Journal of Computational Biophysics and Chemistry

The coronavirus disease (COVID-19) is causing havoc all around the world. The number of active cases and deaths is increasing day by day. The novel coronavirus (CoV) is the causative agent of this disease. For the time being, there is no specific antiviral agent for the cure of COVID-19. A variety of drugs are being repurposed to counteract this disease. Scientists all over the world are striving to get some ideal molecules against this pandemic. Some hybrid molecules have been designed by coupling the privileged scaffolds of known antiviral and antimalarial drugs. This review deals with the hybrid molecules that have been designed and evaluated against the known targets of CoV by in silico techniques.

SARS-CoV-2 is an endemic positive-sense RNA virus naturally transmissible between numerous species with notable infectivity and associated mortality. It is characterized by a poly-adenylated structure capping the genomic terminus. This poly(A) tail is crucial to a cascade of viral replicative activity occurring both extra- and intra-cellular during infection. As a route to proposing potential chemotherapy, this study suggests simple biplanar adenine quadruplexes (A4s) which may fold in specific sequences of the viral genome. To the best of our knowledge, uniquely biplanar A4s have not been previously described in any context. Using molecular modeling techniques and molecular dynamics simulations, some of these non-canonical structures show reasonable stability in a biological context. Notably, mRNA configured as a biplanar A4, shows less dynamic activity than DNA equivalents. This observation may be especially relevant in a physiological context. Furthermore, in contrast to well-characterized guanine quadruplexes, co-ordination with cations appears not to impact on stability. Our molecular dynamics simulations and analyses demonstrate that some A4s are stable in biologically relevant terms. These conclusions may apply to SARS-CoV-2, its variants and other pathogenic RNA viruses.

Nanoclusters such as ${\text{Al}}_{12}$${\text{N}}_{12}$ have received increased attention due to their diverse applications in the fields of optoelectronics and energy storage. In this paper, we have investigated a series of alkaline earth metal (AEM)-encapsulated ${\text{Al}}_{12}$${\text{N}}_{12}$ nanoclusters for hydrogen adsorption. Thermodynamic adsorption parameters, optical and nonlinear optical properties were investigated using density functional theory (DFT) at the B3LYP/6-31G(d,p) level of theory. Encapsulation of AEMs (Be, Mg and Ca) is an effective strategy to improve the NLO reaction and thermodynamic and adsorption properties of ${\text{Al}}_{12}$${\text{N}}_{12}$ nanoclusters. The adsorption energies ranging from $-$26.57kJ/mol to $-$213.33kJ/mol for the three guests (Be, Mg and Ca) capsulated ${\text{Al}}_{12}$${\text{N}}_{12}$ nanoclusters are observed. The adsorption energy is affected by the size of the nanocage. Therefore, Ca- and Mg-encapsulated cages show higher values of adsorption energy. Overall, an increase in adsorption energy ($E_{\mathrm{\text{ad}}}=-31.91$kJ/mol to $-$91.06kJ/mol) is observed for (Be, Mg and Ca) encapsulated ${\text{Al}}_{12}$${\text{N}}_{12}$ nanoclusters compared to untreated ${\text{Al}}_{12}$${\text{N}}_{12}$ and H₂-${\text{Al}}_{12}$${\text{N}}_{12}$ cages. Moreover, adsorption of hydrogen on AEMs encapsulated in ${\text{Al}}_{12}$${\text{N}}_{12}$ leads to a decrease in the HOMO-LUMO energy gap with an enhancement of linear and nonlinear hyperpolarizability. All hydrogen-adsorbed AEMs ${\text{Al}}_{12}$${\text{N}}_{12}$ nanocages exhibit large ${\alpha }_{\mathrm{\text{total}}}$ and $\beta o$ values, suggesting that these systems are potential candidates for optical materials. Various geometrical parameters such as frontier molecular orbitals (FMOs), partial density of states, global quantum descriptor of reactivity, natural bond orbital testing and molecular electrostatic strength analyses were performed to investigate the thermodynamic stability of all the studied systems. The results obtained confirmed that the designed systems are suitable for hydrogen storage. Therefore, we recommend that these systems be investigated for their hydrogen storage and optical properties.

In this paper, density functional theory (DFT) and time-dependent DFT (TDDFT) methods were used to investigate substituent effects and excited-state intramolecular double-proton transfer (ESIDPT) in 1, 3-bis (2-pyridylimino)-4, 7-dihydroxyisoindole (BPI–OH) and its derivatives. The results of a systematic study of the substituent effects of electron-withdrawing groups (F, Cl and Br) on the adjacent sites of the benzene ring were used to regulate the photophysical properties of the molecules and the dynamics of the proton-transfer process. Geometric structure comparisons and infrared (IR) spectroscopic analysis confirmed that strengthening of the intramolecular hydrogen bond in the first excited state (S₁) facilitated proton transfer. Functional analysis of the reduced density gradient confirmed these conclusions. Double-proton transfer in BPI–OH is considered to occur in two steps, i.e., BPI–OH (N) $\to$ BPI–OH (T₁) $\to$ BPI–OH (T₂), in the ground state (S₀) and the S₁ state. The potential-energy curves (PECs) for two-step proton transfer were scanned for both the S₀ and S₁ states to clarify the mechanisms and pathways of proton transfer. The stepwise path in which two protons are consecutively transferred has a low energy barrier and is more rational and favorable. This study shows that the presence or absence of coordinating groups, and the type of coordinating group, affect the hydrogen-bond strength. A coordinating group enhances hydrogen-bond formation, i.e., it promotes excited-state intramolecular proton transfer (ESIPT).

Recombinant tissue-type plasminogen activator (rt-PA, alteplase) is an FDA-approved thrombolytic drug. Designing rt-PA analogs to suppress its inhibition by plasminogen activator inhibitor-1 (PAI-1) without compromising its pharmacological activity has been a continued effort because rt-PA is rapidly inactivated by endogenous PAI-1, leading to the thrombolytic activity of rt-PA being trapped by endogenous PAI-1. Here, incorporating currently available structure of the rt-PA-PAI-1 Michaelis complex structures, this paper uncovers the interstructural biophysics underlying the rt-PA-PAI-1 binding interface, and puts forward a structural biophysical basis for the design of a previously reported rt-PA analogue (T103N, N117Q, KHRR (296-299) AAAA). In addition, this paper proposes a set of rt-PA analogs with lower or higher affinity to PAI-1, including rt-PA (alanine scanning for E_60A, D_189 and R_39), rt-PA (Q60E) and rt-PA (Q60E-F150H-Y151K), towards the release of the trapped thrombolytic activity of rt-PA, and also in the hope that there is still room for the improvement of the efficacy-safety balance of rt-PA in future.

Coronaviruses are a large family of viruses that can cause respiratory infections with varying severity from common cold to severe diseases such as novel coronavirus disease (COVID-19). COVID-19 has been declared as a global pandemic by the World Health Organization on March 11, 2020 and with the development of vaccines it slowed down as of this date. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses its spike glycoprotein (Sgp) to bind human angiotensin-converting enzyme 2 (hACE2) receptor, and mediates membrane fusion and virus entry. The recognition of Sgp to human ACE2 and its high affinity for it has been of great importance since this provides the first step in viral entry to human cells. Therefore, it is crucial to identify key residues (hotspots) in this process. In this study, computational alanine scanning has been performed for Sgp and hACE2. The residues identified with significance in binding and other residues in close proximity were studied further through molecular mechanics-based protein binding free energy change prediction methods. Moreover, the interfacial residues in both proteins were investigated for their cooperative binding. Additionally, folding free energy changes upon mutation to Ala were calculated to assess their effect on stability of Sgp and hACE2. Our results taken together with findings from previous studies revealed the residues that are most significant and are relatively significant in binding of Sgp to human ACE2 protein.

Numerical solution of the time-dependent Schrödinger equation is combined with a statistical procedure for analyzing the time-dependent probability density to look for signatures of quantum phase interference in charge transfer across two donor–bridge–acceptor molecules. The results show a strong dependence of transfer time on relative phase in an initially localized state. Additionally, the transfer time shows a stronger dependence on molecular symmetry for asymmetric initial localizations than symmetric initial localizations.

Elastic network model simulations were performed to investigate the conformational changes of MDM2 protein induced by its native substrate p53 and two small molecule inhibitor (NVP-CGM097 and HDM 201) bindings. Residues Phe 19, Trp 23, Leu 26 were observed to reside in the minima of slowest modes of p53, pointing to the accepted three finger binding model. Pro 27 displays the most significant hinge present in p53 and comes out to be another functionally important residue. Three distinct conserved regions are identified in MDM2. Regions I (residues 50–77) and III (residues 90–105) correspond to the binding interface of MDM2 including $\alpha$ helix-2 ($\alpha 2$), Loop-2 (L2) and $\alpha$ helix-4 ($\alpha 4$) domains which are stabilized during complex formation. Region II (residues 77–90) is a highly flexible region in both unbound and bound forms exhibiting high amplitude collective motion. MDM2 exhibits a scattered profile in the fastest modes of motion, while binding of p53 and inhibitors puts restraints on MDM2 pointing to induced-fit mechanism. Flexible docking using AutoDock Vina is performed to account for the flexible nature of the receptor and to elucidate the essential interactions in the binding cleft. $\alpha 4$ domain controls the size of the cleft by keeping the cleft narrow in unbound MDM2; and open in the bound states. Inhibitors studied in this work (NVP-CGM097 and HDM201), which are recently undergoing clinical trials, succeed in mimicking p53 behavior which would shed light on the rational design of novel anticancer drugs.