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Macrocycles are prominent among drugs for treatment of infectious disease, with many originating from natural products. Herein we report on the discovery of a series of macrocycles structurally related to the natural product hymenocardine. Members of this series were found to inhibit the growth of Plasmodium falciparum , the parasite responsible for most malaria cases, and of four kinetoplastid parasites. Notably, macrocycles more potent than miltefosine, the only oral drug used for the treatment of the neglected tropical disease visceral leishmaniasis, were identified in a phenotypic screen of Leishmania infantum . In vitro profiling highlighted that potent inhibitors had satisfactory cell permeability with a low efflux ratio, indicating their potential for oral administration, but low solubility and metabolic stability. Analysis of predicted crystal structures suggests that optimization should focus on the reduction of π-π crystal packing interactions to reduce the strong crystalline interactions and improve the solubility of the most potent lead.

The discovery of the E3 ligase cereblon (CRBN) as the target of thalidomide and its analogs revolutionized the field of targeted protein degradation (TPD). This ubiquitin-mediated degradation pathway was first harnessed by bivalent degraders. Recently, the emergence of low-molecular-weight molecular glue degraders (MGDs) has expanded the TPD landscape, because MGDs operate via the same mechanism while offering attractive physicochemical properties that are consistent with small-molecule therapeutics. This review delves into the discovery and advancement of MGDs, with case studies on cyclin K and the zinc finger protein IKZF2, highlighting the design principles, biological assays and therapeutic applications. Additionally, it examines the chemical space of molecular glues and outlines the collaborative efforts that are fueling innovation in this field., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Hydrophobic tagging (HyT) technology presents a distinct therapeutic strategy diverging from conventional small molecule drugs, providing an innovative approach to drug design. This review aims to provide an overview of the HyT literature and future outlook to offer guidance for drug design., Areas Covered: In this review, the authors introduce the composition, mechanisms and advantages of HyT technology, as well as summarize the detailed applications of HyT technology in anti-cancer, neurodegenerative diseases (NDs), autoimmune disorders, cardiovascular diseases (CVDs), and other fields. Furthermore, this review discusses key aspects of the future development of HyT molecules., Expert Opinion: HyT emerges as a highly promising targeted protein degradation (TPD) strategy, following the successful development of proteolysis targeting chimeras (PROTAC) and molecular glue. Based on exploring new avenues, modification of the HyT molecule itself potentially enhances the technology. Improved synthetic pathways and emphasis on pharmacokinetic (PK) properties will facilitate the development of HyT. Furthermore, elucidating the biochemical basis by which the compound's hydrophobic moiety recruits the protein homeostasis network will enable the development of more precise assays that can guide the optimization of the linker and hydrophobic moiety.

A principal challenge in the discovery of proteolysis targeting chimeras (PROTACs) as oral medications is their bioavailability. To facilitate drug design, it is therefore essential to identify the chemical space where orally bioavailable PROTACs are more likely to be situated. To this aim, we extracted structure-bioavailability insights from published data using traditional 2D descriptors, thereby shedding light on their potential and limitations as drug design tools. Subsequently, we describe cutting-edge experimental, computational and hybrid design strategies based on 3D descriptors, which show promise for enhancing the probability of discovering PROTACs with high oral bioavailability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Molecular chameleons possess a flexibility that allows them to dynamically shield or expose polar functionalities in response to the properties of the environment. Although the concept of molecular chameleons was introduced already in 1970, interest in them has grown considerably since the 2010s, when drug discovery has focused to an increased extent on new chemical modalities. Such modalities include cyclic peptides, macrocycles and proteolysis-targeting chimeras, all of which reside in a chemical space far from that of traditional small-molecule drugs. Both cell permeability and aqueous solubility are required for the oral absorption of drugs. Engineering these properties, and potent target binding, into the larger new modalities is a more daunting task than for traditional small-molecule drugs. The ability of chameleons to adapt to different environments may be essential for success. In this Review, we provide both general and theoretical insights into the realm of molecular chameleons. We discuss why chameleons have come into fashion and provide a do-it-yourself toolbox for their design; we then provide a glimpse of how advanced in silico methods can support molecular chameleon design., (© 2023. Springer Nature Limited.)

Competing Interests: Competing interests: None declared.

Hepatitis B virus (HBV) infection is a major global health problem that puts people at high risk of death from cirrhosis and liver cancer. The presence of covalently closed circular DNA (cccDNA) in infected cells is considered to be the main obstacle to curing chronic hepatitis B. At present, the cccDNA cannot be completely eliminated by standard treatments. There is an urgent need to develop drugs or therapies that can reduce HBV cccDNA levels in infected cells. We summarize the discovery and optimization of small molecules that target cccDNA synthesis and degradation. These compounds are cccDNA synthesis inhibitors, cccDNA reducers, core protein allosteric modulators, ribonuclease H inhibitors, cccDNA transcriptional modulators, HBx inhibitors and other small molecules that reduce cccDNA levels., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We have analyzed FDA-approved macrocyclic drugs, clinical candidates, and the recent literature to understand how macrocycles are used in drug discovery. Current drugs are mainly used in infectious disease and oncology, while oncology is the major indication for the clinical candidates and in the literature Most macrocyclic drugs bind to targets that have difficult to drug binding sites. Natural products have provided 80-90% of the drugs and clinical candidates, whereas macrocycles in ChEMBL have less complex structures. Macrocycles usually reside in the beyond the Rule of 5 chemical space, but 30-40% of the drugs and clinical candidates are orally bioavailable. Simple bi-descriptor models, i.e., HBD ≤ 7 in combination with either MW < 1000 Da or cLogP > 2.5, distinguished orals from parenterals and can be used as filters in design. We propose that recent breakthroughs in conformational analysis and inspiration from natural products will further improve the de novo design of macrocycles.

The ability to adjust conformations in response to the polarity of the environment, i.e. molecular chameleonicity, is considered to be important for conferring both high aqueous solubility and high cell permeability to drugs in chemical space beyond Lipinski's rule of 5. We determined the conformational ensembles populated by the antiviral drugs asunaprevir, simeprevir, atazanavir and daclatasvir in polar (DMSO-d 6 ) and non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas the first three showed large flexibility in both environments, that translated into major differences in solvent accessible 3D polar surface area within each conformational ensemble. No significant differences in size and polar surface area were observed between the DMSO-d 6 and chloroform ensembles of these three drugs. We propose that such flexible compounds are characterized as "partial molecular chameleons" and hypothesize that their ability to adopt conformations with low polar surface area contributes to their membrane permeability and oral absorption., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Approaches for predicting proteolysis targeting chimera (PROTAC) cell permeability are of major interest to reduce resource-demanding synthesis and testing of low-permeable PROTACs. We report a comprehensive investigation of the scope and limitations of machine learning-based binary classification models developed using 17 simple descriptors for large and structurally diverse sets of cereblon (CRBN) and von Hippel-Lindau (VHL) PROTACs. For the VHL PROTAC set, kappa nearest neighbor and random forest models performed best and predicted the permeability of a blinded test set with >80% accuracy ( k ≥ 0.57). Models retrained by combining the original training and the blinded test set performed equally well for a second blinded VHL set. However, models for CRBN PROTACs were less successful, mainly due to the imbalanced nature of the CRBN datasets. All descriptors contributed to the models, but size and lipophilicity were the most important. We conclude that properly trained machine learning models can be integrated as effective filters in the PROTAC design process., Competing Interests: The authors declare the following competing financial interest(s): F.K., A.G., A.H.G., L.L. and D.M. are employees of Bayer AG., (© 2023 The Authors. Published by American Chemical Society.)

Conformational analysis is central to the design of bioactive molecules. It is particularly challenging for macrocycles due to noncovalent transannular interactions, steric interactions, and ring strain that are often coupled. Herein, we simulated the conformations of five macrocycles designed to express a progression of increasing complexity in environment-dependent intramolecular interactions and verified the results against NMR measurements in chloroform and dimethyl sulfoxide. Molecular dynamics using an explicit solvent model, but not the Monte Carlo method with implicit solvation, handled both solvents correctly. Refinement of conformations at the ab initio level was fundamental to reproducing the experimental observations─standard state-of-the-art molecular mechanics force fields were insufficient. Our simulations correctly predicted the intramolecular interactions between side chains and the macrocycle and revealed an unprecedented solvent-induced conformational switch of the macrocyclic ring. Our results provide a platform for the rational, prospective design of molecular chameleons that adapt to the properties of the environment.

Proteolysis-targeting chimeras (PROTACs) must be cell permeable to reach their target proteins. This is challenging as the bivalent structure of PROTACs puts them in chemical space at, or beyond, the outer limits of oral druggable space. We used NMR spectroscopy and molecular dynamics (MD) simulations independently to gain insights into the origin of the differences in cell permeability displayed by three flexible cereblon PROTACs having closely related structures. Both methods revealed that the propensity of the PROTACs to adopt folded conformations with a low solvent-accessible 3D polar surface area in an apolar environment is correlated to high cell permeability. The chemical nature and the flexibility of the linker were essential for the PROTACs to populate folded conformations stabilized by intramolecular hydrogen bonds, π-π interactions, and van der Waals interactions. We conclude that MD simulations may be used for the prospective ranking of cell permeability in the design of cereblon PROTACs.

Artificial intelligence (AI) is becoming an integral part of drug discovery. It has the potential to deliver across the drug discovery and development value chain, starting from target identification and reaching through clinical development. In this review, we provide an overview of current AI technologies and a glimpse of how AI is reimagining preclinical drug discovery by highlighting examples where AI has made a real impact. Considering the excitement and hyperbole surrounding AI in drug discovery, we aim to present a realistic view by discussing both opportunities and challenges in adopting AI in drug discovery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that might be perceived as affecting the perception of this review., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Our previous efforts have proved that modifications targeting the 150-cavity of influenza neuraminidase can achieve more potent and more selective inhibitors. In this work, four subseries of C5-NH 2 modified oseltamivir derivatives were designed and synthesized to explore every region inside the 150-cavity. Among them, compound 23d was exceptionally potent against the whole panel of Group-1 NAs with IC 50 values ranging from 0.26 to 0.73 nM, being 15-53 times better than oseltamivir carboxylate (OSC) and 7-11 times better than zanamivir. In cellular assays, 23d showed more potent or equipotent antiviral activities against corresponding virus strains compared to OSC with no cytotoxicity. Furthermore, 23d exhibited high metabolic stability in human liver microsomes (HLM) and low inhibitory effect on main cytochrome P450 enzymes. Notably, 23d displayed favorable druggability in vivo and potent antiviral efficacy in the embryonated egg model and mice model. Overall, 23d appears to be a promising candidate for the treatment of influenza virus infection.

Various boron-containing drugs have been approved for clinical use over the past two decades, and more are currently in clinical trials. The increasing interest in boron-containing compounds is due to their unique binding properties to biological targets; for example, boron substitution can be used to modulate biological activity, pharmacokinetic properties, and drug resistance. In this perspective, we aim to comprehensively review the current status of boron compounds in drug discovery, focusing especially on progress from 2015 to December 2020. We classify these compounds into groups showing anticancer, antibacterial, antiviral, antiparasitic and other activities, and discuss the biological targets associated with each activity, as well as potential future developments., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Conformation-dependent 3D descriptors have been shown to provide better predictions of the physicochemical properties of macrocycles than 2D descriptors. However, the computational identification of relevant conformations for macrocycles is nontrivial. Herein, we report that the Caco-2 cell permeability difference between a pair of diastereomeric macrocycles correlated with their solvent accessible 3D polar surface area and radius of gyration. The descriptors were calculated from the macrocycles' solution-phase conformational ensembles and independently from ensembles obtained by conformational sampling. Calculation of the two descriptors for three other stereo- and regioisomeric macrocycles also allowed the correct ranking of their cell permeability. Methods for conformational sampling may thus allow ranking of passive permeability for moderately flexible macrocycles, thereby contributing to the prioritization of macrocycles for synthesis in lead optimization., Competing Interests: The authors declare the following competing financial interest(s): S.Sc. is an employee of AstraZeneca and may own stock or stock options., (© 2021 The Authors. Published by American Chemical Society.)

Lead generation for difficult-to-drug targets that have large, featureless, and highly lipophilic or highly polar and/or flexible binding sites is highly challenging. Here, we describe how cores of macrocyclic natural products can serve as a high-quality in silico screening library that provides leads for difficult-to-drug targets. Two iterative rounds of docking of a carefully selected set of natural-product-derived cores led to the discovery of an uncharged macrocyclic inhibitor of the Keap1-Nrf2 protein-protein interaction, a particularly challenging target due to its highly polar binding site. The inhibitor displays cellular efficacy and is well-positioned for further optimization based on the structure of its complex with Keap1 and synthetic access. We believe that our work will spur interest in using macrocyclic cores for in silico -based lead generation and also inspire the design of future macrocycle screening collections.

An increasing number of drug discovery programs concern compounds in the beyond rule of 5 (bRo5) chemical space, such as cyclic peptides, macrocycles, and degraders. Recent results show that common paradigms of property-based drug design need revision to be applied to larger and more flexible compounds. A virtual event entitled "Solubility, permeability and physico-chemical properties in the bRo5 chemical space" was organized to provide preliminary guidance on how to make the discovery of oral drugs in the bRo5 space more effective. The four speakers emphasized the importance of the bRo5 space as a source of new oral drugs and provided examples of experimental and computational methods specifically tailored for design and optimization in this chemical space., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Macrocycles constitute superior ligands for targets that have flat binding sites but often require long synthetic routes, emphasizing the need for property prediction prior to synthesis. We have investigated the scope and limitations of machine learning classification models and of regression models for predicting the cell permeability of a set of denovo-designed, drug-like macrocycles. 2D-Based classification models, which are fast to calculate, discriminated between macrocycles that had low-medium and high permeability and may be used as virtual filters in early drug discovery projects. Importantly, stereo- and regioisomer were correctly classified. QSPR studies of two small sets of comparator drugs suggested that use of 3D descriptors, calculated from biologically relevant conformations, would allow development of more precise regression models for late phase drug projects. However, a 3D permeability model could only be developed for a rigid series of macrocycles. Comparison of NMR based conformational analysis with in silico conformational sampling indicated that this shortcoming originates from the inability of the molecular mechanics force field to identify the relevant conformations for flexible macrocycles. We speculate that a Kier flexibility index of ≤10 constitutes a current upper limit for reasonably accurate 3D prediction of macrocycle cell permeability., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent coronavirus outbreaks of SARS-CoV-1 (2002-2003), MERS-CoV (since 2012), and SARS-CoV-2 (since the end of 2019) are examples of how viruses can damage health care and generate havoc all over the world. Coronavirus can spread quickly from person to person causing high morbidity and mortality. Unfortunately, the antiviral armamentarium is insufficient to fight these infections. In this chapter, we provide a detailed summary of the current situation in the development of drugs directed against pandemic human coronaviruses. Apart from the recently licensed remdesivir, other antiviral agents discussed in this review include molecules targeting viral components (e.g., RNA polymerase inhibitors, entry inhibitors, or protease inhibitors), compounds interfering with virus-host interactions, and drugs identified in large screening assays, effective against coronavirus replication, but with an uncertain mechanism of action., (© 2021. The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.)

Proteolysis targeting chimeras (PROTACs) induce intracellular degradation of target proteins. Their bifunctional structure puts degraders in a chemical space where ADME properties often complicate drug discovery. Herein we provide the first structural insight into PROTAC cell permeability obtained by NMR studies of a VHL-based PROTAC ( 1 ), which is cell permeable despite having a high molecular weight and polarity and a large number of rotatable bonds. We found that 1 populates elongated and polar conformations in solutions that mimic extra- and intracellular compartments. Conformations were folded and had a smaller polar surface area in chloroform, mimicking a cell membrane interior. Formation of intramolecular and nonclassical hydrogen bonds, π-π interactions, and shielding of amide groups from solvent all facilitate cell permeability by minimization of size and polarity. We conclude that molecular chameleonicity appears to be of major importance for 1 to enter into target cells., Competing Interests: The authors declare the following competing financial interest(s): D.G. is an employee of Nuvisan Innovation Campus Berlin GmbH. A.G and D.M. are employees of Bayer AG., (© 2020 The Authors. Published by American Chemical Society.)

Modelling the solubility of compounds in the "beyond Rule of 5" (bRo5) chemical space is in its infancy and to date only a few studies have been reported in the literature. Based on our own results, and those already published, we conclude that consideration of conformational flexibility and chameleon like behaviour is important, but quantitative models that account for these properties remain to be developed. Inclusion of 3D information appears to be somewhat less important than for cell permeability and extremely challenging due to the difficulties of accurate conformational sampling in the bRo5 space. Currently, methods for modelling of solubility will have to be tailored to the set of investigated compounds., Competing Interests: Conflict of interest: None., (Copyright © 2020 by the authors.)

It has been hypothesised that drugs in the chemical space "beyond the rule of 5" (bRo5) must behave as molecular chameleons to combine otherwise conflicting properties, including aqueous solubility, cell permeability and target binding. Evidence for this has, however, been limited to the cyclic peptide cyclosporine A. Herein, we show that the non-peptidic and macrocyclic drugs roxithromycin, telithromycin and spiramycin behave as molecular chameleons, with rifampicin showing a less pronounced behaviour. In particular roxithromycin, telithromycin and spiramycin display a marked, yet limited flexibility and populate significantly less polar and more compact conformational ensembles in an apolar than in a polar environment. In addition to balancing of membrane permeability and aqueous solubility, this flexibility also allows binding to targets that vary in structure between species. The drugs' passive cell permeability correlates to their 3D polar surface area and corroborate two theoretical models for permeability, developed for cyclic peptides. We conclude that molecular chameleonicity should be incorporated in the design of orally administered drugs in the bRo5 space., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme which regulates the methylation of Lys4 of histone 3 (H3) and is overexpressed in certain cancers. We used structures of H3 substrate analogues bound to LSD1 to design macrocyclic peptide inhibitors of LSD1. A linear, Lys4 to Met-substituted, 11-mer ( 4 ) was identified as the shortest peptide distinctly interacting with LSD1. It was evolved into macrocycle 31, which was >40 fold more potent ( K i = 2.3 μM) than 4 . Linear and macrocyclic peptides exhibited unexpected differences in structure-activity relationships for interactions with LSD1, indicating that they bind LSD1 differently. This was confirmed by the crystal structure of 31 in complex with LSD1-CoREST1, which revealed a novel binding mode at the outer rim of the LSD1 active site and without a direct interaction with FAD. NMR spectroscopy of 31 suggests that macrocyclization restricts its solution ensemble to conformations that include the one in the crystalline complex. Our results provide a solid basis for the design of optimized reversible LSD1 inhibitors., Competing Interests: The authors declare the following competing financial interest(s): M. G. is an employee of Beactica AB., (Copyright © 2020 American Chemical Society.)

Side-chain oxidized cholesterol derivatives, like 25-hydroxycholesterol (25-OH-Chol) are important regulators of cellular cholesterol homeostasis. How transport of oxysterols through the endo-lysosomal pathway contributes to their biological function is not clear. The Niemann-Pick C2 protein (NPC2) is a small lysosomal sterol transfer protein required for export of cholesterol from late endosomes and lysosomes (LE/LYSs). Here, we show that 25-hydroxy-cholestatrienol, (25-OH-CTL), an intrinsically fluorescent analogue of 25-OH-Chol, becomes trapped in LE/LYSs of NPC2-deficient fibroblasts, but can efflux from the cells even in the absence of NPC2 upon removal of the sterol source. Fluorescence recovery after photobleaching (FRAP) of 25-OH-CTL in endo-lysosomes was rapid and extensive and only partially dependent on NPC2 function. Using quenching of NPC2's intrinsic fluorescence, we show that 25-OH-Chol and 25-OH-CTL can bind to NPC2 though with lower affinity compared to cholesterol and its fluorescent analogues, cholestatrienol (CTL) and dehydroergosterol (DHE). This is confirmed by calculations of binding energies which additionally show that 25-OH-CTL can bind in two orientations to NPC2, in stark contrast to cholesterol and its analogues. We conclude that NPC2's affinity for all sterols is energetically favored over their self-aggregation in the lysosomal lumen. Lysosomal export of 25-OH-Chol is not strictly dependent on the NPC2 protein., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Drugs in the chemical space beyond the rule of 5 (bRo5) can modulate targets with difficult binding sites while retaining cell permeability and oral absorption. Reviewing the syntheses of bRo5 drugs approved since 1990 highlights synthetic chemistry's contribution to drug discovery in this space. Initially, bRo5 drugs were mainly natural products and semi-synthetic derivatives. Later, peptidomimetics and de novo designed compounds, that include up to seven chiral centres and macrocyclic rings became dominant. These drugs are prepared by total synthesis, sometimes by routes of more than 25 steps with stereocentres originating from the chiral pool, or being installed by chiral induction or enzymatic resolution. Interestingly, ring-closing metathesis proved to be the method of choice for macrocyclisation in hepatitis C virus protease inhibitors. We conclude that structural simplification, planning of synthetic routes regarding incorporation of stereocentres and macrocyclisation, as well as incorporation of structural knowledge and consideration of chameleonic properties in design, should facilitate drug discovery in bRo5 space., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The replica exchange molecular dynamics (REMD) simulation is demonstrated to readily predict the conformations of the macrocyclic drug lorlatinib, as validated by solution NMR studies. In aqueous solution, lorlatinib adopts a conformer identical to its target bound structure. This conformer is stabilized by an extensive hydrogen bond network to the solvents. In chloroform, lorlatinib populates two conformers with the second one being less polar, which may contribute to lorlatinib's ability to cross cell membranes., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

Niemann-Pick C1 like 1 (NPC1L1) is a sterol transporter expressed in the apical membrane of enterocytes and hepatocytes. NPC1L1 resembles the lysosomal NPC1 protein including an N-terminal domain (NTD), which binds a variety of sterols. The molecular mechanisms underlying this multiligand specificity of the NTD of NPC1L1 (NPC1L1-NTD) are not known. On the basis of the crystal structure of NPC1L1-NTD, we have investigated the structural details of protein-sterol interactions using molecular mechanics Poisson Boltzmann surface area calculations here. We found a good agreement between experimental and calculated binding affinities with similar ranking of various sterol ligands. We defined hydrogen bonding of sterol ligands via the 3'-β-hydroxy group inside the binding pose as instrumental in stabilizing the interaction. A leucine residue (LEU213) at the mouth of the binding pocket transiently opens to allow for the access of sterol into the binding pose. Our calculations also predict that NPC1L1-NTD binds polyene sterols, such as dehydroergosterol or cholestatrienol with high affinity, which validates their use in future experiments as close intrinsically fluorescent cholesterol analogs. A free energy decomposition and computational mutation analysis revealed that the binding of various sterols to NPC1L1-NTD depends critically on specific amino acid residues within the binding pocket. Some of these residues were previously detected as being relevant for intestinal cholesterol absorption. We show that clinically known mutations in the NPC1L1-NTD associated with lowered risk of coronary heart disease result in strongly reduced binding energies, providing a molecular explanation for the clinical phenotype., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

Introducing novel strategies, concepts, and technologies that speed up drug discovery and the drug development cycle is of great importance both in the highly competitive pharmaceutical industry as well as in academia. This Perspective aims to present a "big-picture" overview of recent strategic innovations in medicinal chemistry and drug discovery.

Solvent-exposed regions, or solvent-filled pockets, within or adjacent to the ligand-binding sites of drug-target proteins provide opportunities for substantial modifications of existing small-molecular drug molecules without serious loss of activity. In this review, we present recent selected examples of exploitation of solvent-exposed regions of proteins in drug design and development from the recent medicinal-chemistry literature., (© 2019 Wiley Periodicals, Inc.)

Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains as the only enzyme encoded within the viral genome not targeted by current antiviral drugs. In this work, we report the design, synthesis, and biologic evaluation of a novel series of galloyl derivatives with HIV-1 RNase H inhibitory activity. Most of them showed IC 50 s at sub- to low-micromolar concentrations in enzymatic assays. The most potent compound was II-25 that showed an IC 50 of 0.72 ± 0.07 μM in RNase H inhibition assays carried out with the HIV-1 BH 10 RT. II-25 was 2.8 times more potent than β-thujaplicinol in these assays. Interestingly, II-25 and other galloyl derivatives were also found to inhibit the HIV IN strand transfer activity in vitro. Structure-activity relationships (SAR) studies and molecular modeling analysis predict key interactions with RT residues His539 and Arg557, while providing helpful insight for further optimization of selected compounds., (© 2018 John Wiley & Sons A/S.)

Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five subseries of oseltamivir derivatives were designed and synthesized to improve their activity toward drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases (NAs). The bioassay results showed that compound 21h exhibited antiviral activities similar to or better than those of oseltamivir carboxylate (OSC) against H5N1, H5N2, H5N6, and H5N8. Besides, 21h was 5- to 86-fold more potent than OSC toward N1, N8, and N1-H274Y mutant NAs in the inhibitory assays. Computational studies provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated acceptable oral bioavailability, low acute toxicity, potent antiviral activity in vivo, and high metabolic stability. Overall, the above excellent profiles make 21h a promising drug candidate for the treatment of influenza virus infection.

Conformational flexibility is a major determinant of the properties of macrocycles and other drugs in beyond rule of 5 (bRo5) space. Prediction of conformations is essential for design of drugs in this space, and we have evaluated three tools for conformational sampling of a set of 10 bRo5 drugs and clinical candidates in polar and apolar environments. The distance-geometry based OMEGA was found to yield ensembles spanning larger structure and property spaces than the ensembles obtained by MOE-LowModeMD (MOE) and MacroModel (MC). Both MC and OMEGA but not MOE generated different ensembles for polar and apolar environments. All three conformational search methods generated conformers similar to the crystal structure conformers for 9 of the 10 compounds, with OMEGA performing somewhat better than MOE and MC. MOE and OMEGA found all six conformers of roxithromycin that were identified by NMR in aqueous solutions, whereas only OMEGA sampled the three conformers observed in chloroform. We suggest that characterization of conformers using molecular descriptors, e.g., the radius of gyration and polar surface area, is preferred to energy- or root-mean-square deviation-based methods for selection of biologically relevant conformers in drug discovery in bRo5 space., Competing Interests: The authors declare no competing financial interest.

A series of macrocycles inspired by natural products were synthesized to investigate how side-chains may shield amide bonds and influence cell permeability. NMR spectroscopy and X-ray crystallography revealed that the phenyl group of phenylalanine, but not the side-chains of homologous or aliphatic amino acids, shields the adjacent amide bond through an intramolecular NH-π interaction. This resulted in increased cell permeability, suggesting that NH-π interactions may be used in the design of molecular chameleons.

On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.

Recent years have seen a dramatic increase in the number of drugs approved in chemical space outside of Lipinski's rule of 5, that is in what has been termed beyond rule of 5 (bRo5) space. The development of three major classes of oral drugs that treat HIV and HCV infections and the growing evidence that novel, difficult targets can be accessed has prompted research into understanding design of drugs displaying cell permeability, solubility and ultimately oral bioavailability in bRo5 space. Studies have found a consistent outer property limit for a reasonable chance of de novo designing oral bioavailability. In addition, several property-based guidelines, along with incorporation of chameleonic features, have emerged as strategies to aid design in bRo5 space. A more detailed understanding of the complex and environment dependent conformational landscape will likely be the focus of the next generation of guidelines allowing property predictions of ever more complex compounds. By pushing the boundaries of current orally designable chemical space we hope that discoveries will be made for fundamental science and also for discovery of novel therapeutics., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Conformational flexibility has been proposed to significantly affect drug properties outside rule-of-5 (Ro5) chemical space. Here, we investigated the influence of dynamically exposed polarity on cell permeability and aqueous solubility for a structurally diverse set of drugs and clinical candidates far beyond the Ro5, all of which populated multiple distinct conformations as revealed by X-ray crystallography. Efflux-inhibited (passive) Caco-2 cell permeability correlated strongly with the compounds' minimum solvent-accessible 3D polar surface areas (PSA), whereas aqueous solubility depended less on the specific 3D conformation. Inspection of the crystal structures highlighted flexibly linked aromatic side chains and dynamically forming intramolecular hydrogen bonds as particularly effective in providing "chameleonic" properties that allow compounds to display both high cell permeability and aqueous solubility. These structural features, in combination with permeability predictions based on the correlation to solvent-accessible 3D PSA, should inspire drug design in the challenging chemical space far beyond the Ro5.

Persistent HIV infection requires lifelong treatment and among the 2.1 million new HIV infections that occur every year there is an increased rate of transmitted drug-resistant mutations. This fact requires a constant and timely effort in order to identify and develop new HIV inhibitors with innovative mechanisms. The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only viral encoded enzyme that still lacks an efficient inhibitor despite the fact that it is a well-validated target whose functional abrogation compromises viral infectivity. Identification of new drugs is a long and expensive process that can be speeded up by in silico methods. In the present study, a structure-guided screening is coupled with a similarity-based search on the Specs database to identify a new class of HIV-1 RNase H inhibitors. Out of the 45 compounds selected for experimental testing, 15 inhibited the RNase H function below 100 μM with three hits exhibiting IC 50 values <10 μM. The most active compound, AA , inhibits HIV-1 RNase H with an IC 50 of 5.1 μM and exhibits a Mg-independent mode of inhibition. Site-directed mutagenesis studies provide valuable insight into the binding mode of newly identified compounds; for instance, compound AA involves extensive interactions with a lipophilic pocket formed by Ala502, Lys503, and Trp (406, 426 and 535) and polar interactions with Arg557 and the highly conserved RNase H primer-grip residue Asn474. The structural insights obtained from this work provide the bases for further lead optimization.

We report herein the design and synthesis of a series of 11 novel tacrine-1,2,3-triazole derivatives via a Cu(i)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction. The newly synthesized compounds were evaluated for their inhibition activity against Electrophorus electricus acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BChE) as potential drug targets for Alzheimer's disease (AD). Among the designed compounds, compound 8a2 exhibited potent inhibition against AChE and BChE with IC 50 values of 4.89 μM and 3.61 μM, respectively. Further structure-activity relationship (SAR) and molecular modeling studies may provide valuable insights into the design of better tacrine-triazole analogues with potential therapeutic applications for AD.

Background: Design of inhibitors for HIV-1 reverse transcriptase inhibition (HIV-1 RT) is one of the successful chemotherapies for the treatment of HIV infection. Among the inhibitors available for HIV-1 RT, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have shown to be very promising and clinically approved drugs. However, the efficiency of many of these drugs has been reduced by the drug-resistant variants of HIV-1 RT. The aim of the current review is to provide a summary of lead optimization strategies from the 3D-QSARs studies on NNRTI class from the past 21 years (1995 to 2016)., Methods: The conformation dependent-alignment based (CoMFA and CoMSIA) methods have been proven very successful ligand based strategy in the drug design. Here, CoMFA and CoMSIA studies reported for structurally distinct NNRTIs including thiazolobenzimidazole, dipyridodiazepinone, 1,1,3-trioxo [1,2,4]-thiadiazine, formimidoester disulfides, thiocarbamate, thiazolidinone derivatives, etc. have been discussed in detail. In addition, we explore the position of the functional groups that drive the protein-ligand interaction., Results: The structure-activity relationship (SAR) revealed from CoMFA and CoMSIA studies of these drug classes is not only in agreement with the structure-based method but also provides an efficient way of lead optimization. In addition to molecular docking experiments, protein-ligand interaction fingerprints were calculated in order to understand the common binding mode of NNRTI compounds., Conclusion: Overall, this review enlightens the protein-ligand interactions with a detailed SAR discussion for chemotypes. Such discussion will help medicinal chemist to gain a better understanding for the design of novel and promising NNRTI candidates., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)