Affinity binding of COVID-19 drug candidates (chloroquine/hydroxychloroquine) and serum albumin: Based on photochemistry and molecular docking.

Chloroquine (CQ) and hydroxychloroquine (HCQ) show good efficacy in the treatment of SARS-CoV-2 in the early stage, while they are no longer recommended due to their side effects. As an important drug delivery carrier, serum albumin (SA) is closely related to the efficacy of drugs. Here, the affinity behaviour of chloroquine and hydroxychloroquine with two SA were investigated through the multispectral method of biochemistry and computer simulation. The results showed that the intrinsic emission of both SA was quenched by CQ and HCQ in a spontaneous exothermic entropy reduction static process, which relied mainly on hydrogen bonding and van der Waals forces. The lower binding constants suggested weak binding between the two drugs and SA, which might lead to differences in efficacy and possibly even to varying side effects. Binding site recognition demonstrated that CQ preferred to bind to the two sites of both SA, while HCQ tended to bind to site I of SA. The results of conformational studies demonstrated that CQ and HCQ could affect the structure of both SA by slightly increasing the α-helix content of SA. Finally, we combine the results from experimental start with molecular simulations to suggest drug modifications to guide the design of drugs. This work has important implications for guiding drug design improvements to select CQ derivatives with fewer side effects for the treatment of COVID-19.

Computational study on the affinity of potential drugs to SARS-CoV-2 main protease.

Herein, we report a computational investigation of the binding affinity of dexamethasone, betamethasone, chloroquine and hydroxychloroquine to SARS-CoV-2 main protease using molecular and quantum mechanics as well as molecular docking methodologies. We aim to provide information on the anti-COVID-19 mechanism of the abovementioned potential drugs against SARS-CoV-2 coronavirus. Hence, the 6w63 structure of the SARS-CoV-2 main protease was selected as potential target site for the docking analysis. The study includes an initial conformational analysis of dexamethasone, betamethasone, chloroquine and hydroxychloroquine. For the most stable conformers, a spectroscopic analysis has been carried out. In addition, global and local reactivity indexes have been calculated to predict the chemical reactivity of these molecules. The molecular docking results indicate that dexamethasone and betamethasone have a higher affinity than chloroquine and hydroxychloroquine for their theoretical 6w63 target. Additionally, dexamethasone and betamethasone show a hydrogen bond with the His41 residue of the 6w63 protein, while the interaction between chloroquine and hydroxychloroquine with this amino acid is weak. Thus, we confirm the importance of His41 amino acid as a target to inhibit the SARS-CoV-2 Mpro activity.

In vitro ion channel profile and ex vivo cardiac electrophysiology properties of the R(-) and S(+) enantiomers of hydroxychloroquine.

Hydroxychloroquine (HCQ) is a derivative of the antimalaria drug chloroquine primarily prescribed for autoimmune diseases. Recent attempts to repurpose HCQ in the treatment of corona virus disease 2019 has raised concerns because of its propensity to prolong the QT-segment on the electrocardiogram, an effect associated with increased pro-arrhythmic risk. Since chirality can affect drug pharmacological properties, we have evaluated the functional effects of the R(-) and S(+) enantiomers of HCQ on six ion channels contributing to the cardiac action potential and on electrophysiological parameters of isolated Purkinje fibers. We found that R(-)HCQ and S(+)HCQ block human Kir2.1 and hERG potassium channels in the 1 µM-100 µM range with a 2-4 fold enantiomeric separation. NaV1.5 sodium currents and CaV1.2 calcium currents, as well as KV4.3 and KV7.1 potassium currents remained unaffected at up to 90 µM. In rabbit Purkinje fibers, R(-)HCQ prominently depolarized the membrane resting potential, inducing autogenic activity at 10 µM and 30 µM, while S(+)HCQ primarily increased the action potential duration, inducing occasional early afterdepolarization at these concentrations. These data suggest that both enantiomers of HCQ can alter cardiac tissue electrophysiology at concentrations above their plasmatic levels at therapeutic doses, and that chirality does not substantially influence their arrhythmogenic potential in vitro.

Investigating interactions between chloroquine/hydroxychloroquine and their single enantiomers and angiotensin-converting enzyme 2 by a cell membrane chromatography method.

Chloroquine and hydroxychloroquine have been studied since the early clinical treatment of SARS-CoV-2 outbreak. Considering these two chiral drugs are currently in use as the racemate, high-expression angiotensin-converting enzyme 2 cell membrane chromatography was established for investigating the differences of two paired enantiomers binding to angiotensin-converting enzyme 2 receptor. Molecular docking assay and detection of SARS-CoV-2 spike pseudotyped virus entry into angiotensin-converting enzyme 2-HEK293T cells were also conducted for further investigation. Results showed that each single enantiomer could bind well to angiotensin-converting enzyme 2, but there were differences between the paired enantiomers and corresponding racemate in frontal analysis. R-Chloroquine showed better angiotensin-converting enzyme 2 receptor binding ability compared to S-chloroquine/chloroquine (racemate). S-Hydroxychloroquine showed better angiotensin-converting enzyme 2 receptor binding ability than R-hydroxychloroquine/hydroxychloroquine. Moreover, each single enantiomer was proved effective compared with the control group; compared with S-chloroquine or the racemate, R-chloroquine showed better inhibitory effects at the same concentration. As for hydroxychloroquine, R-hydroxychloroquine showed better inhibitory effects than S-hydroxychloroquine, but it slightly worse than the racemate. In conclusion, R-chloroquine showed better angiotensin-converting enzyme 2 receptor binding ability and inhibitory effects compared to S-chloroquine/chloroquine (racemate). S-Hydroxychloroquine showed better angiotensin-converting enzyme 2 receptor binding ability than R-hydroxychloroquine/hydroxychloroquine (racemate), while the effect of preventing SARS-CoV-2 pseudovirus from entering cells was weaker than R-hydroxychloroquine/hydroxychloroquine (racemate).

Characterization of the Modulatory Effect of Hydroxychloroquine on ACE2 Activity: New Insights in relation to COVID-19.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have shown the ability to inhibit in vitro viral replications of coronaviridae viruses such as SARS-CoV and SARS-CoV-2. However, clinical trial outcomes have been disparate, suggesting that CQ and HCQ antiviral mechanisms are not fully understood. Based on three-dimensional structural similarities between HCQ and the known ACE2 specific inhibitor MLN-4760, we compared their modulation on ACE2 activity. Here we describe, for the first time, in a cell-free in vitro system that HCQ directly and dose-dependently inhibits the activity of recombinant human ACE2, with a potency similar to the MLN-4760. Further analysis suggests that HCQ binds to a noncompetitive site other than the one occupied by MLN-4760. We also determined that the viral spike glycoprotein segment that comprises the RBD segment has no effect on ACE2 activity but unexpectedly was able to partially reverse the inhibition induced by HCQ but not that by MLN-4760. In summary, here we demonstrate the direct inhibitory action of HCQ over the activity of the enzyme ACE2. Then, by determining the activity of ACE2, we reveal that the interaction with the spike protein of SARS-CoV-2 leads to structural changes that at least partially displace the interaction of the said enzyme with HCQ. These results may help to explain why the effectiveness of HCQ in clinical trials has been so variable. Additionally, this knowledge could be used for to develop techniques for the detection of SARS-CoV-2.

Drug-drug interactions between treatment specific pharmacotherapy and concomitant medication in patients with COVID-19 in the first wave in Spain.

Primary aim was to assess prevalence and severity of potential and real drug-drug interactions (DDIs) among therapies for COVID-19 and concomitant medications in hospitalized patients with confirmed SARS-CoV-2 infection. The secondary aim was to analyze factors associated with rDDIs. An observational single center cohort study conducted at a tertiary hospital in Spain from March 1st to April 30th. rDDIs refer to interaction with concomitant drugs prescribed during hospital stay whereas potential DDIs (pDDIs) refer to those with domiciliary medication. DDIs checked with The University of Liverpool resource. Concomitant medications were categorized according to the Anatomical Therapeutic Chemical classification system. Binomial logistic regression was carried out to identify factors associated with rDDIs. A total of 174 patients were analyzed. DDIs were detected in 152 patients (87.4%) with a total of 417 rDDIs between COVID19-related drugs and involved hospital concomitant medication (60 different drugs) while pDDIs were detected in 105 patients (72.9%) with a total of 553 pDDIs. From all 417 rDDIs, 43.2% (n = 180) were associated with lopinavir/ritonavir and 52.9% (n = 221) with hydroxychloroquine, both of them the most prescribed (106 and 165 patients, respectively). The main mechanism of interaction observed was QTc prolongation. Clinically relevant rDDIs were identified among 81.1% (n = 338) ('potential interactions') and 14.6% (n = 61) (contraindicated) of the patients. Charlson index (OR 1.34, 95% IC 1.02-1.76) and number of drugs prescribed during admission (OR 1.42, 95% IC 1.12-1.81) were independently associated with rDDIs. Prevalence of patients with real and pDDIs was high, especially those clinically relevant. Both comorbidities and polypharmacy were found as risk factors independently associated with DDIs development.

Mapping the effect of drugs on ACE2 as a novel target site for COVID-19 therapy.

Angiotensin converting enzyme 2 (ACE2) has potentially conflicting roles in health and disease. COVID-19 coronavirus binds to human cells via ACE2 receptor, which is expressed on almost all body organs. Boosting the ACE2 receptor levels on heart and lung cells may provide more cellular enter to virus thereby worsening the infection. Therefore, among the drug targets, ACE2 is suggested as a vital target of COVID-19 therapy. This hypothesis is based on the protective role of the drugs acting on ACE2. Therefore, this review discusses the impact and challenges of using ACE2 as a target in the current therapy of COVID-19.

Computational and experimental studies on the inhibitory mechanism of hydroxychloroquine on hERG.

Hydroxychloroquine (HCQ) was noted to produce severe cardiac arrhythmia, an adverse effect as its use against severe acute respiratory syndrome caused by coronavirus 2 (SAES-CoV-2). HCQ is an antimalarial drug with quinoline structure. Some other quinoline compounds, such as fluoroquinolone antibiotics (FQs), also lead to arrhythmias characterized by QT prolongation. QT prolongation is usually related to the human ether-a-go-go-related gene (hERG) potassium channel inhibitory activity of most drugs. In this research, molecular docking was used to study the potential inhibitory activities of HCQ as well as other quinolines derivatives and hERG potassium channel protein. The possible causes of these QT prolongation effects were revealed. Molecular docking and patch clamp experiments showed that HCQ could bind to hERG and inhibit the efflux of potassium ion preferentially in the repolarization stage. The IC50 of HCQ was 8.6 µM ± 0.8 µM. FQs, which are quinoline derivatives, could also bind to hERG molecules. The binding energies of FQs varied according to their molecular polarity. It was found that drugs with a quinoline structure, particularly with high molecular polarity, can exert a significant potential hERG inhibitory activity. The potential side effects of QT prolongation during the development and use of quinolines should be carefully considered.

Development of a chiral HPLC method for the separation and quantification of hydroxychloroquine enantiomers.

Hydroxychloroquine (2-[[4-[(7-Chloroquinolin-4-yl) amino]pentyl](ethyl) amino]-ethanol, HCQ), an effective anti-malarial drug, has been tested in the clinics for potential treatment of severe coronavirus disease 2019 (COVID-19). Despite the controversy around the clinical benefits of HCQ, the existence of a chiral center in the molecule to possess two optical isomers suggests that there might be an enantiomeric difference on the treatment of COVID-19. Due to their poor resolution and the inability of quantification by previously reported methods for the analysis of HCQ enantiomers, it is necessary to develop an analytical method to achieve baseline separation for quantitative and accurate determination of the enantiomeric purity in order to compare the efficacy and toxicity profiles of different enantiomers. In this study, we developed and validated an accurate and reproducible normal phase chiral high-performance liquid chromatography (HPLC) method for the analysis of two enantiomers of HCQ, and the method was further evaluated with biological samples. With this newly developed method, the relative standard deviations of all analytes were lower than 5%, and the limits of quantification were 0.27 µg/ml, 0.34 µg/ml and 0.20 µg/ml for racemate, R- and S-enantiomer, respectively. The present method provides an essential analytical tool for preclinical and clinical evaluation of HCQ enantiomers for potential treatment of COVID-19.

Unveiling the Molecular Structure of Antimalarial Drugs Chloroquine and Hydroxychloroquine in Solution through Analysis of 1H NMR Chemical Shifts.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been standard antimalarial drugs since the early 1950s, and very recently, the possibility of their use for the treatment of COVID-19 patients has been considered. To understand the drug mode of action at the submicroscopic level (atoms and molecules), molecular modeling studies with the aid of computational chemistry methods have been of great help. A fundamental step in such theoretical investigations is the knowledge of the predominant drug molecular structure in solution, which is the real environment for the interaction with biological targets. Our strategy to access this valuable information is to perform density functional theory (DFT) calculations of 1H NMR chemical shifts for several plausible molecular conformers and then find the best match with experimental NMR profile in solution (since it is extremely sensitive to conformational changes). Through this procedure, after optimizing 30 trial distinct molecular structures (ωB97x-D/6-31G(d,p)-PCM level of calculation), which may be considered representative conformations, we concluded that the global minimum (named M24), stabilized by an intramolecular N-H hydrogen bond, is not likely to be observed in water, chloroform, and dimethyl sulfoxide (DMSO) solution. Among fully optimized conformations (named M1 to M30, and MD1 and MD2), we found M12 (having no intramolecular H-bond) as the most probable structure of CQ and HCQ in water solution, which is a good approximate starting geometry in drug-receptor interaction simulations. On the other hand, the preferred CQ and HCQ structure in chloroform (and CQ in DMSO-d6) solution was assigned as M8, showing the solvent effects on conformational preferences. We believe that the analysis of 1H NMR data in solution can establish the connection between the macro level (experimental) and the sub-micro level (theoretical), which is not so apparent to us and appears to be more appropriate than the thermodynamic stability criterion in conformational analysis studies.

Leveraging coronavirus binding to gangliosides for innovative vaccine and therapeutic strategies against COVID-19.

Covid-19 is an infectious respiratory disease due to a coronavirus named SARS-CoV-2. A critical step of the infection cycle is the binding of the virus spike S protein to the cellular ACE-2 receptor. This interaction involves a receptor binding domain (RBD) located at the center of the S trimer, whereas the lateral N-terminal domain (NTD) displays a flat ganglioside binding site that enables the virus to bind to lipid rafts of the plasma membrane, where the ACE-2 receptor resides. S protein binding to lipid rafts can be blocked by hydroxychloroquine, which binds to gangliosides, and by azithromycin, which binds to the NTD. Based on these data, we identified the NTD of SARS-CoV-2 as a promising target for both therapeutic and vaccine strategies, a notion later supported by the discovery, in convalescent Covid-19 patients, of a neutralizing antibody (4A8) that selectively binds to the NTD. The 4A8 epitope overlaps the ganglioside binding domain, denying any access of the virus to lipid rafts when the antibody is bound to the S protein. Thus, our data explain why antibody binding to the tip of the NTD results in SARS-CoV-2 neutralization. The high level of conservation of the ganglioside binding domain of SARS-CoV-2 (100% identity in 584 of 600 isolates analyzed worldwide) offers unique opportunities for innovative vaccine/therapeutic strategies.

Chloroquine and Hydroxychloroquine Interact Differently with ACE2 Domains Reported to Bind with the Coronavirus Spike Protein: Mediation by ACE2 Polymorphism.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection inducing coronavirus disease 2019 (COVID-19) is still an ongoing challenge. To date, more than 95.4 million have been infected and more than two million deaths have been officially reported by the WHO. Angiotensin-converting enzyme (ACE) plays a key role in the disease pathogenesis. In this computational study, seventeen coding variants were found to be important for ACE2 binding with the coronavirus spike protein. The frequencies of these allele variants range from 3.88 × 10-3 to 5.47 × 10-6 for rs4646116 (K26R) and rs1238146879 (P426A), respectively. Chloroquine (CQ) and its metabolite hydroxychloroquine (HCQ) are mainly used to prevent and treat malaria and rheumatic diseases. They are also used in several countries to treat SARS-CoV-2 infection inducing COVID-19. Both CQ and HCQ were found to interact differently with the various ACE2 domains reported to bind with coronavirus spike protein. A molecular docking approach revealed that intermolecular interactions of both CQ and HCQ exhibited mediation by ACE2 polymorphism. Further explorations of the relationship and the interactions between ACE2 polymorphism and CQ/HCQ would certainly help to better understand the COVID-19 management strategies, particularly their use in the absence of specific vaccines or drugs.

Chloroquine and hydroxychloroquine in the treatment of COVID-19: the never-ending story.

The anti-malarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been suggested as promising agents against the new coronavirus SARS-CoV-2 that induces COVID-19 and as a possible therapy for shortening the duration of the viral disease. The antiviral effects of CQ and HCQ have been demonstrated in vitro due to their ability to block viruses like coronavirus SARS in cell culture. CQ and HCQ have been proposed to reduce immune reactions to infectious agents, inhibit pneumonia exacerbation, and improve lung imaging investigations. CQ analogs have also revealed the anti-inflammatory and immunomodulatory effects in treating viral infections and related ailments. There was, moreover, convincing evidence from early trials in China about the efficacy of CQ and HCQ in the anti-COVID-19 procedure. Since then, research and studies have been massive to ascertain these drugs' efficacy and safety in treating the viral disease. In the present review, we construct a synopsis of the main properties and current data concerning the metabolism of CQ/HCQ, which were the basis of assessing their potential therapeutic roles against the new coronavirus infection. The effective role of QC and HCQ in the prophylaxis and therapy of COVID-19 infection is discussed in light of the latest international medical-scientific research results. KEY POINTS: • Data concerning metabolism and properties of CQ/HCQ are discussed. • The efficacy of CQ/HCQ against COVID-19 has been the subject of contradictory results. • CQ/HCQ has little or no effect in reducing mortality in SARS-CoV-2-affected patients.

First principle simulation of coated hydroxychloroquine on Ag, Au and Pt nanoparticles.

From the first month of the COVID-19 pandemic, the potential antiviral properties of hydroxychloroquine (HCQ) and chloroquine (CQ) against SARS-CoV-2 suggested that these drugs could be the appropriate therapeutic candidates. However, their side effects directed clinical tests towards optimizing safe utilization strategies. The noble metal nanoparticles (NP) are promising materials with antiviral and antibacterial properties that can deliver the drug to the target agent, thereby reducing the side effects. In this work, we applied both the quantum mechanical and classical atomistic molecular dynamics approaches to demonstrate the adsorption properties of HCQ/CQ on Ag, Au, AgAu, and Pt nanoparticles. We found the adsorption energies of HCQ/CQ towards nanoparticles have the following trend: PtNP > AuNP > AuAgNP > AgNP. This shows that PtNP has the highest affinity in comparison to the other types of nanoparticles. The (non)perturbative effects of this drug on the plasmonic absorption spectra of AgNP and AuNP with the time-dependent density functional theory. The effect of size and composition of NPs on the coating with HCQ and CQ were obtained to propose the appropriate candidate for drug delivery. This kind of modeling could help experimental groups to find efficient and safe therapies.

Analogue discovery of safer alternatives to HCQ and CQ drugs for SAR-CoV-2 by computational design.

COVID-19 outbreak poses a severe health emergency to the global community. Due to availability of limited data, the selection of an effective treatment is a challenge. Hydroxychloroquine (HCQ), a chloroquine (CQ) derivative administered for malaria and autoimmune diseases, has been shown to be effective against both Severe Acute Respiratory Syndrome (SARS-CoV-1) and SARS-CoV-2. Apart from the known adverse effects of these drugs, recently the use of CQ and HCQ as a potential treatment for COVID-19 is under flux globally. In this study, we focused on identifying a more potent analogue of HCQ and CQ against the spike protein of SAR-CoV-2 that can act as an effective antiviral agent for COVID-19 treatment. Systematic pharmacokinetics, drug-likeness, basicity predictions, virtual screening and molecular dynamics analysis (200 ns) were carried out to predict the inhibition potential of the analogous compounds on the spike protein. This work identifies the six potential analogues, out of which two compounds, namely 1-[1-(6-Chloroquinolin-4-yl) piperidin-4-yl]piperidin-3-ol and (1R,2R)-2-N-(7-Chloroquinolin-4-yl)cyclohexane-1,2-diamine interact with the active site of the spike protein similar to HCQ and CQ respectively with augmented safety profile.

Formulation and stability study of hydroxychloroquine sulfate oral suspensions.

Hydroxychloroquine is an antimalarial drug indicated in the treatment of acute attacks of malaria due to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also used for the treatment of rheumatoid arthritis, discoid and systemic lupus erythematosus, and more recently proposed in COVID-19 therapy. Hydroxychloroquine is only available in tablets which are not easy to administer for pediatric and geriatric patients, and patients unable to swallow such as patients found in intensive care units. The aim of this work was to develop and optimize a ready to use liquid hydroxychloroquine formulation and to carry out the corresponding chemical and microbiological stability studies. The formulation was evaluated for ease of preparation, physical properties, and palatability. Its stability was performed at ambient temperature and under refrigeration. After 6 months of stability testing, the results showed no pH change, no drug loss, no microbial development, and no visual change. The formulation, employing excipients in a range that EMA has recommended, showed chemical and microbiological stability for at least 6 months even in the worst storage conditions.

Nanomedicine Reformulation of Chloroquine and Hydroxychloroquine.

The chloroquine family of antimalarials has a long history of use, spanning many decades. Despite this extensive clinical experience, novel applications, including use in autoimmune disorders, infectious disease, and cancer, have only recently been identified. While short term use of chloroquine or hydroxychloroquine is safe at traditional therapeutic doses in patients without predisposing conditions, administration of higher doses and for longer durations are associated with toxicity, including retinotoxicity. Additional liabilities of these medications include pharmacokinetic profiles that require extended dosing to achieve therapeutic tissue concentrations. To improve chloroquine therapy, researchers have turned toward nanomedicine reformulation of chloroquine and hydroxychloroquine to increase exposure of target tissues relative to off-target tissues, thereby improving the therapeutic index. This review highlights these reformulation efforts to date, identifying issues in experimental designs leading to ambiguity regarding the nanoformulation improvements and lack of thorough pharmacokinetics and safety evaluation. Gaps in our current understanding of these formulations, as well as recommendations for future formulation efforts, are presented.

A potential solution to avoid overdose of mixed drugs in the event of Covid-19: Nanomedicine at the heart of the Covid-19 pandemic.

Since 2020, the world is facing the first global pandemic of 21st century. Among all the solutions proposed to treat this new strain of coronavirus, named SARS-CoV-2, the vaccine seems a promising way but the delays are too long to be implemented quickly. In the emergency, a dual therapy has shown its effectiveness but has also provoked a set of debates around the dangerousness of a particular molecule, hydroxychloroquine. In particular, the doses to be delivered, according to the studies, were well beyond the acceptable doses to support the treatment without side effects. We propose here to use all the advantages of nanovectorization to address this question of concentration. Using quantum and classical simulations we will show in particular that drug transport on boron nitrogen oxide nanosheets increases the effectiveness of the action of these drugs. This will definitely allow to decrease the drug quantity needing to face the disease.

Preparation and physicochemical stability of 50 mg/mL hydroxychloroquine oral suspension in SyrSpendⓇ SF PH4 (dry).

In the context of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, hydroxychloroquine has been proposed as a potential agent to treat patients with COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 infection. Older adults are more susceptible to COVID-19 and some patients may require admission to the intensive care unit, where oral drug administration of solid forms may be compromised in many COVID-19 patients. However, a liquid formulation of hydroxychloroquine is not commercially available. This study describes how to prepare a 50 mg/mL hydroxychloroquine oral suspension using hydroxychloroquine sulfate powder and SyrSpendⓇ SF PH4 (dry) suspending vehicle. Moreover, a fully validated stability-indicating method has been developed to demonstrate the physicochemical stability of the compounded hydroxychloroquine oral suspension over 60 days under refrigeration (5 ± 3 °C). Finally, use of the proposed oral suspension provides a reliable solution to perform safe and accurate administration of hydroxychloroquine to patients with SARS-CoV-2 infection.

Molecular Descriptors of Some Chemicals that Prevent COVID-19.

BACKGROUND: Topological index is a numerical molecular descriptor that plays an important role in structure-property/structure-activity modeling. A large number of works on multiplicative degree based indices have been developed. However, no attention is paid to investigating their chemical significance. Investigation of the chemical importance of such indices is needed. The computation of topological indices for different chemical structures and networks is a current topic of interest in mathematical chemistry. OBJECTIVE: The objective of the present work is to examine the usefulness of the multiplicative degree based indices in quantitative structure property/activity relationship modeling. In addition, we intend to compute the indices for some anti-COVID-19 chemicals. MATERIALS AND METHODS: The regression analysis for octane data set is performed using MATLAB and Excel to check the predictability of the indices. The sensitivity test is conducted to examine the isomer discrimination ability. To study the indices for chemical structures preventing COVID-19, different combinatorial computation methods are utilized. RESULTS AND DISCUSSION: The regression models governing the structural dependence of different properties and activities are derived. The supremacy of the indices as useful molecular descriptors compared to some well-known and most used descriptors is established. Explicit expressions of the indices for hydroxychloroquine, remdesivir (GS-5734) and theaflavin are obtained. CONCLUSION: As the indices are shown to have remarkable efficiency in quantitative structure property/activity relationship modeling and isomer discrimination, the outcomes can predict different properties and activities of the chemicals under consideration.