CoMFA analysis of the interactions of antipicornavirus compounds in the binding pocket of human rhinovirus-14. [Erratum to document cited in CA116(15):143280r] (original) (raw)

Arylketotetramethylene Analogues of Disoxaril with Anti-Human Rhinovirus 14 Activity

Antiviral Chemistry and Chemotherapy, 1997

Arylketotetramethylene analogues of disoxaril (WIN 51711) were synthesized by reaction of 1-aryl-5chloropentan-1-ones with 2-(4-hydroxyphenyl)-4,5dihydro oxazoles, ethyl 4-hydroxybenzoates and 4hydroxybenzonitrile. The new derivatives were tested for antiviral activity against various human rhinovirus (HRV) serotypes. The best activity was exhibited by the ethoxycarbonyl derivatives, whereas the oxazoline counterparts were less active and the cyano derivatives totally inactive. 5-[4-(4,5-Dihydro-2-oxazolyl}phenoxy]-1-(4-methoxyphenyl}pentan-1-one and ethyl 4-[5-(4-methylthiophenyl}-5-oxopentoxy] benzoate were more active than, and as active as, disoxaril, respectively, against HRV-14. Moreover, they were 10 times less cytotoxic.

Structural analysis of a series of antiviral agents complexed with human rhinovirus 14

Proceedings of the National Academy of Sciences, 1988

The binding to human rhinovirus 14 of a series of eight antiviral agents that inhibit picornaviral uncoating after entry into host cells has been characterized crystallographically. All of these bind into the same hydrophobic pocket within the viral protein VP1 beta-barrel structure, although the orientation and position of each compound within the pocket was found to differ. The compounds cause the protein shell to be less flexible, thereby inhibiting disassembly. Although the antiviral potency of these compounds varies by 120-fold, they all induce the same conformational changes on the virion. The interactions of these compounds with the viral capsid are consistent with their observed antiviral activities against human rhinovirus 14 drug-resistant mutants and other rhinovirus serotypes. Crystallographic studies of one of these mutants confirm the partial sequencing data and support the finding that this is a single mutation that occurs within the binding pocket.

Antiviral capsid-binding compounds can inhibit the adsorption of minor receptor rhinoviruses

Antiviral Research, 1994

The effect of four structurally diverse capsid-binding compounds on the adsorption of seven human rhinoviruses (HRV), representative for both receptor and antiviral groupings was studied using infective center assays. Antiviral compounds studied included a pyridazinamine (R 61837), an isoxazole (WIN 51711), a flavan (4',6-dichloroflavan) and a chalcone (Ro-09410). Minor receptor viruses studied were HRV 1A, HRV 2 and HRV 29 (antiviral group B), major receptor viruses were HRV 9, HRV 39 and HRV 14, HRV 35 (antiviral group B and A, respectively). The adsorption of four out.of the seven serotypes was inhibited by some antiviral compounds, but not by others, indicating that the conformational alterations induced by antiviral compounds can vary considerably within a given serotype, depending on the chemical nature of the antiviral compound used. A correlation between inhibition of adsorption and receptor grouping or antiviral grouping could not be found.

and X-ray Crystal Structure Studies and In Vitro Antiviral Activity Evaluations

2011

We report on the synthesis of 4-hydroxycoumarin dimers 1-15 bearing an aryl substituent on the central linker and fused benzopyranocoumarin derivatives 16-20 and on their in vitro broad anti-DNA and RNA virus activity evaluations. The chemical identities and structure of compounds 1-20 were deduced from their homo-and heteronuclear NMR measurements whereas the conformational properties of 5, 14 and 20 were assessed by the use of 1D difference NOE enhancements. Unequivocal proof of the stereostructure of compounds 7, 9, 16 and 18 was obtained by single crystal X-ray diffraction method. The

Heterocyclic pharmacochemistry of new rhinovirus antiviral agents: A combined computational and experimental study

European Journal of Medicinal Chemistry, 2017

Rhinovirus (RV), member of the Enterovirus genus, is known to be involved in more than half of the common colds. Through advances in molecular biology, rhinoviruses have also been associated with exacerbations of chronic pulmonary diseases (e.g. asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis). In the current investigation, we develop a novel series of 4,5-dimethoxybenzyl derivatives that potently inhibits rhinovirus replication. Compound (S)-7f blocks RV-B14 replication with an EC 50 value of 0.25 µM and shows a low toxicity in HeLa cells (CC 50 > 271 µM). Enantioseparation followed by an absolute configuration determination by a Mosher's method revealed the interest of enantiopure compounds. Molecular docking studies permitted the identification of key biological interactions within the drug-binding pocket and an in silico drug-like study revealed a good potential for the development of these derivatives.

Antirhinoviral activity of heterocyclic analogs of Win 54954

Journal of Medicinal Chemistry, 1992

A variety of heterocyclic analogs of Win 54954 have been synthesized and tested in vitro against human rhinovirus type 14 (HRV-14) in a plaque reduction assay. The more active compounds were tested against 14 additional serotypes, and the concentration which inhibited 80% of the serotypes tested (MICN) was measured. One compound, 37, exhibited activity comparable to Win 59454. Physicochemical as well as electrostatic parameters were calculated and the results subjected t o a QSAR analysis in an effort t o explain differences in activity observed between these compounds; however, no meaningful correlation with biological activity was found with any of these parameters.

The effect of various compounds on the COVID mechanisms, from chemical to molecular aspects

Biophysical chemistry, 2022

The novel coronavirus that caused COVID-19 pandemic is SARS-CoV-2. Although various vaccines are currently being used to prevent the disease's severe consequences, there is still a need for medications for those who become infected. The SARS-CoV-2 has a variety of proteins that have been studied extensively since the virus's advent. In this review article, we looked at chemical to molecular aspects of the various structures studied that have pharmaceutical activity and attempted to find a link between drug activity and compound structure. For example, designing of the compounds which bind to the allosteric site and modify hydrogen bonds or the salt bridges can disrupt SARS-CoV2 RBD-ACE2 complex. It seems that quaternary ammonium moiety and quinolin-1ium structure could act as a negative allosteric modulator to reduce the tendency between spike-ACE2. Pharmaceutical structures with amino heads and hydrophobic tails can block envelope protein to prevent making mature SARS-CoV-2. Also, structures based on naphthalene pharmacophores or isosteres can form a strong bond with the PLpro and form a π-π and the Mpro's active site can be occupied by octapeptide compounds or linear compounds with a similar fitting ability to octapeptide compounds. And for protein RdRp, it is critical to consider pH and pKa so that pKa regulation of compounds to comply with patients is very effective, thus, the presence of tetrazole, phenylpyrazole groups, and analogs of pyrophosphate in the designed drugs increase the likelihood of the RdRp active site inhibition. Finally, it can be deduced that designing hybrid drug molecules along with considering the aforementioned characteristics would be a suitable approach for developing medicines in order to accurate targeting and complete inhibition this virus.