles were covered until the beginning of 2007. This ring system is difficult to synthesize and there are only handful of literatures between 2007 and 2020 describing their chemistry. Herein we will discuss synthesis of benzene fused eight membered sulfur containing ring system and bridged eight membered sulfur containing rings along with reactions of eight membered sulfur containing rings for synthesis of cyclic alkynes, their cycloaddition reactions and synthesis of chiral thiofulvenes. Additionally, we will also report a kinetic investigation, NMR study and ring strain/reactivity involving such ring systems. © 2022 Elsevier Ltd. All rights reserved.