Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

The emergence in late 2019 of the coronavirus SARS-CoV-2 has resulted in the breakthrough of the COVID-19 pandemic that is presently affecting a growing number of countries. The development of the pandemic has also prompted an unprecedented effort of the scientific community to understand the molecular bases of the virus infection and to propose rational drug design strategies able to alleviate the serious COVID-19 morbidity. In this context, a strong synergy between the structural biophysics and molecular modeling and simulation communities has emerged, resolving at the atomistic level the crucial protein apparatus of the virus and revealing the dynamic aspects of key viral processes. In this Review, we focus on how in silico studies have contributed to the understanding of the SARS-CoV-2 infection mechanism and the proposal of novel and original agents to inhibit the viral key functioning. This Review deals with the SARS-CoV-2 spike protein, including the mode of action that this structural protein uses to entry human cells, as well as with nonstructural viral proteins, focusing the attention on the most studied proteases and also proposing alternative mechanisms involving some of its domains, such as the SARS unique domain. We demonstrate that molecular modeling and simulation represent an effective approach to gather information on key biological processes and thus guide rational molecular design strategies

Quinoxalinetacrine QT78, a cholinesterase inhibitor as a potential ligand for Alzheimer’s disease therapy

We report the synthesis and relevant pharmacological properties of the quinoxalinetacrine (QT) hybrid QT78 in a project targeted to identify new non-hepatotoxic tacrine derivatives for Alzheimer\u2019s disease therapy. We have found that QT78 is less toxic than tacrine at high concentrations (from 100 \ub5M to 1 mM), less potent than tacrine as a ChE inhibitor, but shows selective BuChE inhibition (IC50 (hAChE) = 22.0 \ub1 1.3 \ub5M; IC50 (hBuChE) = 6.79 \ub1 0.33 \ub5M). Moreover, QT78 showed effective and strong neuroprotection against diverse toxic stimuli, such as rotenone plus oligomycin-A or okadaic acid, of biological significance for Alzheimer\u2019s disease

Exploring the Potential of Sulfonamide-Dihydropyridine Hybrids as Multitargeted Ligands for Alzheimer’s Disease Treatment

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease that has a heavy social and economic impact on all societies and for which there is still no cure. Multitarget-directed ligands (MTDLs) seem to be a promising therapeutic strategy for finding an effective treatment for this disease. For this purpose, new MTDLs were designed and synthesized in three steps by simple and cost-efficient procedures targeting calcium channel blockade, cholinesterase inhibition, and antioxidant activity. The biological and physicochemical results collected in this study allowed us the identification two sulfonamide-dihydropyridine hybrids showing simultaneous cholinesterase inhibition, calcium channel blockade, antioxidant capacity and Nrf2-ARE activating effect, that deserve to be further investigated for AD therapy.This work was supported by the Regional Council of Franche-Comté (2022Y-13659 and 13660 Accurate Project).Peer reviewe

Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids

The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] = 1.1 +/- 0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 = 600 +/- 80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] = 5,700 +/- 2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] = 3,950 +/- 94 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13-15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective hAChE and selective irreversible hMAO B inhibitor which might be considered as a promising compound for further development for the treatment of AD

Microscopic interactions between ivermectin and key human and viral proteins involved in SARS-CoV-2 infection

The identification of chemical compounds able to bind specific sites of the human/viral proteins involved in the SARS-CoV-2 infection cycle is a prerequisite to design effective antiviral drugs. Here we conduct a molecular dynamics study with the aim to assess the interactions of ivermectin, an antiparasitic drug with broad-spectrum antiviral activity, with the human Angiotensin-Converting Enzyme 2 (ACE2), the viral 3CLpro and PLpro proteases, and the viral SARS Unique Domain (SUD). The drug/target interactions have been characterized in silico by describing the nature of the non-covalent interactions found and by measuring the extent of their time duration along the MD simulation. Results reveal that the ACE2 protein and the ACE2/RBD aggregates form the most persistent interactions with ivermectin, while the binding with the remaining viral proteins is more limited and unspecific. This journal i

Thermodynamics of the Interaction between the Spike Protein of Severe Acute Respiratory Syndrome Coronavirus-2 and the Receptor of Human Angiotensin-Converting Enzyme 2. Effects of Possible Ligands

Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 1000000 deaths all over the world and still lacks a medical treatment despite the attention of the whole scientific community. Human angiotensin-converting enzyme 2 (ACE2) was recently recognized as the transmembrane protein that serves as the point of entry of SARS-CoV-2 into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the protein complex. Moreover, the free energy of binding between ACE2 and the active receptor binding domain of the SARS-CoV-2 spike protein is evaluated quantitatively, providing for the first time the thermodynamics of virus-receptor recognition. Furthermore, the action of different ACE2 ligands is also examined in particular in their capacity to disrupt SARS-CoV-2 recognition, also providing via a free energy profile the quantification of the ligand-induced decreased affinity. These results improve our knowledge on molecular grounds of the SARS-CoV-2 infection and allow us to suggest rationales that could be useful for the subsequent wise molecular design for the treatment of COVID-19 cases

Synthesis, structural and conformational study of some amides derived from 3-methyl-3-azabicyclo[3.2.1]octan-8α(β)-amines

Some amides (1α-7α and 1β-7β) derived from 3-methyl-3-azabicyclo[3.2.1]octan-8α(β)-amines were synthesized and studied by IR, 1H and 13C NMR spectroscopies. The assignment of all carbon and protons resonances was achieved through the application of one dimensional selective NOE and two dimensional NMR techniques: homonuclear NOESY and heteronuclear 1H-13C gHSQC correlated spectroscopies. Total correlation spectroscopy (TOCSY) experiments were also carried out. In CDCl3 solution, at room temperature, all compounds adopt a chair-envelope conformation with the N-CH3 group in equatorial disposition. In the α-epimers the piperidine ring is puckered at C8 to relieve the interactions between the amido group and the H6(7)x protons. α- and β-Epimers show a preferred trans disposition for the NH-CO group and free rotation of the NH-CO-R group around the C8-NH bond. Finally, NMR and IR data reveal that compounds 7α and 7β adopt in CDCl3 solution a preferred s-cis conformation for the O{double bond, long}C-C{double bond, long}C system, the proportion of this conformation increasing when the polarity of the solvent decreases.A.I. Madrid thanks the University of Alcalá for a research fellowship. J. Bellanato thanks Spanish Dirección General de Investigación (MEC), Project FIS2004-00108, for partial financial support

Synthesis, structural and conformational study of some amides derived from N-methylpiperazine

Some amides (1-6) derived from N-methylpiperazine were synthesized and studied by IR, 1H and 13C NMR spectroscopy. In CDCl3 solution, at room temperature, a fast interconversion of the piperazine ring with the N-CH3 group in equatorial position can be proposed. α,β-unsaturated compounds 4 and 5 adopt in liquid state and in solution (CCl4, CCl2{double bond, short}CCl2, CDCl3) both s-cis and s-trans conformations.A.I. Madrid thanks the University of Alcalá for a research fellowship. J. Bellanato thanks Spanish Dirección General de Investigación (MEC), Project FIS2004-00108, for partial financial support

Studies on the affinity of 6-[(: N -(cyclo)aminoalkyl)oxy]-4 H -chromen-4-ones for sigma 1/2 receptors

Sigma (σ) receptors represent attractive targets for the development of potential agents for the treatment of several disorders, including Alzheimer's disease and neuropathic pain. In the search for multitarget small molecules (MSMs) against such disorders, we have re-discovered chromenones as new affine σ1/σ2 ligands. 6-(4-(Piperidin-1-yl)butoxy)-4H-chromen-4-one (7), a previously identified MSM with potent dual-target activities against acetylcholinesterase and monoamine oxidase B, also exhibited σ1/σ2 affinity. 6-(3-(Azepan-1-yl)propoxy)-4H-chromen-4-one (20) showed a Ki value for σ1 of 27.2 nM (selectivity (σ1/σ2) = 28), combining the desired σ1 receptor affinity with a dual inhibitory capacity against both acetyl- and butyrylcholinesterase. 6-((5-Morpholinopentyl)oxy)-4H-chromen-4-one (12) was almost equipotent to S1RA, an established σ1 receptor antagonist