COVID-19 Drug Discovery Research Articles

Anti- COVID-19 drug discovery by flavonoid derivatives: an extensive computational drug design approach.

The present study deals with the in-silico analyses of several flavonoid derivatives to explore COVID-19 through pharmacophore modelling, molecular docking, molecular dynamics, drug-likeness, and ADME properties. The initial literature study revealed that many flavonoids, including luteolin, quercetin, kaempferol, and baicalin may be useful against SARS β-coronaviruses, prompting the selection of their potential derivatives to investigate their abilities as inhibitors of COVID-19. The findings were streamlined using in silico molecular docking, which revealed promising energy-binding interactions between all flavonoid derivatives and the targeted protein. Notably, compounds 8, 9, 13, and 15 demonstrated higher potency against the coronavirus Mpro protein (PDB ID 6M2N). Compound 8 has a -7.2 Kcal/mol affinity for the protein and binds to it by hydrogen bonding with Gln192 and π-sulfur bonding with Met-165. Compound 9 exhibited a significant interaction with the main protease, demonstrating an affinity of -7.9 kcal/mol. Gln-192, Glu-189, Pro-168, and His-41 were the principle amino acid residues involved in this interaction. The docking score for compound 13 is -7.5 Kcal/mol, and it binds to the protease enzyme by making interactions with Leu-41, π-sigma, and Gln-189. These interactions include hydrogen bonding and π-sulfur. The major protease and compound 15 were found to bind with a favourable affinity of -6.8 Kcal/mol. This finding was further validated through molecular dynamic simulation for 1ns, analysing parameters such as RMSD, RMSF, and RoG profiles. The RoG values for all four of the compounds varied significantly (35.2-36.4). The results demonstrated the stability of the selected compounds during the simulation. After passing the stability testing, the compounds underwent screening for ADME and drug-likeness properties, fulfilling all the necessary criteria. The findings of the study may support further efforts for the discovery and development of safe drugs to treat COVID-19.

Targeting SARS-CoV-2 Spike and Main protease with phytochemicals from Herbs and spices: Molecular Docking and dynamics simulation studies.

Abstract COVID-19, a pandemic disease has affected 480 million people and caused 6 million deaths around the world. Despite the progress made in COVID-19 drug discovery, SARS-CoV-2, the causative agent of this disease continuously mutates and rapidly evolves into new variants. This increases the challenges in drug discovery for COVID-19. As natural products serve as sources of drugs forever, this study applies computational techniques in predicting the natural compounds in herbs and spices of household origin as SARS-CoV-2 spike and protease inhibitors and also verifies the top hits against spike and protease mutants associated with SARS-CoV-2 variants of concern. This study reveals Hesperidin, Diosgenin, Fenugreekine, Epigallocatechin gallate and Quercetin as SARS-CoV-2 spike and protease inhibitors, which acts better than the drug Remdesivir. The efficiency of the top hits was also been verified against the mutants, which reveals Diosgenin and Fenugreekine as the most efficient natural compounds against SARS-CoV-2 spike mutants (N501Y, E484K, K417N and K417T), which are associated with SARS-CoV-2 variants of concern. Additionally, Hesperidin is proven to have better binding efficiency against Mpro mutants (Y54C, A191V, T190I and N142S). Overall, this study concludes that Hesperidin, Diosgenin and Fenugreekine could combat both SARS-CoV-2 and its variants effectively.

An Overview of SARS-CoV-2 Potential Targets, Inhibitors, and Computational Insights to Enrich the Promising Treatment Strategies.

The rapid spread of the SARS-CoV-2 virus has emphasized the urgent need for effective therapies to combat COVID-19. Investigating the potential targets, inhibitors, and in silico approaches pertinent to COVID-19 are of utmost need to develop novel therapeutic agents and reprofiling of existing FDA-approved drugs. This article reviews the viral enzymes and their counter receptors involved in the entry of SARS-CoV-2 into host cells, replication of genomic RNA, and controlling the host cell physiology. In addition, the study provides an overview of the computational techniques such as docking simulations, molecular dynamics, QSAR modeling, and homology modeling that have been used to find the FDA-approved drugs and other inhibitors against SARS-CoV-2. Furthermore, a comprehensive overview of virus-based and host-based druggable targets from a structural point of view, together with the reported therapeutic compounds against SARS-CoV-2 have also been presented. The current study offers future perspectives for research in the field of network pharmacology investigating the large unexplored molecular libraries. Overall, the present in-depth review aims to expedite the process of identifying and repurposing drugs for researchers involved in the field of COVID-19 drug discovery.

Study anti-viral drugs for their efficiency against multiple SARS CoV-2 drug targets within molecular docking, molecular quantum similarity, and chemical reactivity indices frameworks

The study focused on drug discovery for COVID-19, emphasizing the challenges posed by the pandemic and the importance of understanding the virus’s biology. The research utilized molecular docking and quantum similarity analyses to explore potential ligands for SARS-CoV-2 RNA-dependent RNA polymerase. Docking Results Docking outcomes for various ligands, including Oseltamivir, Prochloraz, Valacyclovir, Baricitinib, Molnupiravir, Penciclovir, Famciclovir, Lamivudine, and Nitazoxanide, were presented. Interactions between ligands and specific residues in the RNA-dependent RNA polymerase were analyzed. Reactivity Descriptors Global parameters, such as electronic chemical potential, chemical hardness, global softness, and global electrophilicity, were computed for the ligands. For the local reactivity descriptors, the Fukui Functions were used. Fukui functions, representing electrophilic and nucleophilic sites, were calculated for selected ligands (Valacyclovir and Penciclovir). Nucleophilic character assignments for specific molecular regions were discussed, providing insights into potential charge-donating interactions. Results and Discussion Challenges in COVID-19 drug discovery, such as virus mutability, rapid evolution, and resource limitations, were summarized. Progress in vaccine development and the need for ongoing research to address variants and breakthrough cases were emphasized. Overlap Operator Analysis Higher MQSM between Lamivudine and Molnupiravir (0.5742) indicates structural and electronic similarity. Lowest MQSM between Oseltamivir and Prochloraz (0.2233) implies structural dissimilarity. Coulomb Operator Analysis Higher MQSM between Lamivudine and Molnupiravir (0.9178) suggests both structural and electronic similarity. Lowest MQSM between Baricitinib and Famciclovir (0.6001) indicates greater structural diversity. Measurements above 0.5 in Table 3 suggest electronic similarity, emphasizing the electronic aspects in molecular analysis. In this sense, it study employed a multi-faceted approach combining molecular docking, quantum similarity analyses, and chemical reactivity assessments to explore potential drug candidates for COVID-19. The findings provide valuable insights into ligand interactions, reactivity patterns, and the challenges associated with drug discovery in the context of the global pandemic.

The Role of Traditional Chinese Medicine and Chinese Pharmacopoeia in the Evaluation and Treatment of COVID-19.

The epidemic prompted by COVID-19 continues to spread, causing a great risk to the general population's safety and health. There are still no drugs capable of curing it. Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) are the two other diseases caused by coronaviruses. Traditional Chinese Medicine (TCM) showed benefits in treating SARS and MERS by preventing the disease early, substantially mitigating symptoms, shortening the treatment period, and minimizing risks and adverse reactions caused by hormone therapy. Although several vaccines have been developed and are being used for the treatment of COVID-19, existing vaccines cannot provide complete protection against the virus due to the rapid evolution and mutation of the virus, as mutated viral epitopes evade the vaccine's target and decrease the efficacy of vaccines. Thus, there is a need to develop alternative options. TCM has demonstrated positive effects in the treatment of COVID-19. Previous research studies on TCM showed broad-spectrum antiviral activity, offering a range of possibilities for their potential use against COVID-19. This study shed some light on common TCM used for SARS and MERS outbreaks and their effective use for COVID-19 management. This study provides new insights into COVID-19 drug discovery.

Quantum chemical characterization and molecular docking analysis of Hydroxychloroquine on noble Metal-Loaded silica nano Composites: Implications for COVID-19 drug discovery

Repurposing existing drugs and assessing commercially available inhibitors against druggable viral sites might be a potent approach for expediting the drug development in the swiftly evolving COVID-19 pandemic. The toxicity of antiviral drugs can be effectively reduced by using nanostructures in targeted drug delivery. Here, we go over the Hydroxychloroquine (HCQ) expected to interact and adsorb with noble metal-loaded silica nano composites (Ag, Au, and Pt). The spectra of absorption of HCQ and complexes were examined with different solvent solution of protic and aprotic solvents by the Time Dependent Density Functional Theory (TD-DFT) method. Frontier Molecular Orbitals (FMOs) determinedthe electrontransfer inside the molecule. A visual depiction of the molecule's ESP mapwith colour code representation was used to analyse the distribution of charge inside the molecule. The druglikeness and lipophilicity properties were considered during the drug delivery process to assess whether the molecule was suitable for use as a drug molecule. Finally, the ligand and complexes were carried out for molecular docking investigation with the selected proteins.

In-Silico Screening of Mitragynine Derivates from the Genus Mitragyna Korth Targeting the Main Protease of the SARS-COV-2

Coronavirus Diseases 2019, caused by SARS-CoV-2, has been a significant threat to global public health. Unfortunately, effective COVID-19 vaccines and clinically-proven anti-SARS-CoV-2 drugs remain unavailable. This study was carried out aiming to predict the potential effect of mitragynine derivates from the Genus Mitragyna Korth as an inhibitor of Mpro, the main protease of the SARS-CoV-2, by in silico molecular docking study. The crystal structure of the main protease of SARS-CoV-2 as an active site target was obtained from the PDB database (rcsb.org) with PDB ID: 5R84 and 6LU7 with the native ligand of Z31792168 and N3, respectively. The analysis of in silico molecular docking was conducted using Autodock 4.2.6 (100 docking runs). The central grid was placed on HIS41 and CYS145 with a grid box comprised of 40x30x34 (for protein 5R84) and 36x62x40 (for protein 6LU7) points spaced by 0.375 Å was centered on the active site of X=9,812; Y=-0,257; Z=20,849 and X=-9.732; Y=11.403; X=68,483 (XYZ-coordinates), respectively. Our research indicated that mitrjavine and ajmalicine exhibit greater potential inhibition of the active site on the Mpro of SARS-CoV-2, even stronger than native ligands. We believed that these compounds are promising candidates to be examined in further COVID-19 drug discovery studies.

Synthesis and Molecular Docking of New 1,2,3-triazole Carbohydrates with COVID-19 Proteins.

We have established this paper to recommend a novel way for the preparation of carbohydrates encompassing a 1,2,3-triazole motif that was prepared using an efficient click chemistry synthesis. The SARS-CoV-2 coronavirus epidemic continues to spread at a fast rate worldwide. The main protease (Mpro) is useful target for anti-COVID-19 agents. Triazoles are frequently found in many bioactive products, such as coronavirus inhibitors. Click reactions are facilitated via the activation of copper nanoparticles, different substrates have been tested using this adopted procedure given in all cases, in high yields and purity. Other interesting comparative docking analyses will be the focus of this article. Calculations of quantitative structure-activity relationships will be studied. Copper nanoparticles were produced by the reaction of cupric acetate monohydrate with oleylamine and oleic acid. To a solution, 5-(azidomethyl)-2,2,7,7-tetramethyltetrahydro-5Hbis([ 1,3]dioxolo)[4,5-b:4',5'-d]pyran 2 (200 mg, 0.72 mmol, 1 eq.) in toluene (15 mL) was added into a mixture of N-(prop-2-yn-1-yl)benzamide derivatives 1a-d (1.5 eq.) and copper nanoparticles (0.57 mg, 0.036 mmol, 0.05 eq.). A novel series of 1,2,3-triazole carbohydrate skeletons were modeled and efficiently synthesized. Based on the observations, virtual screening using molecular docking was performed to identify novel compounds that can bind with the protein structures of COVID-19 (PDB ID: 6LU7 and 6W41). We believed that the 1,2,3-triazole carbohydrate derivatives could aid in COVID-19 drug discovery. The formations of targeted triazoles were confirmed by different spectroscopic techniques (FT-IR, 1H NMR, 13C NMR, and CHN analyses). The docking scores of the newly synthesized triazole are attributed to the presence of hydrogen bonds together with many interactions between the ligands and the active amino acid residue of the receptor. The comparison of the interactions of the drugs, remdesivir and triazole, in the largest pocket of 6W41 and 6LU7 is also presented.

Investigation of the interactions of HSA and SARS-CoV-2 papain-like protease against eugenol for novel COVID-19 drug discovery: spectroscopic and insilico study

Coronavirus family consist of a member known as SARS-CoV-2, spread drastically in 2019 (Covid-19), affecting millions of people worldwide. Till date there is no clear-clinical therapy or drug, targeted to cure this serious disease. Researches are going on to prevent this corona virus. Here, we tried to explore a novel SARS-CoV-2 papain-like protease as a potential inhibitor. Finally, eugenol was docked with this protease to find prime SARS-inhibitors. In silico studies revealed that eugenol binds to the active site of SARS-CoV-2 papain-like protease with appropriate binding. Moreover, the MD simulation for 100 ns and MMPBSA calculation reveals that eugenol possess potential phytotherapeutic properties against COVID-19. The interaction of eugenol with human serum albumin has been examined by using fluorescence, UV–vis spectroscopy, circular dichroism as well as computational techniques such as molecular docking, molecular dynamic simulation and MMPBSA calculation. Overall investigation shows eugenol having good affinity for HSA K a 6.80 × 106 M−1. Communicated by Ramaswamy H. Sarma

Current Approaches to COVID-19 Drug Discovery and Safety Assessment.

Various methods currently being explored to treat COVID-19 were discussed during a symposium at the Fall 2022 ACS conference. These methods included the inhibiting of immune responses and viral replication pathways as well as repurposing known drugs.

Insight into designing of 2-pyridone derivatives for COVID-19 drug discovery - A computational study.

Presently, the prime global focus is on SARS-CoV-2, as no fully established, licensed medicine has been found thus far, in spite of the existence of various reports and administration of partially proven certain class of natural products. However, in case of natural products, the extraction and purification limit their application. This situation drives researchers to explore synthetically viable drugs. In the present investigation, twenty-three 2-pyridone synthetic derivatives (P1-P23) have been theoretically tested for their suitability as potential inhibitors for COVID-19 main protease through DFT, molecular docking, and molecular dynamics simulations. DFT calculations offer insights into structure–property relationships, while ADMET studies indicate the pharmacological characteristics of these molecules. Molecular docking studies ascertain the nature and mode of interactions of these entities with COVID-19 main protease. Furthermore, covalent docking has been carried out to verify the feasibility of the formation of a covalent bond with the active site. The top protein-inhibitor complexes, such as P18, P11, and P12, were identified based on their glide score. These molecules, along with the covalent docked complexes, namely P18 and P16, were selected and subjected to molecular dynamics simulations. The 100 ns simulation process exhibited that the covalent docked ones, due to their stable form could serve as lead compounds against SARS-CoV-2. Hence, this study affirms the potential candidature of 2-pyridone-based inhibitors.

Targeting COVID-19 pandemic: in silico evaluation of 2-hydroxy-1, 2-diphenylethanone N(4)-methyl-N(4)-phenylthiosemicarbazone as a potential inhibitor of SARS-CoV-2.

The global spread of the COVID-19 pandemic caused by the etiological agent, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), triggered researchers to identify and develop novel antiviral therapeutics. Herein, we report a new molecule 2-hydroxy-1,2-diphenylethanone N(4)-methyl-N(4)-phenyl thiosemicarbazone (BMPTSC), as a potential inhibitor of SARS-CoV-2. BMPTSC was synthesized, characterized by IR and NMR studies, and the structural parameters were analyzed computationally by B3LYP/cc-pVDZ method. Molecular docking studies were performed to get insights into the energetics and compatibility of BMPTSC against various SARS-CoV-2 drug targets. The best docking poses of target protein-BMPTSC complex structures were further subjected to molecular dynamics (MD) simulations. Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations on the binding of BMPTSC with the target proteins viz. spike glycoprotein and ACE-2 protein showed energy values of −179.87 and −145.61 kJ/mol, respectively. Moreover, BMPTSC obeys Lipinski’s rule, and further in silico assessment of oral bioavailability, bioactivity scores, ADME, drug-likeness, and medicinal chemistry friendliness suggests that this molecule is a promising candidate for the COVID-19 drug discovery process.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11224-022-02033-8.

Fragment-based design of SARS-CoV-2 Mpro inhibitors.

The SARS-CoV-2 virus has been identified as a causative agent for COVID-19 pandemic. About more than 6.3 million fatalities have been attributed to COVID-19 worldwide to date. Finding a viable cure for the illness is urgently needed in light of the present pandemic. The prominence of main protease in the life cycle of virus shapes the main protease as a viable target for design and development of antiviral agents to combat COVID-19. The current study presents the fragment linking strategy to design the novel Mpro inhibitors for COVID-19. A total of 293,451 fragments from diversified libraries have been screened for their binding affinity towards Mpro enzyme. The best 1600 fragment hits were subjected to fragment joining to achieve 100 new molecules using Schrödinger software. The resulting molecules were further screened for their Mpro binding affinity, ADMET, and drug-likeness features. The best 13 molecules were selected, and the first 6 compounds were investigated for their ligand-receptor complex stability through a molecular dynamics study using GROMACS software. The resulting molecules have the potential to be further evaluated for COVID-19 drug discovery.

A Comprehensive Review of Andrographis paniculata (Burm. f.) Nees and Its Constituents as Potential Lead Compounds for COVID-19 Drug Discovery.

The COVID-19 pandemic has intensively disrupted global health, economics, and well-being. Andrographis paniculata (Burm. f.) Nees has been used as a complementary treatment for COVID-19 in several Asian countries. This review aimed to summarize the information available regarding A. paniculata and its constituents, to provide critical points relating to its pharmacological properties, safety, and efficacy, revealing its potential to serve as a source of lead compounds for COVID-19 drug discovery. A. paniculata and its active compounds possess favorable antiviral, anti-inflammatory, immunomodulatory, and antipyretic activities that could be beneficial for COVID-19 treatment. Interestingly, recent in silico and in vitro studies have revealed that the active ingredients in A. paniculata showed promising activities against 3CLpro and its virus-specific target protein, human hACE2 protein; they also inhibit infectious virion production. Moreover, existing publications regarding randomized controlled trials demonstrated that the use of A. paniculata alone or in combination was superior to the placebo in reducing the severity of upper respiratory tract infection (URTI) manifestations, especially as part of early treatment, without serious side effects. Taken together, its chemical and biological properties, especially its antiviral activities against SARS-CoV-2, clinical trials on URTI, and the safety of A. paniculata, as discussed in this review, support the argument that A. paniculata is a promising natural source for drug discovery regarding COVID-19 post-infectious treatment, rather than prophylaxis.

Natural Products with Tandem Anti-inflammatory, Immunomodulatory and Anti-SARS-CoV/2 Effects: A Drug Discovery Perspective against SARS-CoV-2.

COVID-19 is still causing long-term health consequences, mass deaths, and collapsing healthcare systems around the world. There are no efficient drugs for its treatment. However, previous studies revealed that SARS-CoV-2 and SARS-CoV have 96% and 86.5% similarities in cysteine proteases (3CLpro) and papain-like protease (PLpro) sequences, respectively. This resemblance could be important in the search for drug candidates with antiviral effects against SARS-CoV-2. This paper is a compilation of natural products that inhibit SARS-CoV 3CLpro and PLpro and, concomitantly, reduce inflammation and/or modulate the immune system as a perspective strategy for COVID-19 drug discovery. It also presents in silico studies performed on these selected natural products using SARS-CoV-2 3CLpro and PLpro as targets to propose a list of hit compounds. The plant metabolites were selected in the literature based on their biological activities on SARS-CoV proteins, inflammatory mediators, and immune response. The consensus docking analysis was performed using four different packages. Seventy-nine compounds reported in the literature with inhibitory effects on SARS-CoV proteins were reported as anti-inflammatory agents. Fourteen of them showed immunomodulatory effects in previous studies. Five and six of these compounds showed significant in silico consensus as drug candidates that can inhibit PLpro and 3CLpro, respectively. Our findings corroborated recent results reported on anti-SARS-CoV-2 in the literature. This study revealed that amentoflavone, rubranoside B, savinin, psoralidin, hirsutenone, and papyriflavonol A are good drug candidates for the search of antibiotics against COVID-19.

Intrinsically Disordered Proteins: Perspective on COVID-19 Infection and Drug Discovery.

Since the beginning of the COVID-19 pandemic caused by SARS-CoV-2, millions of patients have been diagnosed and many of them have died from the disease worldwide. The identification of novel therapeutic targets are of utmost significance for prevention and treatment of COVID-19. SARS-CoV-2 is a single-stranded RNA virus with a 30 kb genome packaged into a membrane-enveloped virion, transcribing several tens of proteins. The belief that the amino acid sequence of proteins determines their 3D structure which, in turn, determines their function has been a central principle of molecular biology for a long time. Recently, it has been increasingly realized, however, that there is a large group of proteins that lack a fixed or ordered 3D structure, yet they exhibit important biological activities—so-called intrinsically disordered proteins and protein regions (IDPs/IDRs). Disordered regions in viral proteins are generally associated with viral infectivity and pathogenicity because they endow the viral proteins the ability to easily and promiscuously bind to host proteins; therefore, the proteome of SARS-CoV-2 has been thoroughly examined for intrinsic disorder. It has been recognized that, in fact, the SARS-CoV-2 proteome exhibits significant levels of structural order, with only the nucleocapsid (N) structural protein and two of the nonstructural proteins being highly disordered. The spike (S) protein of SARS-CoV-2 exhibits significant levels of structural order, yet its predicted percentage of intrinsic disorder is still higher than that of the spike protein of SARS-CoV. Noteworthy, however, even though IDPs/IDRs are not common in the SARS-CoV-2 proteome, the existing ones play major roles in the functioning and virulence of the virus and are thus promising drug targets for rational antiviral drug design. Presented here is a COVID-19 perspective on the intrinsically disordered proteins, summarizing recent results on the SARS-CoV-2 proteome disorder features, their physiological and pathological relevance, and their prominence as prospective drug target sites.

Structural insights into the substrate-binding site of main protease for the structure-based COVID-19 drug discovery.

An attractive drug target to combat COVID-19 is the main protease (Mpro ) because of its key role in the viral life cycle by processing the polyproteins translated from the viral RNA. Studying the crystal structures of the protease is important to enhance our understanding of its mechanism of action at the atomic-level resolution, and consequently may provide crucial structural insights for structure-based drug discovery. In the current study, we report a comparative structural analysis of the Mpro substrate binding site for both apo and holo forms to identify key interacting residues and conserved water molecules during the ligand-binding process. It is shown that in addition to the catalytic dyad residues (His41 and Cys145), the oxyanion hole residues (Asn142-Ser144) and residues His164-Glu166 form essential parts of the substrate-binding pocket of the protease in the binding process. Furthermore, we address the issue of the substrate-binding pocket flexibility and show that two adjacent loops in the Mpro structures (residues Thr45-Met49 and Arg188-Ala191) with high flexibility can regulate the binding cavity' accessibility for different ligand sizes. Moreover, we discuss in detail the various structural and functional roles of several important conserved and mobile water molecules within and around the binding site in the proper enzymatic function of Mpro . We also present a new docking protocol in the framework of the ensemble docking strategy. The performance of the docking protocol has been evaluated in predicting ligand binding pose and affinity ranking for two popular docking programs; AutoDock4 and AutoDock Vina. Our docking results suggest that the top-ranked poses of the most populated clusters obtained by AutoDock Vina are the most important representative docking runs that show a very good performance in estimating experimental binding poses and affinity ranking.

Discovery of highly potent SARS-CoV-2 Mpro inhibitors based on benzoisothiazolone scaffold

The COVID-19 pandemic has drastically impacted global economies and public health. Although vaccine development has been successful, it was not sufficient against more infectious mutant strains including the Delta variant indicating a need for alternative treatment strategies such as small molecular compound development. In this work, a series of SARS-CoV-2 main protease (Mpro) inhibitors were designed and tested based on the active compound from high-throughput diverse compound library screens. The most efficacious compound (16b-3) displayed potent SARS-CoV-2 Mpro inhibition with an IC50 value of 116 nM and selectivity against SARS-CoV-2 Mpro when compared to PLpro and RdRp. This new class of compounds could be used as potential leads for further optimization in anti COVID-19 drug discovery.

Application of Artificial Intelligence for the Prediction of Solvation Free Energies for Covid-19 Drug Discovery

Solvation free energy is a key indicator of the effectiveness of a drug molecule. There are several applications of predicting the solvation free energies of chemical compounds using quantum mechanical methods. However, these methods take a long time and are costly. For that reason, the application of recently developed artificial intelligence techniques for the prediction of solvation free energies is becoming increasingly valuable in drug discovery to address time and the high-cost issues with traditional quantum mechanical approaches. In this paper, we present application of two different artificial intelligence models for predicting solute-solvent free solvation energy for Covid-19 drug design. The research involves building, training, evaluating and comparing the performances of the two models on a large dataset, then predicting solvation free energies for 138 known APIs and 28 organic solvents that could potentially be used as a Covid-19 medicine. The potential repurposing of 138 drugs for Covid-19 from solubility perspective is novel. We demonstrate the application of the AI models and derive several conclusions regarding suitability of the APIs and their efficacy. We conclude our research by providing insights on how our work can be put to future use towards drug development.

Ligand-based quantitative structural assessments of SARS-CoV-2 3CLpro inhibitors: An analysis in light of structure-based multi-molecular modeling evidences

Due to COVID-19, the whole world is undergoing a devastating situation, but treatment with no such drug candidates still has been established exclusively. In that context, 69 diverse chemicals with potential SARS-CoV-2 3CLpro inhibitory property were taken into consideration for building different internally and externally validated linear (SW-MLR and GA-MLR), non-linear (ANN and SVM) QSAR, and HQSAR models to identify important structural and physicochemical characters required for SARS-CoV-2 3CLpro inhibition. Importantly, 2-oxopyrrolidinyl methyl and benzylester functions, and methylene (hydroxy) sulphonic acid warhead group, were crucial for retaining higher SARS-CoV-2 3CLpro inhibition. These GA-MLR and HQSAR models were also applied to predict some already repurposed drugs. As per the GA-MLR model, curcumin, ribavirin, saquinavir, sepimostat, and remdesivir were found to be the potent ones, whereas according to the HQSAR model, lurasidone, saquinavir, lopinavir, elbasvir, and paritaprevir were the highly effective SARS-CoV-2 3CLpro inhibitors. The binding modes of those repurposed drugs were also justified by the molecular docking, molecular dynamics (MD) simulation, and binding energy calculations conducted by several groups of researchers. This current work, therefore, may be able to find out important structural parameters to accelerate the COVID-19 drug discovery processes in the future.