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The voltage-gated sodium channel subtype 1.2 (NaV1.2) is instrumental in the initiation of action potentials in the nervous system, making it a natural drug target for neurological diseases. Therefore, there is much pharmacological interest in finding blockers of NaV1.2 and improving their affinity and selectivity properties. An extensive family of peptide toxins from cone snails (conotoxins) block NaV channels, thus they provide natural templates for the design of drugs targeting NaV channels. Unfortunately, progress was hampered due to the absence of any NaV structures. The recent determination of cryo-EM structures for NaV channels has finally broken this impasse. Here, we use the NaV1.2 structure in complex with μ-conotoxin KIIIA (KIIIA) in computational studies with the aim of improving KIIIA’s affinity and blocking capacity for NaV1.2. Only three KIIIA amino acid residues are available for mutation (S5, S6, and S13). After performing molecular modeling and simulations on NaV1.2–KIIIA complex, we have identified the S5R, S6D, and S13K mutations as the most promising for additional contacts. We estimate these contacts to boost the affinity of KIIIA for NaV1.2 from nanomole to picomole domain. Moreover, the KIIIA[S5R, S6D, S13K] analogue makes contacts with all four channel domains, thus enabling the complete blocking of the channel (KIIIA partially blocks as it has contacts with three domains). The proposed KIIIA analogue, once confirmed experimentally, may lead to novel anti-epileptic drugs.

The rapidly evolving Coronavirus 2019 (COVID-19) pandemic has led to millions of deaths around the world, highlighting the pressing need to develop effective antiviral pharmaceuticals. Recent efforts with computer-aided rational drug discovery have allowed detailed examination of drug-macromolecule interactions primarily by molecular mechanics (MM) techniques. Less widely applied in COVID-19 drug modeling is density functional theory (DFT), a quantum mechanics (QM) method that enables electronic structure calculations and elucidations of reaction mechanisms. Here, we review recent advances in applying DFT in molecular modeling studies of COVID-19 pharmaceuticals. We start by providing an overview of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs and targets, followed by a brief introduction to DFT. We then provide a discussion of different approaches by which DFT has been applied. Finally, we discuss essential factors to consider when incorporating DFT in future drug modeling research.

International audience; Histone methyltransferase DOT1L catalyzes mono-, di- and trimethylation of histone 3 at lysine residue 79 (H3K79) and hypermethylation of H3K79 has been linked to the development of acute leukemias characterized by the MLL (mixed-lineage leukemia) rearrangements (MLLr cells). The inhibition of H3K79 methylation inhibits MLLr cells proliferation, and an inhibitor specific for DOT1L, pinometostat, was in clinical trials (Phase Ib/II). However, the compound showed poor pharmacological properties. Thus, there is a need to find new potent inhibitors of DOT1L for the treatment of rearranged leukemias. Here we present the design, synthesis, and biological evaluation of a small molecule that inhibits in the nM level the enzymatic activity of hDOT1L, H3K79 methylation in MLLr cells with comparable potency to pinometostat, associated with improved metabolic stability and a characteristic cytostatic effect.

Two decades of research have proven the relevance of ion channel expression for tumor progression in virtually every indication, and it has become clear that inhibition of specific ion channels will eventually become part of the oncology therapeutic arsenal. However, ion channels play relevant roles in all aspects of physiology, and specificity for the tumor tissue remains a challenge to avoid undesired effects. Eag1 (KV 10.1) is a voltage-gated potassium channel whose expression is very restricted in healthy tissues outside of the brain, while it is overexpressed in 70% of human tumors. Inhibition of Eag1 reduces tumor growth, but the search for potent inhibitors for tumor therapy suffers from the structural similarities with the cardiac HERG channel, a major off-target. Existing inhibitors show low specificity between the two channels, and screenings for Eag1 binders are prone to enrichment in compounds that also bind HERG. Rational drug design requires knowledge of the structure of the target and the understanding of structure-function relationships. Recent studies have shown subtle structural differences between Eag1 and HERG channels with profound functional impact. Thus, although both targets' structure is likely too similar to identify leads that exclusively bind to one of the channels, the structural information combined with the new knowledge of the functional relevance of particular residues or areas suggests the possibility of selective targeting of Eag1 in cancer therapies. Further development of selective Eag1 inhibitors can lead to first-in-class compounds for the treatment of different cancers. ispartof: MEDICINAL RESEARCH REVIEWS vol:42 issue:1 pages:183-226 ispartof: location:United States status: published

Focal adhesion kinase (FAK) is a tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. In cancer cells, FAK promotes the progression and metastasis of tumours. In this study, we used structure-based virtual screening to filter a library of more than 210K compounds against the focal adhesion targeting FAK-focal adhesion targeting (FAT) domain to identify 25 virtual hit compounds which were screened in the invasive breast cancer line (MDA-MB-231). Most notably, compound I showed low micromolar antiproliferative activity, as well as antimigratory activity. Moreover, examination in a model of triple negative breast cancer (TNBC), revealed that, despite not effecting FAK phosphorylation, compound I significantly impairs proliferation whilst impairing focal adhesion growth and turnover leading to reduced migration. Further optimisation and synthesis of analogues of the lead compound I using a four-step synthetic procedure was performed, and analogues were assessed for their antiproliferative activity against three breast cancer (MDA-MB-231, T47D, BT474) cell lines and one pancreatic cancer (MIAPaCa2) cell line. Compound 5f was identified as a promising lead compound with IC50 values in the range of 4.59&ndash, 5.28 &mu, M in MDA-MB-231, T47D, BT474, and MIAPaCa2. Molecular modelling and pharmacokinetic studies provided more insight into the therapeutic features of this new series.

The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer, inflammation, obesity, and cardiovascular disease. Recently, the discovery of novel BRD4 inhibitors has garnered substantial interest. Starting from scaffold hopping of the reported compound dihydroquinazolinone (PFI-1), a series of coumarin derivatives were designed and synthesised as a new chemotype of BRD4 inhibitors. Interestingly, the representative compounds 13 exhibited potent BRD4 binding affinity and cell proliferation inhibitory activity, and especially displayed a favourable PK profile with high oral bioavailability (F = 49.38%) and metabolic stability (T1/2 = 4.2 h), meaningfully making it as a promising lead compound for further drug development., Graphical Abstract

Roughly a third of the world’s population is estimated to have latent Mycobacterium tuberculosis infection, being at risk of developing active tuberculosis (TB) during their lifetime. Given the inefficacy of prophylactic measures and the increase of drug-resistant M. tuberculosis strains, there is a clear and urgent need for the development of new and more efficient chemotherapeutic agents, with selective toxicity, to be implemented on patient treatment. The component enzymes of the shikimate pathway, which is essential in mycobacteria and absent in humans, stand as attractive and potential targets for the development of new drugs to treat TB. This review gives an update on published work on the enzymes of the shikimate pathway and some insight on what can be potentially explored towards selective drug development.

α-Methylacyl-CoA racemase (AMACR; P504S) is a promising novel drug target for prostate and other cancers. Assaying enzyme activity is difficult due to the reversibility of the ‘racemisation’ reaction and the difficulties in the separation of epimeric products; consequently few inhibitors have been described and no structure–activity relationship study has been performed. This paper describes the first structure–activity relationship study, in which a series of 23 known and potential rational AMACR inhibitors were evaluated. AMACR was potently inhibited (IC 50 = 400–750 nM) by ibuprofenoyl-CoA and derivatives. Potency was positively correlated with inhibitor lipophilicity. AMACR was also inhibited by straight-chain and branched-chain acyl-CoA esters, with potency positively correlating with inhibitor lipophilicity. 2-Methyldecanoyl-CoAs were ca. 3-fold more potent inhibitors than decanoyl-CoA, demonstrating the importance of the 2-methyl group for effective inhibition. Elimination substrates and compounds with modified acyl-CoA cores were also investigated, and shown to be potent inhibitors. These results are the first to demonstrate structure–activity relationships of rational AMACR inhibitors and that potency can be predicted by acyl-CoA lipophilicity. The study also demonstrates the utility of the colorimetric assay for thorough inhibitor characterisation.

The angiotensin-converting enzyme (ACE) is a two-domain dipeptidylcarboxypeptidase, which has a direct involvement in the control of blood pressure by performing the hydrolysis of angiotensin I to produce angiotensin II. At the same time, ACE hydrolyzes other substrates such as the vasodilator peptide bradykinin and the anti-inflammatory peptide N-acetyl-SDKP. In this sense, ACE inhibitors are bioactive substances with potential use as medicinal products for treatment or prevention of hypertension, heart failures, myocardial infarction, and other important diseases. This review examined the most recent literature reporting ACE inhibitors with the help of molecular modeling. The examples exposed here demonstrate that molecular modeling methods, including docking, molecular dynamics (MD) simulations, quantitative structure-activity relationship (QSAR), etc, are essential for a complete structural picture of the mode of action of ACE inhibitors, where molecular docking has a key role. Examples show that too many works identified ACE inhibitory activities of natural peptides and peptides obtained from hydrolysates. In addition, other works report non-peptide compounds extracted from natural sources and synthetic compounds. In all these cases, molecular docking was used to provide explanation of the chemical interactions between inhibitors and the ACE binding sites. For docking applications, most of the examples exposed here do not consider that: (i) ACE has two domains (nACE and cACE) with available X-ray structures, which are relevant for the design of selective inhibitors, and (ii) nACE and cACE binding sites have large dimensions, which leads to non-reliable solutions during docking calculations. In support of the solution of these problems, the structural information found in Protein Data Bank (PDB) was used to perform an interaction fingerprints (IFPs) analysis applied on both nACE and cACE domains. This analysis provides plots that identify the chemical interactions between ligands and both ACE binding sites, which can be used to guide docking experiments in the search of selective natural components or novel drugs. In addition, the use of hydrogen bond constraints in the S2 and S2′ subsites of nACE and cACE are suggested to guarantee that docking solutions are reliable.

Rational drug design implies usage of molecular modeling techniques such as pharmacophore modeling, molecular dynamics, virtual screening, and molecular docking to explain the activity of biomolecules, define molecular determinants for interaction with the drug target, and design more efficient drug candidates. Kinases play an essential role in cell function and therefore are extensively studied targets in drug design and discovery. Kinase inhibitors are clinically very important and widely used antineoplastic drugs. In this review, computational methods used in rational drug design of kinase inhibitors are discussed and compared, considering some representative case studies.

G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes.

Protein kinases are key enzymes in many signal transduction pathways, and play a crucial role in cellular proliferation, differentiation, and various cell regulatory processes. However, aberrant function of kinases has been associated with cancers and many other diseases. Consequently, competitive inhibition of the ATP binding site of protein kinases has emerged as an effective means of curing these diseases. Over the past three decades, thousands of protein kinase inhibitors (PKIs) with varying molecular frames have been developed. Large-scale data mining of the Protein Data Bank resulted in a database of 2139 non-redundant high-resolution X-ray crystal structures of PKIs bound to protein kinases. This provided us with a unique opportunity to study molecular determinants for the molecular recognition of PKIs. A chemoinformatic analysis of 2139 PKIs resulted in findings that PKIs are “flat” molecules with high aromatic ring counts and low fractions of sp3 carbon. All but one PKI possessed one or more aromatic rings. More importantly, it was found that the average weighted hydrogen bond count is inversely proportional to the number of aromatic rings. Based on this linear relationship, we put forward the exchange rule of hydrogen bonding interactions and non-bonded π-interactions. Specifically, a loss of binding affinity caused by a decrease in hydrogen bonding interactions is compensated by a gain in binding affinity acquired by an increase in aromatic ring-originated non-bonded interactions (i.e., π–π stacking interactions, CH–π interactions, cation–π interactions, etc.), and vice versa. The very existence of this inverse relationship strongly suggests that both hydrogen bonding and aromatic ring-originated non-bonded interactions are responsible for the molecular recognition of PKIs. As an illustration, two representative PKI–kinase complexes were employed to examine the relative importance of different modes of non-bonded interactions for the molecular recognition of PKIs. For this purpose, two FDA-approved PKI drugs, ibrutinib and lenvatinib, were chosen. The binding pockets of both PKIs were thoroughly examined to identify all non-bonded intermolecular interactions. Subsequently, the strengths of interaction energies between ibrutinib and its interacting residues in tyrosine kinase BTK were quantified by means of the double hybrid DFT method B2PLYP. The resulting energetics for the binding of ibrutinib in tyrosine kinase BTK showed that CH–π interactions and π–π stacking interactions between aromatic rings of the drug and hydrophobic residues in its binding pocket dominate the binding interactions. Thus, this work establishes that, in addition to hydrogen bonding, aromatic rings function as important molecular determinants for the molecular recognition of PKIs. In conclusion, our findings support the following pharmacophore model for ATP-competitive kinase inhibitors: a small molecule features a scaffold of one or more aromatic rings which is linked with one or more hydrophilic functional groups. The former has the structural role of acting as a scaffold and the functional role of participating in aromatic ring-originated non-bonded interactions with multiple hydrophobic regions in the ATP binding pocket of kinases. The latter ensure water solubility and form hydrogen bonds with the hinge region and other hydrophilic residues of the ATP binding pocket.

Due to the synergic relationship between medical chemistry, bioinformatics and molecular simulation, the development of new accurate computational tools for small molecules drug design has been rising over the last years. The main result is the increased number of publications where computational techniques such as molecular docking,de novodesign as well as virtual screening have been used to estimate the binding mode, site and energy of novel small molecules. In this work I review some tools, which enable the study of biological systems at the atomistic level, providing relevant information and thereby, enhancing the process of rational drug design.

The angiotensin II (Ang II) type 1 and type 2 receptors (AT1R and AT2R) orchestrate an array of biological processes that regulate human health. Aberrant function of these receptors triggers pathophysiological responses that can ultimately lead to death. Therefore, it is important to design and synthesize compounds that affect beneficially these two receptors. Cardiovascular disease, which is attributed to the overactivation of the vasoactive peptide hormone Αng II, can now be treated with commercial AT1R antagonists. Herein, recent achievements in rational drug design and synthesis of molecules acting on the two AT receptors are reviewed. Quantitative structure activity relationships (QSAR) and molecular modeling on the two receptors aim to assist the search for new active compounds. As AT1R and AT2R are GPCRs and drug action is localized in the transmembrane region the role of membrane bilayers is exploited. The future perspectives in this field are outlined. Tremendous progress in the field is expected if the two receptors are crystallized, as this will assist the structure based screening of the chemical space and lead to new potent therapeutic agents in cardiovascular and other diseases.

The thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix α2, loop L5 and helix α3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design.

Cancer immunotherapy based on antibodies targeting the immune checkpoint PD-1/PD-L1 pathway has seen unprecedented clinical responses and constitutes the new paradigm in cancer therapy. The antibody-based immunotherapies have several limitations such as high production cost of the antibodies or their long half-life. Small-molecule inhibitors of the PD-1/PD-L1 interaction have been highly anticipated as a promising alternative or complementary therapeutic to the monoclonal antibodies (mAbs). Currently, the field of developing anti-PD-1/PD-L1 small-molecule inhibitors is intensively explored. In this paper, we review anti-PD-1/PD-L1 small-molecule and peptide-based inhibitors and discuss recent structural and preclinical/clinical aspects of their development. Discovery of the therapeutics based on small-molecule inhibitors of the PD-1/PD-L1 interaction represents a promising but challenging perspective in cancer treatment.

1. SUMMARYMyeloperoxidase (MPO) which belongs to the peroxidase family, is found in mammalian neutrophils. This heme enzyme contributes to the production of (pseudo)halogenous acid such as HOCl which oxidizes proteins, cell membrane, DNA and RNA causing death for the pathogens. It has an antimicrobial effect due to HOCl secreting inside the phagosomes of the neutrophils, whereas it will be released outside neutrophils causing oxidative damages for the host tissues. Proteins, lipids, lipoproteins, DNA and RNA are potential targets of the MPO resulting in several chronic syndromes. Many researchers have discovered the harmful effects of MPO and its products demonstrating its role in many inflammatory chronic diseases such as: Cardiovascular diseases as in atherosclerosis. MPO contribution in atherosclerosis development has been demonstrated. Neurodegenerative diseases also was related to MPO: such as Alzheimer’s disease (AD), multiple sclerosis (MSc) and Parkinson’s disease The enzyme has been also pointed out in other diseases such as renal disease and cancer.For these reasons, MPO as a target of drug discovery has attracted the attention of many researchers. X-ray 3D structures were resolved for this enzyme, biological activity and mechanism of action were investigated in depth, and many medicinal chemists have investigated and screened for new MPO inhibitors. Indeed, this cumulative work including X-ray data, the role of MPO in different pathologies, MPO inhibitory mechanism of action, screening and various chemical entities that inhibit MPO, provided sufficient elements to start a new drug design and drug discovery process on MPO.The aim of the present study was to apply a rational drug design approach to the myeloperoxidase inhibition: from in silico to pharmacological activity. This includes:─ Conducting high throughput virtual screening in order to find new potential hits to inhibit MPO followed by mechanism of inhibition determination. ─ Selecting one hit and then implementing a whole pharmacomodulation process in order to increase the potency of the inhibition greater than the starting hit and to improve the selectivity.Firstly, a rational drug design process was launched to find new hits using high throughput virtual screening. The chosen database for the screening was ASINEX database published in ZINC.X-ray structure of human peroxidase complexed to cyanide and thiocyanate (PDB 1DNW) was selected to conduct High-Throughput Virtual Screening (HTVS). Three successive protocols with different levels of accuracy in the docking and scoring processes were used starting with HTVS, followed by Standard Precision (SP) and finally with Xtra Precision (XP). The quality of the docking process performed was validated by docking a set of 60 chosen molecules of varying chemical structure and known as MPO inhibitors. From the result of the HTVS conducted on 1,350,000 compounds, the 100 best compounds were selected. Among them, 81 molecules were available for purchase from ASINEX, those compounds were tested with a MPO inhibition assay. Thirty-two compounds (39 %) were active, but only 8 compounds were selected, featuring different chemical structures with IC50 values ranging between 0.46 ± 0.07 and 12 ± 3 μM. Among these molecules, two compounds were the best and considered as hits. One has purinedione structure which is similar with the structure of thioxanthine derivatives (F9, IC50=0.46±0.07μM). The second compound has a hexahydropyrimidine structure (A1, IC50 = 0.5 ± 0.1 μM) The most common interactions found among all 8 docked ligands are the ionic bond with Glu102 and a stacking (shifted or not) with pyrrole ring D of the prosthetic group. Hydrogen bonds with Glu102, Thr100, Gln91, Arg239, or the propionate groups of the heme are also found in several docked geometries of the complexes. Interestingly, interactions with Glu102 and pyrrole ring D of the heme were also seen with fluorotryptamine derivatives and also salicylhydroxamic acid (SHA).For measuring MPO-dependent LDL oxidation, the two best compounds were tested. Compounds A1 and F9 showed good inhibition on MPO-dependent LDL oxidation (62 ± 6, 4.5 ± 0.9, 11 ± 2% and 11 ± 2, 2.6 ± 0.8, 6 ± 4%, respectively).Consequently, in order to determine the mechanism of inhibition transient-state kinetics were further investigated of all the 8 selected compounds.Both new lead compounds (A1 and F9) act as electron donors of both Compound I and Compound II of MPO. The reaction with Compound I was significantly faster (k2 ≫ k3). As a consequence, the enzyme is trapped in the Compound II state. They reversibly inactivated the enzyme blocking the harmful halogenation activity of MPO by transferring it to the MPO peroxidase cycle. In the present study, 8 active and reversible MPO inhibitors were selected. They act as electron donors of the oxidoreductase and efficiently block the halogenation activity with reversible inactivation. Two of the selected compounds have a submicromolar activity and inhibit MPO-dependent LDL oxidation. The high-throughput virtual screening was proved to be a successful tool to find new leads of MPO inhibitors. Conducting HTVS on a large-scale database enabled selection of novel scaffolds of MPO inhibitors never explored before in less time and at less expenses.Finding 8 new different chemical scaffolds through the first step of this drug discovery process led us to choose a new hit, compound A1, which has a hexahydropyrimidine structure, compound F9 was not chosen despite being more active due to its similarity to compounds discovered by AstraZeneca. To conduct pharmacomodulation, a validation of the docking procedure was conducted by comparing the X-ray structures of MPO with 2-(3,5-bistrifluoromethylbenzylamino)-6-oxo-1H-pyrimidine-5- carbohydroxamic acid, HX1, and SHA in the X-ray structures of human MPO in complex with cyanide and thiocyanate (PDB code 1DNW) as well as in complex with HX1 (PDB code 4C1M). Compound A1 was docked into both target structures 1DNW and 4C1M. In both cases, A1 showed almost the same poses.Based on the binding modes of A1, different strategies were developed for the design of derivatives which were mainly focused on the substitution of the aromatic rings A and B, the 2 amino groups and the side chain bridges.Pharmacomodulation was carried out on the hit A1 with different strategies:─ Investigating the role of hydroxyl groups on both aromatic rings─ Shifting the position of the amino groups in the hexahydropyrimidine ring to obtain piperazine derivatives and introduction of fluorine ─ Eliminating of one ring and of an amino group in the hexahydropyrimidine ring leading to piperidine derivatives ─ Opening the hexahydropyrimidine ring while keeping amine function and changing the length of the bridge between this amino group and aromatic ring as well as the impact of substitutions on aromatic rings.─ Hybridization of fluorotryptamine derivatives (effective MPO inhibitors) with hit A1.Based on of the docking experiments, 37 designed compounds were synthesized. The assessment of inhibition of the chlorination activity of MPO was undertaken over the 37 compounds. The hit A1 IC50 = 500 nM. The best compounds inhibiting MPO exhibited the following characteristics:─ One amino group on the bridge between aromatic rings was sufficient for the establishment of binding to Glu102 ─ The presence of three methylene groups between the secondary amine and an aromatic ring improved the inhibition of chlorination and thus decreased the IC50 values. These results showed that the position of the hydroxyl group is important. The distance between the hydrogen bond acceptor (HBA) group of one aromatic ring and the amino group is very important. The docking experiments of bisarylpropylamine derivatives showed ionic and hydrogen bonding interactions between Glu102 and hydroxyl group on aromatic ring linked to the longer side chain.─ Hybridized compounds which carry a fluorotryptamine instead of the phenol ring obtained by hybridization of hit A1 and the potent MPO inhibitors fluorotryptamine derivatives. Actually, compound 38 (which had one aromatic ring and a propyl bridge attached to indole ring) had an IC50 = 54 nM which was 10 times more powerful than the starting hit.The 3 best compounds were tested to examine the transient kinetics. They act as electron donors of the oxidoreductase and efficiently shift MPO from the chlorination cycle to the peroxidase cycle. Due to the similarity of the best compound 38 to serotonin it was tested with the two other best compounds on serotonin transporter (SERT) to examine the selectivity between MPO and SERT.Compound 38 had higher selectivity over MPO but the best selective compound was 28 that contains two aromatic rings carrying one hydroxyl and one fluorine.Electron density maps were conducted to predict the site of oxidation. Results suggested it occurs preferentially at the benzene ring or the indole ring in the best compounds.Determination of redox potentials for the synthesized compounds were tested. Best compounds act as electron donors allowing a one-electron reduction of Compound I.In conclusion, the present study succeeded through rational drug design including structure-based drug design and HTVS to identify new chemical entities for MPO inhibition. Eight compounds were more active than the starting hit A1 with submicromolar inhibition potency. Hybridization and structure based design also gave improvement of selectivity of inhibitors against MPO such as compound 38. Bis-arylalkylamine derivatives are a new group of MPO inhibitors with higher selectivity which could be a new hit for future development., Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie), info:eu-repo/semantics/nonPublished

Histone deacetylase 6 (HDAC6) is unique hydrolase within HDAC family, having pleiotropic deacetylase activity against alpha-tubulin, cortactin and dynein. Comprehensively, HDAC6 controls cell motility, apoptosis and protein folding, whereas alterations in its structure and function are related to the pathogenesis of cancer, neurodegeneration and inflammation. To define structural motifs which guide HDAC6 selectivity, we developed and compared three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) models for HDAC1 and HDAC6 inhibitors. The reduction of the bias in conformer generation was supported by virtual docking study by using crystal structures of human HDAC1 and HDAC6 isoforms. Following these findings, the combined ligand-based and fragment-based drug design methodologies were used in the design of selective HDAC6 inhibitors. Group of the most promising novel ligands was selected based on the predicted HDAC6 selectivity, pharmacokinetic profile, synthetic tractability, and in silico cytotoxicity against the wide range of human cancer cell lines.

Hepatitis B virus (HBV) infection is a prime cause of liver diseases such as hepatitis, cirrhosis and hepatocellular carcinoma. The current drugs clinically available are nucleot(s)ide analogues that inhibit viral reverse transcriptase activity. Most drugs of this class are reported to have viral resistance with breakthrough. Recent advances in methods for in silico virtual screening of chemical libraries, together with a better understanding of the resistance mechanisms of existing drugs have expedited the discovery and development of novel anti-viral drugs. This review summarizes the current status of knowledge about and viral resistance of HBV drugs, approaches for the development of novel drugs as well as new viral and host targets for future drugs.

© 2018 by the authors. This review summarises the current knowledge of Gomesin (Gm), an 18-residue long, cationic anti-microbial peptide originally isolated from the haemocytes of the Brazilian tarantula Acanthoscurria gomesiana. The peptide shows potent cytotoxic activity against clinically relevant microbes including Gram-positive and Gram-negative bacteria, fungi, and parasites. In addition, Gm shows in-vitro and in-vivo anti-cancer activities against several human and murine cancers. The peptide exerts its cytotoxic activity by permeabilising cell membranes, but the underlying molecular mechanism of action is still unclear. Due to its potential as a therapeutic agent, the structure and membrane-binding properties, as well as the leakage and cytotoxic activities of Gm have been studied using a range of techniques. This review provides a summary of these studies, with a particular focus on biophysical characterisation studies of peptide variants that have attempted to establish a structure-activity relationship. Future studies are still needed to rationalise the binding affinity and cell-type-specific selectivity of Gm and its variants, while more pre-clinical studies are required to develop Gm into a therapeutically useful peptide.

Haem is believed to be the target of some of the historically most important antimalarial drugs, most notably chloroquine. This target is almost ideal as haem is host-derived and the process targeted, haemozoin formation, is a physico-chemical process with no equivalent in the host. The result is that the target remains viable despite resistance to current drugs, which arises from mutations in parasite membrane transport proteins. Recent advances in high-throughput screening methods, together with a better understanding of the interaction of existing drugs with this target, have created new prospects for discovering novel haem-targeting chemotypes and for target-based structural design of new drugs. Finally, the discovery that Schistosoma mansoni also produces haemozoin suggests that new drugs of this type may be chemotherapeutic not only for malaria, but also for schistosomiasis. These recent developments in the literature are reviewed.

Antimicrobial resistance represents a significant challenge to future healthcare provision. An acronym ESKAPEE has been derived from the names of the organisms recognised as the major threats although there are a number of other organisms, notably Neisseria gonorrhoeae, that have become equally challenging to treat in the clinic. These pathogens are characterised by the ability to rapidly develop and/or acquire resistance mechanisms in response to exposure to different antimicrobial agents. A key part of the armoury of these pathogens is a series of efflux pumps, which effectively exclude or reduce the intracellular concentration of a large number of antibiotics, making the pathogens significantly more resistant. These efflux pumps are the topic of considerable interest, both from the perspective of basic understanding of efflux pump function, and its role in drug resistance but also as targets for the development of novel adjunct therapies. The necessity to overcome antimicrobial resistance has encouraged investigations into the characterisation of resistance-modifying efflux pump inhibitors to block the mechanisms of drug extrusion, thereby restoring antibacterial susceptibility and returning existing antibiotics into the clinic. A greater understanding of drug recognition and transport by multidrug efflux pumps is needed to develop clinically useful inhibitors, given the breadth of molecules that can be effluxed by these systems. This review discusses different bacterial EPIs originating from both natural source and chemical synthesis and examines the challenges to designing successful EPIs that can be useful against multidrug resistant bacteria.

Watshara Shoombuatong,1 Veda Prachayasittikul,1,2 Nuttapat Anuwongcharoen,1 Napat Songtawee,1 Teerawat Monnor,1 Supaluk Prachayasittikul,1 Virapong Prachayasittikul,2 Chanin Nantasenamat1,2 1Center of Data Mining and Biomedical Informatics, 2Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand Abstract: This study represents the first large-scale study on the chemical space of inhibitors of dipeptidyl peptidase-4 (DPP4), which is a potential therapeutic protein target for the treatment of diabetes mellitus. Herein, a large set of 2,937 compounds evaluated for their ability to inhibit DPP4 was compiled from the literature. Molecular descriptors were generated from the geometrically optimized low-energy conformers of these compounds at the semiempirical AM1 level. The origins of DPP4 inhibitory activity were elucidated from computed molecular descriptors that accounted for the unique physicochemical properties inherently present in the active and inactive sets of compounds as defined by their respective half maximal inhibitory concentration values of less than 1 µM and greater than 10 µM, respectively. Decision tree analysis revealed the importance of molecular weight, total energy of a molecule, topological polar surface area, lowest unoccupied molecular orbital, and number of hydrogen-bond donors, which correspond to molecular size, energy, surface polarity, electron acceptors, and hydrogen bond donors, respectively. The prediction model was subjected to rigorous independent testing via three external sets. Scaffold and chemical fragment analysis was also performed on these active and inactive sets of compounds to shed light on the distinguishing features of the functional moieties. Docking of representative active DPP4 inhibitors was also performed to unravel key interacting residues. The results of this study are anticipated to be useful in guiding the rational design of novel and robust DPP4 inhibitors for the treatment of diabetes. Keywords: QSAR, decision tree, scaffold analysis, fragment analysis, antidiabetic, molecular docking, rational drug design

Indazole is considered a very important scaffold in medicinal chemistry. It is commonly found in compounds with diverse biological activities, e.g., antimicrobial and anti-inflammatory agents. Considering that infectious diseases are associated to an inflammatory response, we designed a set of 2H-indazole derivatives by hybridization of cyclic systems commonly found in antimicrobial and anti-inflammatory compounds. The derivatives were synthesized and tested against selected intestinal and vaginal pathogens, including the protozoa Giardia intestinalis, Entamoeba histolytica, and Trichomonas vaginalis; the bacteria Escherichia coli and Salmonella enterica serovar Typhi; and the yeasts Candida albicans and Candida glabrata. Biological evaluations revealed that synthesized compounds have antiprotozoal activity and, in most cases, are more potent than the reference drug metronidazole, e.g., compound 18 is 12.8 times more active than metronidazole against G. intestinalis. Furthermore, two 2,3-diphenyl-2H-indazole derivatives (18 and 23) showed in vitro growth inhibition against Candida albicans and Candida glabrata. In addition to their antimicrobial activity, the anti-inflammatory potential for selected compounds was evaluated in silico and in vitro against human cyclooxygenase-2 (COX-2). The results showed that compounds 18, 21, 23, and 26 display in vitro inhibitory activity against COX-2, whereas docking calculations suggest a similar binding mode as compared to rofecoxib, the crystallographic reference.

Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein.

Hepatitis C virus (HCV) is the major etiological agent of human non-A and non-B hepatitis, affecting more than 170 million people worldwide. While the current standard of care for the treatment of HCV infection is ribavirin in combination with interferon-α (IFN-α), this therapeutic regimen presents several drawbacks, mainly related to important and serious side effects, to resistance issues, and to the lack of efficacy for the treatment of specific viral genotypes. In 2011, the FDA approved two HCV-targeted antivirals, namely boceprevir and telaprevir. These two drugs inhibit the protease activity of the viral enzyme NS3/4A, and in Phase III clinical trials proved to be effective in achieving sustained virological response rate up to 75%. However, problems associated with these therapeutic regimens still exist and need to be addressed. Intense research efforts in the field are aimed at discovering small-molecule inhibitors of HCV enzymes and proteins such as NS5B and NS5A and at developing NS3 protease inhibitors active against resistant viruses expressing mutated NS3 protease. The most recent advances for the rational drug design of such inhibitors are here reviewed.

Reversed-phase thin-layer chromatographic (RP TLC) retention coefficients for a newly designed series of N-phenyl-3-methyl succinimide derivatives, of a rationally expected anticonvusant activity, were determined as parameters of their lipophilicity. Basic pharmacokinetic descriptors of the agents were calculated in silico with the use of the established medicinal chemistry/drug design software. Highly significant, predictive relationships were found between the chromatographic retention constants and the bioactivity descriptors, which are assumed to account for drug absorption, distribution, elimination and toxicity (ADMETox) in humans. Among the agents investigated, the compounds with halogen substituent (Compounds nos. 9-13 in Fig. 1), were identified as the best drug candidates, because of their predicted proper pharmacokinetics, and have been selected for further research and development studies on new antiepileptic drugs. At the same time, among the congeners studied these can be indicated, which should not be rationally subjected to bioactivity tests.