Molecular Interaction Profile Research Articles

CovEpiAb: a comprehensive database and analysis resource for immune epitopes and antibodies of human coronaviruses.

Coronaviruses have threatened humans repeatedly, especially COVID-19 caused by SARS-CoV-2, which has posed a substantial threat to global public health. SARS-CoV-2 continuously evolves through random mutation, resulting in a significant decrease in the efficacy of existing vaccines and neutralizing antibody drugs. It is critical to assess immune escape caused by viral mutations and develop broad-spectrum vaccines and neutralizing antibodies targeting conserved epitopes. Thus, we constructed CovEpiAb, a comprehensive database and analysis resource of human coronavirus (HCoVs) immune epitopes and antibodies. CovEpiAb contains information on over 60000 experimentally validated epitopes and over 12000 antibodies for HCoVs and SARS-CoV-2 variants. The database is unique in (1) classifying and annotating cross-reactive epitopes from different viruses and variants; (2) providing molecular and experimental interaction profiles of antibodies, including structure-based binding sites and around 70000 data on binding affinity and neutralizing activity; (3) providing virological characteristics of current and past circulating SARS-CoV-2 variants and in vitro activity of various therapeutics; and (4) offering site-level annotations of key functional features, including antibody binding, immunological epitopes, SARS-CoV-2 mutations and conservation across HCoVs. In addition, we developed an integrated pipeline for epitope prediction named COVEP, which is available from the webpage of CovEpiAb. CovEpiAb is freely accessible at https://pgx.zju.edu.cn/covepiab/.

Aspirin as a potential drug repurposing candidate targeting estrogen receptor alpha in breast cancer: a molecular dynamics and in-vitro study

Estrogen receptor alpha (ERα) is expressed by 70% of breast cancers (BCs). Any deregulation in ERα signaling is crucial for the initiation and progression of BC. Because of development of resistance to anti-estrogenic compounds, repurposing existing drugs is an apt strategy to avoid a long drug-discovery process. Substantial epidemiologic evidence suggests that Aspirin use reduces the risk of different cancers including BC, while its role as an adjuvant or a possible antineoplastic agent in cancer treatment is being investigated. In this study, we attempted to explore possibilities of ERα inhibition by Aspirin which may act through competitive binding to the ligand binding domain (LBD) of ERα. A list of 48 ERα-LBD crystal structures bound with agonists, antagonists, and selective ER modulators (SERMs) was thoroughly analysed to determine interaction patterns specific to each ligand category. Exhaustive docking and 500 ns molecular dynamics (MD) studies were performed on three ERα - Aspirin complexes generated using agonist, antagonist, and SERM-bound crystal structures. Besides, three ERα crystal structures bound to agonist, antagonist, and SERM respectively were also subjected to MD simulations. Aspirin showed good affinity to LBD of ERα. Comparative analyses of binding patterns, conformational changes and molecular interaction profiles from the docking results and MD trajectories suggests that Aspirin was most stable in complex generated using SERM bound crystal structure of ERα and showed interactions with Gly-521, Ala-350, Leu-525 and Thr-347 like SERMs. In addition, in-vitro assays, qPCR, and immunofluorescent assay demonstrated the decline in the expression of ERα in MCF-7 upon treatment with Aspirin. These preliminary bioinformatical and in-vitro findings may form the basis to consider Aspirin as a potential candidate for targeting ERα, especially in tamoxifen-resistant cancers. Communicated by Ramaswamy H. Sarma

Computational Risk Assessment of Persistence, Bioaccumulation, and Toxicity of Novel Flame-Retardant Chemicals.

Novel brominated flame retardants (NBFRs) have emerged as chemicals of environmental concern, as they have been widely used as an alternative to polybrominated diphenyl ethers (PBDEs). Considering the similar structural features of NBFRs and PBDEs necessitates a comprehensive investigation to understand the physicochemical relationships of these compounds and their ability to alter biological functions. In this study, we investigated the persistent nature of NBFRs in terms of thyroid-disrupting potential by understanding the structure-stability aspects using density functional theory (DFT)-based reactivity parameters and interactions via molecular docking and molecular dynamics (MD) simulations. The results indicate that the DFT-based stability descriptor (chemical hardness) is associated with the persistent nature of NBFRs. The computed molecular interaction profile revealed prominent interactions between thyroid receptor-β (TR-β) and NBFRs. Stable trajectory and interactions with TR-β were obtained with ATE, p-TBX, PBT, PBEB, and TBBPA-DBPE during 100 ns of MD simulation. The results of these studies have suggested that the presence of a higher number of halogenated atoms increases the stability vis-à-vis the persistence and endocrine disruption potential of NBFRs.

In Silico ADMET and Molecular Interaction Profiles of Phytochemicals from Medicinal Plants in Dakshina Kannada

AbstractThe success or failure of a potential drug depends on its absorption, distribution, metabolism, excretion and toxicity (ADMET) characteristics, and these features are usually rate-limiting in the drug development process. Hence, it is essential to know about the predicted ADMET properties of the most promising leads to avoid the risk of late-stage attrition. This project focuses on in silico screening of ADMET properties of phytochemicals found in Dakshina Kannada's medicinal plants, which include Tinospora cordifolia, Azadirachta indica, Ocimum sanctum, and Plectranthus amboinicus, mainly known for their antimicrobial properties.The physicochemical properties, bioactivity scores, ADMET, and molecular interactions of the selected phytoconstituents were determined by QikProp, Molinspiration, ADMETlab 2.0, ProTox-II, and GLIDE. In addition, molecular docking checked for their binding interactions with target proteins 1JIJ and 4 HOE of Staphylococcus aureus and Candida albicans, respectively, as they were well known for their antimicrobial properties. In this studies, rosmarinic acid was well interacted phytochemical with both target proteins and has highest docking score.The physicochemical properties showed that all compounds fell under the recommended molecular weight, volume, and polar surface area range. Xanosporic acid violated two rules of Lipinski's Rule of Five, indicating that it may have problems with oral bioavailability. The ADME properties for most of the phytocompounds were within the recommended ranges; hence, they are promising candidates for drug development. Most phytoconstituents showed good bioactivity scores, indicating they have good druglikeness properties. On the analysis of the toxicity, most of the phytoconstituents were found to be noncarcinogenic and nonmutagenic. Therefore, this data can further be utilized as primary tools for determining the biological actions of these plants.Xanosporic acid was found to violate two out of three rules of Lipinski. Similarly, ursolic acid and oleanolic acid also showed a few undesirable properties. All other compounds otherwise showed desirable properties and hence are promising candidates for drug development. This data can be further utilized as primary tool for determining the biological actions of the plants.

An Approach to Antifungal Efficacy through Well Diffusion Analysis and Molecular Interaction Profile of Polyherbal Formulation

In the current scenario, there is a thirst for research against emerging microorganisms, and it becomes challenging to introduce new drugs against organism virulence are pretty interesting. Herbal medicines are now gaining popularity as a treatment option for various diseases worldwide. The present study analyzes the antifungal effect of a polyherbal formulation through in vitro well diffusion method using fungal strains such as Candida albicans, Aspergillus niger, Aspergillus fumigatus, Cryptococcus neoformans, and Sporothrix schenckii. Molecular docking is done using the Auto dock vina tool to predict the mechanism of action of the phytomolecules present in the polyherbal formulation. The molecular interactions are visualized using molecular modelling (PyMOL) software. The antifungal effect was observed in a concentration-dependent manner with a significant zone of inhibition. Also, phytomolecules in polyherbal formulation showed potential inhibition on CYP450 Lanosterol 14 α-demethylase 1, 3 β-Glucan synthase, and Thymidylate synthase from docking analysis.

Analyzing Indole-fused benzooxazepines as inhibitors of apoptosis pathway-related proteins using multifaceted computational medicinal chemistry

In this study, quantum chemical (QC) investigations, virtual screening, molecular docking, and molecular dynamics analysis of indole-fused benzooxazepines derivatives (IFBOs) are presented. The ab-initio density function theory (DFT) using Becke's three parameters hybrid functional (B3LYP) and Hartree-Fock (HF) with 6-311+G(d) level of theory were used to optimize IFBOs. The most suitable level is determined as DFT(B3LYP)6-311+G(d) by correlation of observed and calculated results of IFBOs (1-8). IR, NMR, quantum chemical descriptors, and frontier molecular orbitals (FMOs) were examined in detail. Similarly, virtual drug-likeness screening of IFBOs (1-8) was also performed including molecular descriptors (MDs) and bioactivity score (BS) along with absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were computed to reveal their biological activity. Moreover, their potential anticancer activity target was explored by molecular docking and molecular dynamics analyses. Mainly apoptosis pathway-related protein targets including caspase 8, caspase 3, Bcl-2, Bcl-xl, BAD, BAX and poly-ADP-ribose-polymerase-1 (PARP1) were studied to find the most prominent target of IFBOs to display their potential anticancer activity. As a result, IFBO-7 revealed the best molecular interaction profile with PARP1 and showed its potent inhibitory activity.

The Structural, Biological, and In-Silico Profiling of Novel Capryloyl Tetra-Glucoside and Aliphatic Ester Constituents from the Abutilon indicum Offers New Perspectives on the Treatment of Pain and Inflammation

Abutilon indicum L. (Malvaceae), more often referred to as Peeli booti, Kanghi, and Kakhi, is a perennial shrub found in many countries of Asia. Traditionally, this plant is used as a diuretic to treat inflammation, discomfort, urethral infections, and gout. Inflammation and pain are key topics of interest for researchers throughout the globe, since they are linked to almost every illness that could affect humans or animals. The present study was conducted to isolate the phytoconstituents from the methanolic extract of Abutilon indicum collected from the Bihar state Koshi river belt in India, and to evaluate the isolated phytoconstituents’ ability to reduce nociception and inflammation. Furthermore, molecular docking was performed to investigate the molecular interaction profile, with possible therapeutic targets for anti-inflammatory medicines. A. indicum methanolic extract yielded two novel phytocompounds identified as 5′-hydroxyhexyl n-hexadecanoate (AB-01) and n-octanoyl-β-D-glucopyranosyl-(2′-1′′)-β-D-glucopyranosyl-(2′′-1′′′)-β-D-glucopyranosyl-(2′′′-1′′′′)-β-D-glucopyranoside (AB-05), together with three previously recognized phytocompounds such as ester glucoside. All isolated molecules were tested for the efficacy of analgesic and anti-inflammatory characteristics at doses of 5 and 10 mg/kg body weight. The isolated compound’s molecular interaction profile with anti-inflammatory drug targets cyclooxygenase-2 and tumor necrosis factor-alpha possessed high potential energy in molecular docking. These findings may aid in developing anti-inflammatory and analgesic drugs from A. indicum.

Structural, functional, molecular, and biological evaluation of novel triterpenoids isolated from Helichrysum stoechas (L.) Moench. Collected from Mediterranean Sea bank: Misurata- Libya

Helichrysum stoechas (L.) Moench (Family Compositae) is a medicinal herb endowed with several pharmacological activities. Ethanolic extract of the aerial parts of the plant was used for the isolation of lignoceric acid (HS-02), lanost-5- en-3β-ol- 26-oic acid (HS-03), and lanost-5-en-26-oic acid-3β-olyl palmitate (HS-04). All molecules were screened for anti-inflammatory and analgesic activities at 5 and 10 mg/kg body weight doses, and the TEST program assessed their toxicity. The molecular interaction profile with numerous anti-inflammatory drug targets was investigated by molecular docking. Compounds HS-03 and HS-04 showed a significant reduction in paw volume compared to the control group challenged with carrageenan in the rats, and prolongation of the paw licking/jumping and reduction in the number of writhes was noted after the injection of acetic acid in mice. In a hot plate test, all compounds showed significant pain inhibition. These findings might aid in the development of anti-inflammatory and anti-analgesic therapies.

Potential of Natural Alkaloids From Jadwar (Delphinium denudatum) as Inhibitors Against Main Protease of COVID-19: A Molecular Modeling Approach.

The ongoing pandemic coronavirus disease (COVID-19) caused by a novel corona virus, namely, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has had a major impact on global public health. COVID-19 cases continue to increase across the globe with high mortality rates in immunocompromised patients. There is still a pressing demand for drug discovery and vaccine development against this highly contagious disease. To design and develop antiviral drugs against COVID-19, the main protease (Mpro) has emerged as one of the important drug targets. In this context, the present work explored Jadwar (Delphinium denudatum)–derived natural alkaloids as potential inhibitors against Mpro of SARS-CoV-2 by employing a combination of molecular docking and molecular dynamic simulation–based methods. Molecular docking and interaction profile analysis revealed strong binding on the Mpro functional domain with four natural alkaloids viz. panicutine (−7.4 kcal/mol), vilmorrianone (−7.0 kcal/mol), denudatine (−6.0 kcal/mol), and condelphine (−5.9 kcal/mol). The molecular docking results evaluated by using the MD simulations on 200 nanoseconds confirmed highly stable interactions of these compounds with the Mpro. Additionally, mechanics/generalized Born/Poisson–Boltzmann surface area (MM/G/P/BSA) free energy calculations also affirmed the docking results. Natural alkaloids explored in the present study possess the essential drug-likeness properties, namely, absorption, distribution, metabolism, and excretion (ADME), and are in accordance with Lipinski’s rule of five. The results of this study suggest that these four bioactive molecules, namely, condelphine, denudatine, panicutine, and vilmorrianone, might be effective candidates against COVID-19 and can be further investigated using a number of experimental methods.

Synthesis, antioxidant activity and bioinformatics studies of L-3-hydroxytyrosine templated N-alkyl/aryl substituted urea/thioureas

A new series of urea/thiourea derivatives have been efficiently synthesized from the reaction of L-3-hydroxytyrosine with selective isocyanates/isothiocyanates and characterized by Infra-red, proton & carbon-13 nuclear magnetic resonance spectral and mass spectrometry studies. All the synthesized compounds have been screened for their antioxidant activity by 1,1-diphenyl1-2-picrylhydrazyl radical assay, ferric reducing antioxidant power assay and also studied their molecular docking interaction profiles against 1N8Q and 3NRZ enzymatic proteins. The in vitro antioxidant activity has further supported by quantitative structure activity relationship, absorption, distribution, metabolism, and excretion & toxicity studies, bioactivity studies & enzyme inhibition assay and identified that they were potentially bound to ASP490 & ASP361 aminoacid residue in chain A of 1N8Q protein and GLN1194 aminoacid residue in chain L of 3NRZ protein and are responsible for potential antioxidant activity. It is proved that urea derivatives linked with 4-fluoro & 4-nitro and thiourea derivatives linked with 3-chloro & 4-fluoro have exhibited promising antioxidant activity. In eventual synthesized compounds have been identified as potential blood–brain barrier penetrable compounds and proficient central nervous system active neuro-protective antioxidant agents as they have envisaged as easily penetrable to blood–brain barrier thresholds, a neuroprotective property.

Virtual repurposing of ursodeoxycholate and chenodeoxycholate as lead candidates against SARS-Cov2-Envelope protein: A molecular dynamics investigation

Drug repurposing is an apt choice to combat the currently prevailing global threat of COVID-19, caused by SARS-Cov2in absence of any specific medication/vaccine. The present work employs state of art computational methods like homology modelling, molecular docking and molecular dynamics simulations to evaluate the potential of two widely used surfactant drugs namely chenodeoxycholate(CDC) and ursodeoxycholate (UDC), to bind to the envelope protein of SARS-Cov2(SARS-Cov2-E).The monomeric unit of SARS-Cov2-E was modelled from a close homologue (>90% sequence identity) and a pentameric assembly was modelled using symmetric docking, followed by energy minimization in a DPPC membrane environment. The minimized structure was used to generate best scoring SARS-Cov2-E–CDC/UDC complexes through blind docking. These complexes were subjected to 230 ns molecular dynamics simulations in triplicates in a DPPC membrane environment. Comparative analyses of structural properties and molecular interaction profiles from the MD trajectories revealed that, both CDC and UDC could stably bind to SARS-Cov2-E through H-bonds, water-bridges and hydrophobic contacts with the transmembrane-channelresidues.T30 was observed to be a key residue for CDC/UDC binding. CDC/UDC binding affected the H-bonding pattern between adjacent monomeric chains, slackening the compact transmembrane region of SARS-Cov2-E. Additionally, the polar functional groups of CDC/UDC facilitated entry of a large number of water molecules into the channel. These observations suggest CDC/UDC as potential candidates to hinder the survival of SARS-Cov2 by disrupting the structure of SARS-Cov2-E and facilitating the entry of solvents/polar inhibitors inside the viral cell. Communicated by Ramaswamy H. Sarma

Nature's therapy for COVID-19: Targeting the vital non-structural proteins (NSP) from SARS-CoV-2 with phytochemicals from Indian medicinal plants

BackgroundContaining COVID-19 is still a global challenge. It has affected the "normal" world by targeting its economy and health sector. The effect is shifting of focus of research from life threatening diseases like cancer. Thus, we need to develop a medical solution at the earliest. The purpose of this present work was to understand the efficacy of 22 rationally screened phytochemicals from Indian medicinal plants obtained from our previous work, following drug-likeness properties, against 6 non-structural-proteins (NSP) from SARS-CoV-2. Methods100 ns molecular dynamics simulations were performed, and relative binding free energies were computed by MM/PBSA. Further, principal component analysis, dynamic cross correlation and hydrogen bond occupancy were analyzed to characterize protein–ligand interactions. Biological pathway enrichment analysis was also carried out to elucidate the therapeutic targets of the phytochemicals in comparison to SARS-CoV-2. ResultsThe potential binding modes and favourable molecular interaction profile of 9 phytochemicals, majorly from Withania somnifera with lowest free binding energies, against the SARS-CoV-2 NSP targets were identified. It was understood that phytochemicals and 2 repurposed drugs with steroidal moieties in their chemical structures formed stable interactions with the NSPs. Additionally, human target pathway analysis for SARS-CoV-2 and phytochemicals showed that cytokine mediated pathway and phosphorylation pathways were with the most significant p-value. ConclusionsTo summarize this work, we suggest a global approach of targeting multiple proteins of SARS-CoV-2 with phytochemicals as a natural alternative therapy for COVID-19. We also suggest that these phytochemicals need to be tested experimentally to confirm their efficacy.

In silico screening of glycogen synthase kinase-3β targeted ligands against acetylcholinesterase and its probable relevance to Alzheimer’s disease

Alzheimer’s disease (AD) is a growing global health concern that affects 10% of the population aged above 65 years. A growing body of evidence indicates that multi-targeted drugs might be useful therapeutic options owing to the heterogeneity of AD pathology. The current study exploited advanced computational biology tools to identify ligands that might display effective binding to two protein targets in the context of AD. The present study used in silico virtual screening of small molecules library to identify effectiveness against two AD targets viz. acetyl cholinesterase (AChE) and glycogen synthase kinase-3β (GSK-3β). PyRX-Python prescription with AutodockVina was used to generate binding energy profiles. Further screening was accomplished using SwissADME and molecular interaction studies. The present study obtained 48 ligands (absolute binding energy >8 kcal/mol), by virtual screening of 100 ligands. Among those, 13 ligands (BRW, 6VK, 6Z5, SMH, X37, 55E, 65 A, IQ6, 6VL, 6VM, F1B, 6Z2 and GVP) were selected based on blood brain barrier (BBB) permeability, acceptable ADME properties as well as their molecular interaction profiles with the aforementioned AD-targets. The present study has predicted certain molecules that appear worthy to be tested for effectiveness against two AD targets, namely AChE and GSK-3β. However, the results warrant further wet laboratory validation, as computational studies are merely predictive in nature. This approach might be useful for future treatment of AD. Communicated by Ramaswamy H. Sarma

Structural elucidation of SARS-CoV-2 vital proteins: Computational methods reveal potential drug candidates against main protease, Nsp12 polymerase and Nsp13 helicase

Recently emerged SARS-CoV-2 caused a major outbreak of coronavirus disease 2019 (COVID-19) and instigated a widespread fear, threatening global health safety. To date, no licensed antiviral drugs or vaccines are available against COVID-19 although several clinical trials are under way to test possible therapies. During this urgent situation, computational drug discovery methods provide an alternative to tiresome high-throughput screening, particularly in the hit-to-lead-optimization stage. Identification of small molecules that specifically target viral replication apparatus has indicated the highest potential towards antiviral drug discovery. In this work, we present potential compounds that specifically target SARS-CoV-2 vital proteins, including the main protease, Nsp12 RNA polymerase and Nsp13 helicase. An integrative virtual screening and molecular dynamics simulations approach has facilitated the identification of potential binding modes and favourable molecular interaction profile of corresponding compounds. Moreover, the identification of structurally important binding site residues in conserved motifs located inside the active site highlights relative importance of ligand binding based on residual energy decomposition analysis. Although the current study lacks experimental validation, the structural information obtained from this computational study has paved way for the design of targeted inhibitors to combat COVID-19 outbreak.

Computational aided mechanistic understanding of Camellia sinensis bioactive compounds against co-chaperone p23 as potential anticancer agent.

Co-chaperon p23 has been well established as molecular chaperon for the heat shock protein 90 (Hsp90) that further leads to immorality in cancer cells by providing defense against Hsp90 inhibitors, and as stimulating agent for generating overexpressed antiapoptotic proteins, that is, Hsp70 and Hsp27. The natural compounds such as catechins from Camellia sinensis (green tea) are also well known for inhibition activity against various cancer. However, molecular interaction profile and potential lead bioactive compounds against co-chaperon p23 from green tea are not yet reported. To this context, we study the various secondary metabolites of green tea against co-chaperon p23 using structure-based virtual screening from Traditional Chinese Medicine (TCM) database. Following 26 compounds were obtained from TCM database and further studied for extra precision molecular docking that showed binding score between -10.221 and -2.276 kcal/mol with co-chaperon p23. However, relative docking score to known inhibitors, that is, ailanthone (-4.54 kcal/mol) and gedunin ( 3.60 kcal/mol) along with ADME profile analysis concluded epicatechin (-7.013 kcal/mol) and cis-theaspirone (-4.495 kcal/mol) as potential lead inhibitors from green tea against co-chaperone p23. Furthermore, molecular dynamics simulation and molecular mechanics generalized born surface area calculations validated that epicatechin and cis-theaspirone have significantly occupied the active region of co-chaperone p23 by hydrogen and hydrophobic interactions with various residues including most substantial amino acids, that is, Thr90, Ala94, and Lys95. Hence, these results supported the fact that green tea contained potential compounds with an ability to inhibit the cancer by disrupting the co-chaperon p23 activity.

Evaluation of caffeine as inhibitor against collagenase, elastase and tyrosinase using in silico and in vitro approach

Skin ageing results from enhanced activation of intracellular enzymes such as collagenases, elastases and tyrosinase, stimulated by intrinsic ageing and photoageing factors. Recently, caffeine-based cosmetics are introduced that demonstrates to slow down skin photoageing process. However, no attempts have been done so for to understand caffeine functional inhibitory activity against photoageing related enzymes. Hence, this study established the caffeine molecular interaction and inhibition activity profiles against respective enzymes using in silico and in vitro methods, respectively. Results from in silico study indicates that caffeine has comparatively good affinity with collagenase (−4.6 kcal/mol), elastase (−3.36 kcal/mol) and tyrosinase (−2.86 kcal/mol) and formed the stable protein-ligand complex as validated by molecular dynamics simulation (protein-ligand contacts, RMSD, RMSF and secondary structure changes analysis). Moreover, in vitro data showed that caffeine (1000 µg/mL) has statistically significant maximum inhibition activity of 41.86, 36.44 and 13.72% for collagenase, elastase and tyrosinase, respectively.

Methyl Chavicol and Its Synthetic Analogue as Possible Antioxidant and Antilipase Agents Based on the In Vitro and In Silico Assays.

This study investigated the in vitro and in silico biological properties of the methyl chavicol (MC) and its analogue 2-[(4-methoxyphenyl)methyl]oxirane (MPMO), emphasizing the antioxidant and antilipase effects. MPMO was synthesized from MC that reacted with meta-chloroperbenzoic acid and, after separation and purification, was identified by 1H and 13C NMR and GC-MS. The antioxidant activity was investigated by DPPH, cooxidation β-carotene/linoleic acid, and thiobarbituric acid assays. With the use of colorimetric determination, the antilipase effect on the pancreatic lipase was tested, while the molecular interaction profiles were evaluated by docking molecular study. MC (IC50 = 312.50 ± 2.28 μg/mL) and MPMO (IC50 = 8.29 ± 0.80 μg/mL) inhibited the DPPH free radical. The inhibition of lipid peroxidation (%) was 73.08 ± 4.79 and 36.16 ± 4.11 to MC and MPMO, respectively. The malonaldehyde content was significantly reduced in the presence of MC and MPMO. MC and MPMO inhibited the pancreatic lipase in 58.12 and 26.93%, respectively. MC and MPMO (−6.1 kcal·mol−1) produced a binding affinity value lower than did diundecylphosphatidylcholine (−5.6 kcal·mol−1). These findings show that MC and MPMO present antioxidant and antilipase activities, which may be promising molecular targets for the treatment of diseases associated with oxidative damage and lipid metabolism.

Similarity-based modeling in large-scale prediction of drug-drug interactions.

Drug-drug interactions (DDIs) are a major cause of adverse drug effects and a public health concern, as they increase hospital care expenses and reduce patients' quality of life. DDI detection is, therefore, an important objective in patient safety, one whose pursuit affects drug development and pharmacovigilance. In this article, we describe a protocol applicable on a large scale to predict novel DDIs based on similarity of drug interaction candidates to drugs involved in established DDIs. The method integrates a reference standard database of known DDIs with drug similarity information extracted from different sources, such as 2D and 3D molecular structure, interaction profile, target and side-effect similarities. The method is interpretable in that it generates drug interaction candidates that are traceable to pharmacological or clinical effects. We describe a protocol with applications in patient safety and preclinical toxicity screening. The time frame to implement this protocol is 5-7 h, with additional time potentially necessary, depending on the complexity of the reference standard DDI database and the similarity measures implemented.

What Does It Take to Synergistically Combine Sub-Potent Natural Products into Drug-Level Potent Combinations?

There have been renewed interests in natural products as drug discovery sources. In particular, natural product combinations have been extensively studied, clinically tested, and widely used in traditional, folk and alternative medicines. But opinions about their therapeutic efficacies vary from placebo to synergistic effects. The important questions are whether synergistic effects can sufficiently elevate therapeutic potencies to drug levels, and by what mechanisms and at what odds such combinations can be assembled. We studied these questions by analyzing literature-reported cell-based potencies of 190 approved anticancer and antimicrobial drugs, 1378 anticancer and antimicrobial natural products, 99 natural product extracts, 124 synergistic natural product combinations, and 122 molecular interaction profiles of the 19 natural product combinations with collective potency enhanced to drug level or by >10-fold. Most of the evaluated natural products and combinations are sub-potent to drugs. Sub-potent natural products can be assembled into combinations of drug level potency at low probabilities by distinguished multi-target modes modulating primary targets, their regulators and effectors, and intracellular bioavailability of the active natural products.

Reversed binding of a small molecule ligand in homologous chemokine receptors – differential role of extracellular loop 2

The majority of small molecule compounds targeting chemokine receptors share a similar pharmacophore with a centrally located aliphatic positive charge and flanking aromatic moieties. Here we describe a novel piperidine-based compound with structural similarity to previously described CCR8-specific agonists, but containing a unique phenyl-tetrazol moiety which, in addition to activity at CCR8 was also active at CCR1. Single point mutations were introduced in CCR1 and CCR8, and their effect on small molecule ligand-induced receptor activation was examined through inositol trisphosphate (IP(3) ) accumulation. The molecular interaction profile of the agonist was verified by molecular modeling. The chemokine receptor conserved glutamic acid in TM-VII served as a common anchor for the positively charged amine in the piperidine ring. However, whereas the phenyl-tetrazol group interacted with TyrIV:24 (Tyr(172) ) and TyrIII:09 (Tyr(114) ) in the major binding pocket (delimited by TM-III to VII) of CCR8, it also interacted with TrpII:20 (Trp(90) ) and LysII:24 (Lys(94) ) in the minor counterpart (delimited TM-I to III, plus TM-VII) in CCR1. A straightening of TM-II by Ala-substitution of ProII:18 confirmed its unique role in CCR1. The extracellular loop 2 (ECL-2) contributed directly to the small molecule binding site in CCR1, whereas it contributed to efficacy, but not potency in CCR8. Despite high ligand potency and efficacy and receptor similarity, this dual-active and bitopic compound binds oppositely in CCR1 and CCR8 with different roles of ECL-2, thereby expanding and diversifying the influence of extracellular receptor regions in drug action.