Drug Promiscuity Research Articles

Synapse-Specific Trapping of SNARE Machinery Proteins in the Anesthetized Drosophila Brain.

General anesthetics disrupt brain network dynamics through multiple pathways, in part through postsynaptic potentiation of inhibitory ion channels as well as presynaptic inhibition of neuroexocytosis. Common clinical general anesthetic drugs, such as propofol and isoflurane, have been shown to interact and interfere with core components of the exocytic release machinery to cause impaired neurotransmitter release. Recent studies however suggest that these drugs do not affect all synapse subtypes equally. We investigated the role of the presynaptic release machinery in multiple neurotransmitter systems under isoflurane general anesthesia in the adult female Drosophila brain using live-cell super-resolution microscopy and optogenetic readouts of exocytosis and neural excitability. We activated neurotransmitter-specific mushroom body output neurons and imaged presynaptic function under isoflurane anesthesia. We found that isoflurane impaired synaptic release and presynaptic protein dynamics in excitatory cholinergic synapses. In contrast, isoflurane had little to no effect on inhibitory GABAergic or glutamatergic synapses. These results present a distinct inhibitory mechanism for general anesthesia, whereby neuroexocytosis is selectively impaired at excitatory synapses, while inhibitory synapses remain functional. This suggests a presynaptic inhibitory mechanism that complements the other inhibitory effects of these drugs.

Mengatasi Kenakalan Remaja Melalui Pendidikan Agama Islam: Peran Guru yang Signifikan di SMP Negeri 26 Makassar

In today’s world, juvenile deliquency is becoming an increasingly troubling social problem. These trends often include acts such as drug use, fighting, promiscuity, and other illegal activities. Teachers play an important role in addresing this problem in the context of islamic education. Knowing students is a very important and interesting issue to discuss because someone whose name is student is part of the younger generation and in the eyes of natioon, state and religion. In this study, researchers use a qualitative descriptive approach, which is a research procedure based on descriptive data in the form of oral or written words from reseach subjects or informants who have been observed and have the characteristics that the data provided is original data according to situations and conditions that cannot be manipulated and uses systematic and accountable methods. Based on the results of research obtained by reseachers through observation and interviews with informants, there are several forms of juvenile delinquency that occur in SMP Negri 26 Makassar : 1) noisy in class during class hours, 2) this turbing friends who are focused on learning activities, 3) after skipping lessons, 4) smoking. The eforts of religus education teachers in overcoming students delinquency are to pay more attention to children who are especially “naughty” (seeking attention).

Proteome level analysis of drug-resistant Prevotella melaninogenica for the identification of novel therapeutic candidates.

The management of infectious diseases has become more critical due to the development of novel pathogenic strains with enhanced resistance. Prevotella melaninogenica, a gram-negative bacterium, was found to be involved in various infections of the respiratory tract, aerodigestive tract, and gastrointestinal tract. The need to explore novel drug and vaccine targets against this pathogen was triggered by the emergence of antimicrobial resistance against reported antibiotics to combat P. melaninogenica infections. The study involves core genes acquired from 14 complete P. melaninogenica strain genome sequences, where promiscuous drug and vaccine candidates were explored by state-of-the-art subtractive proteomics and reverse vaccinology approaches. A stringent bioinformatics analysis enlisted 18 targets as novel, essential, and non-homologous to humans and having druggability potential. Moreover, the extracellular and outer membrane proteins were subjected to antigenicity, allergenicity, and physicochemical analysis for the identification of the candidate proteins to design multi-epitope vaccines. Two candidate proteins (ADK95685.1 and ADK97014.1) were selected as the best target for the designing of a vaccine construct. Lead B- and T-cell overlapped epitopes were joined to generate potential chimeric vaccine constructs in combination with adjuvants and linkers. Finally, a prioritized vaccine construct was found to have stable interactions with the human immune cell receptors as confirmed by molecular docking and MD simulation studies. The vaccine construct was found to have cloning and expression ability in the bacterial cloning system. Immune simulation ensured the elicitation of significant immune responses against the designed vaccine. In conclusion, our study reported novel drug and vaccine targets and designed a multi-epitope vaccine against the P. melaninogenica infection. Further experimental validation will help open new avenues in the treatment of this multi-drug-resistant pathogen.

Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles

Alkyl isonitriles, R—NC, have previously been shown to ligate the heme (haem) iron of cytochromes P450 in both accessible oxidation states (ferrous, Fe2+, and ferric, Fe3+). Herein, the preparation of four steroid-derived isonitriles and their interactions with several P450s, including the steroidogenic CYP17A1 and CYP106A2, as well as the more promiscuous drug metabolizers CYP3A4 and CYP2D6, is described. It was found that successful ligation of the heme iron by the isonitrile functionality for a given P450 depends on both the position and stereochemistry of the isonitrile on the steroid skeleton. Spectral studies indicate that isonitrile ligation of the ferric heme is stable upon reduction to the ferrous form, with reoxidation resulting in the original complex. A crystallographic structure of CYP17A1 with an isonitrile derived from pregnanalone further confirmed the interaction and identified the absolute stereochemistry of the bound species.

Pharmacological profiling identifies divergent chemosensitivities of differentiating and maturing iPSC-derived human cortical neuron populations.

Neuronal differentiation and maturation are extended developmental processes. To determine whether neurons at different developmental stages have divergent chemosensitivities, we screened differentiating and maturing neuronal populations using a small compound library comprising FDA-approved and investigational drugs. Using a neurotoxicity assay format, both respective neuronal population-based screening campaigns performed robustly (Z-factors = 0.7-0.8), although the hit rate for the differentiating neurons (2.8%) was slightly higher than for maturing neurons (1.9%). While the majority of hits were toxic to both neuronal populations, these hits predominantly represented promiscuous drugs. Other drugs were selectively neurotoxic, with receptor tyrosine kinase inhibitors disproportionally represented after confirmation. Ponatinib and amuvatinib were neuroinhibitory for differentiating and maturing neurons, respectively. Chemoinformatic analyses confirmed differences in potential drug targets that may be differentially expressed during neuronal development. Subsequent studies demonstrated neuronal expression of AXL, an amuvatinib target, in both neuronal populations. However, functional AXL activity was confirmed only in the maturing neuronal population as determined by AXL phosphorylation in response to GAS6, the cognate ligand of AXL, and concurrent STAT3Y705 phosphorylation. Differentiating neurons were unresponsive to the effects of GAS6 suggesting that the AXL-STAT3 signaling axis was nonfunctional. Amuvatinib treatment of maturing neuronal cultures significantly reduced pAXL levels. These studies indicate that neuronal developmental states may exhibit unique chemosensitivities and that drugs may have different neuro-inhibitory effects depending upon the developmental stage of the neuronal population.

Activity Models of Key GPCR Families in the Central Nervous System: A Tool for Many Purposes.

G protein-coupled receptors (GPCRs) are targets of many drugs, of which ∼25% are indicated for central nervous system (CNS) disorders. Drug promiscuity affects their efficacy and safety profiles. Predicting the polypharmacology profile of compounds against GPCRs can thus provide a basis for producing more precise therapeutics by considering the targets and the anti-targets in that family of closely related proteins. We provide a tool for predicting the polypharmacology of compounds within prominent GPCR families in the CNS: serotonin, dopamine, histamine, muscarinic, opioid, and cannabinoid receptors. Our in-house algorithm, "iterative stochastic elimination" (ISE), produces high-quality ligand-based models for agonism and antagonism at 31 GPCRs. The ISE models correctly predict 68% of CNS drug-GPCR interactions, while the "similarity ensemble approach" predicts only 33%. The activity models correctly predict 56% of reported activities of DrugBank molecules for these CNS receptors. We conclude that the combination of interactions and activity profiles generated by screening through our models form the basis for subsequent designing and discovering novel therapeutics, either single, multitargeting, or repurposed.

Casting a Wider Net When Fishing for Mechanisms of Anesthesia.

Casting a Wider Net When Fishing for Mechanisms of Anesthesia.

HMM-based profiling identifies the binding to divalent cations and nucleotides as common denominators of suramin targets

Introduction: Suramin is one of the pharmacopeia’s most promiscuous drugs. Originally developed for African trypanosomiasis, suramin was also used for onchocerciasis and it has been proposed as an anticancer agent, antiviral drug, therapy for arthritis, autism, and antidote for snake bites. Target proteins of suramin have been described from different species. Here we identify the common motifs among these various targets, aiming to explain the promiscuous nature of suramin.Methods: We have searched for suramin target proteins in the literature and in chemical databases. Applying rigorous inclusion criteria, a list of 44 diverse proteins was assembled with experimental evidence for direct interaction with, and inhibition by, suramin. Hidden Markov model-based target profiling was performed by running the full set of Pfam protein family domains against these proteins.Results: Common denominators were identified by mapping the identified Pfam domains to molecular function gene ontology terms. This in silico pipeline identified nucleotide binding, nucleic acid binding, and binding to divalent cations as the most common denominators of the suramin targets.Discussion: Our results suggest that the extraordinary polypharmacology of suramin may be caused by its ability to inhibit the interaction of proteins with nucleotides or nucleic acids and with divalent cations (Mg2+, Ca2+, Zn2+). Suramin is well known to inhibit nucleotide receptors and nucleic acid-binding enzymes. The association with divalent cations is new and might be key towards the design of better, more selective inhibitors.

MmpL3 Inhibition as a Promising Approach to Develop Novel Therapies against Tuberculosis: A Spotlight on SQ109, Clinical Studies, and Patents Literature.

Tuberculosis (TB) is accountable for considerable global morbidity and mortality. Effective TB therapy with multiple drugs completes in about six months. The longer duration of TB therapy challenges patient compliance and contributes to treatment collapse and drug resistance (DR) progress. Therefore, new medications with an innovative mechanism of action are desperately required to shorten the TB therapy's duration and effective TB control. The mycobacterial membrane protein Large 3 (MmpL3) is a novel, mycobacteria-conserved and recognized promiscuous drug target used in the development of better treatments for multi-drug resistance TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). This article spotlights MmpL3, the clinical studies of its inhibitor (SQ109), and the patent literature. The literature on MmpL3 inhibitors was searched on PubMed and freely available patent databases (Espacenet, USPTO, and PatentScope). SQ109, an analog of ethambutol (EMB), is an established MmpL3 inhibitor and has completed Phase 2b-3 clinical trials. Infectex and Sequella are developing orally active SQ109 in partnership to treat MDR pulmonary TB. SQ109 has demonstrated activity against drug-sensitive (DS) and drug-resistant (DR) Mycobacterium tuberculosis (Mtb) and a synergistic effect with isoniazid (INH), rifampicin (RIF), clofazimine (CFZ), and bedaquiline (BNQ). The combination of SQ109, clofazimine, bedaquiline, and pyrazinamide (PZA) has been patented due to its excellent anti-TB activity against MDR-TB, XDR-TB, and latent-TB. The combinations of SQ109 with other anti-TB drugs (chloroquine, hydroxychloroquine, and sutezolid) have also been claimed in the patent literature. SQ109 is more potent than EMB and could substitute EMB in the intensive stage of TB treatment with the three- or four-drug combination. Developing MmpL3 inhibitors is a promising approach to fighting the challenges associated with DS-TB and DR-TB. The authors foresee MmpL3 inhibitors such as SQ109 as future drugs for TB treatment.

Stigma, discrimination and HIV or AIDS: an empirical investigation of Asian immigrants and refugees in Canada

PurposeHIV or AIDS remains invisible and dismissed by most South Asians living in Canada as HIV or AIDS issues are perceived as an offshoot of Western lifestyle linked with drug use and promiscuity. This paper aims to look into how people living with HIV or AIDS (PLWHA) cope with prejudice and stigma.Design/methodology/approachTo guide this research, a constructivist grounded theory approach was adopted as the theoretical and methodological framework. The authors reached the participants through a Toronto-based group that works with PLWHA. The authors chose their respondents in a snowball method and interviewed them both in person and online.FindingsThis paper identifies how South Asian immigrants and refugees/refugees with HIV or AIDS claimants are vulnerable to discrimination in Canada due to the following factors, which include but are not limited to: a lack of information about HIV and AIDS incidence in the community; and the Canadian health system's inability to respond appropriately to the lack of information.Practical implicationsHIV service engagements should take place within the context of a constellation of local traditions, or standardized expectations of patient engagement with HIV services can be counterproductive.Originality/valueIt is critical that governmental action prioritizes increasing public understanding of stigma. To minimize the consequences of HIV-related discrimination and stigma, misconceptions about HIV transmission must be debunked.

Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists.

Fatty acid mimetics (FAM) are bioactive molecules acting through the binding sites of endogenous fatty acid metabolites on enzymes, transporters, and receptors. Due to the special characteristics of these binding sites, FAMs share common chemical features. Pharmacological modulation of fatty acid signaling has therapeutic potential in multiple pathologies, and several FAMs have been developed as drugs. We aimed to elucidate the promiscuity of FAM drugs on lipid-activated transcription factors and tested 64 approved compounds for activation of RAR, PPARs, VDR, LXR, FXR, and RXR. The activity screening revealed nuclear receptor agonism of several FAM drugs and considerable promiscuity of NSAIDs, while other compound classes evolved as selective. These screening results were not anticipated by three well-established target prediction tools, suggesting that FAMs are underrepresented in bioactivity data for model development. The screening dataset may therefore valuably contribute to such tools. Oxaprozin (RXR), tianeptine (PPARδ), mycophenolic acid (RAR), and bortezomib (RAR) exhibited selective agonism on one nuclear receptor and emerged as attractive leads for the selective optimization of side activities. Additionally, their nuclear receptor agonism may contribute relevant and valuable polypharmacology.

NILAI-NILAI PENDIDIKAN AKHLAK DI DALAM KITAB AL-RISALATUL QUSYARIYAH

Reality in people's lives proves that education is not able to produce quality output evenly. Evidenced by the still many crimes occur in the community, for example stealing, children against their parents, the rise of drug users, murder, adultery, gambling, brawl, sexual harassment, promiscuity, and many other crimes. Drug abuse has increased from time to time in Indonesia This study aims to determine the values ​​of moral education according to Imam Qusyairi in the book Ar Risalatul Qusyairiyah. This type of research is library research and qualitative descriptive approach. Research Results The values ​​of moral education contained in this book are sincere, repentant, trustworthy, patient, happy, glorifying teachers, friendship The application of moral education values ​​in learning both formal, non-formal, and informal is guiding students to have quality faith, piety and noble character.

Characterizing the Relationship Between the Chemical Structures of Drugs and their Activities on Primary Cultures of Pediatric Solid Tumors

Despite continued efforts to develop new treatments, there is an urgent need to discover new drug leads to treat tumors exhibiting primary or secondary resistance to existing drugs. Cell cultures derived from patient-derived orthotopic xenografts are promising pre-clinical models to better predict drug response in cancer recurrence. The aim of the study was to investigate the relationship between the physiochemical properties of drugs and their in vitro potency as well as identifying chemical scaffolds biasedtowards selectivity or promiscuity of such drugs. The bioactivities of 158 drugs screened against cell cultures derived from 30 cancer orthotopic patient-derived xenograft (O-PDX) models were considered. Drugs were represented by physicochemical descriptors and chemical structure fingerprints. Supervised learning was employed to model the relationship between features and in vitro potency. Drugs with in vitro potency for alveolar rhabdomyosarcoma and osteosarcoma tend to have a higher number of rings, two carbon-hetero bonds and halogens. Selective and promiscuous scaffolds for these phenotypic targets were identified. Highly-predictive models of in vitro potency were obtained across these 30 targets, which can be applied to unseen molecules via a webserver (https://rnewbie.shinyapps.io/Shobek-master). It is possible to identify privileged chemical scaffolds and predict the in vitro potency of unseen molecules across these 30 targets This information and models should be helpful to select which molecules to screen against these primary cultures of pediatric solid tumors.

The Structure and Mechanism of Drug Transporters.

Drug transporters are integral membrane proteins that play a critical role in drug disposition by affecting absorption, distribution, and excretion. They translocate drugs, as well as endogenous molecules and toxins, across membranes using ATP hydrolysis, or ion/concentration gradients. In general, drug transporters are expressed ubiquitously, but they function in drug disposition by being concentrated in tissues such as the intestine, the kidneys, the liver, and the brain. Based on their primary sequence and their mechanism, transporters can be divided into the ATP-binding cassette (ABC), solute-linked carrier (SLC), and the solute carrier organic anion (SLCO) superfamilies. Many X-ray crystallography and cryo-electron microscopy (cryo-EM) structures have been solved in the ABC and SLC transporter superfamilies or of their bacterial homologs. The structures have provided valuable insight into the structural basis of transport. This chapter will provide particular focus on the promiscuous drug transporters because of their effect on drug disposition and the challenges associated with them.

Biological Profiling Enables Rapid Mechanistic Classification of Phenotypic Screening Hits and Identification of KatG Activation-Dependent Pyridine Carboxamide Prodrugs With Activity Against Mycobacterium tuberculosis.

Compounds with novel modes of action are urgently needed to develop effective combination therapies for the treatment of tuberculosis. In this study, a series of compounds was evaluated for activity against replicating Mycobacterium tuberculosis and Vero cell line toxicity. Fourteen of the compounds with in vitro activities in the low micrometer range and a favorable selectivity index were classified using reporter strains of M. tuberculosis which showed that six interfered with cell wall metabolism and one disrupted DNA metabolism. Counter-screening against strains carrying mutations in promiscuous drug targets argued against DprE1 and MmpL3 as hits of any of the cell wall actives and eliminated the cytochrome bc 1 complex as a target of any of the compounds. Instead, whole-genome sequencing of spontaneous resistant mutants and/or counter-screening against common isoniazid-resistant mutants of M. tuberculosis revealed that four of the six cell wall-active compounds, all pyridine carboxamide analogues, were metabolized by KatG to form InhA inhibitors. Resistance to two of these compounds was associated with mutations in katG that did not confer cross-resistance to isoniazid. Of the remaining seven compounds, low-level resistance to one was associated with an inactivating mutation in Rv0678, the regulator of the MmpS5-MmpL5 system, which has been implicated in non-specific efflux of multiple chemotypes. Another mapped to the mycothiol-dependent reductase, Rv2466c, suggesting a prodrug mechanism of action in that case. The inability to isolate spontaneous resistant mutants to the seven remaining compounds suggests that they act via mechanisms which have yet to be elucidated.

Drugs, host proteins and viral proteins: how their promiscuities shape antiviral design.

The reciprocal nature of drug specificity and target specificity implies that the same is true for their respective promiscuities. Protein promiscuity has two broadly different types of footprint in drug design. The first is relaxed specificity of binding sites for substrates, inhibitors, effectors or cofactors. The second involves protein-protein interactions of regulatory processes such as signal transduction and transcription, and here protein intrinsic disorder plays an important role. Both viruses and host cells exploit intrinsic disorder for their survival, as do the design and discovery programs for antivirals. Drug action, strictly speaking, always relies upon promiscuous activity, with drug promiscuity enlarging its scope. Drug repurposing searches for additional promiscuity on the part of both the drug and the target in the host. Understanding the subtle nuances of these promiscuities is critical in the design of novel and more effective antivirals.

Structure-based drug repositioning explains ibrutinib as VEGFR2 inhibitor.

Many drugs are promiscuous and bind to multiple targets. On the one hand, these targets may be linked to unwanted side effects, but on the other, they may achieve a combined desired effect (polypharmacology) or represent multiple diseases (drug repositioning). With the growth of 3D structures of drug-target complexes, it is today possible to study drug promiscuity at the structural level and to screen vast amounts of drug-target interactions to predict side effects, polypharmacological potential, and repositioning opportunities. Here, we pursue such an approach to identify drugs inactivating B-cells, whose dysregulation can function as a driver of autoimmune diseases. Screening over 500 kinases, we identified 22 candidate targets, whose knock out impeded the activation of B-cells. Among these 22 is the gene KDR, whose gene product VEGFR2 is a prominent cancer target with anti-VEGFR2 drugs on the market for over a decade. The main result of this paper is that structure-based drug repositioning for the identified kinase targets identified the cancer drug ibrutinib as micromolar VEGFR2 inhibitor with a very high therapeutic index in B-cell inactivation. These findings prove that ibrutinib is not only acting on the Bruton’s tyrosine kinase BTK, against which it was designed. Instead, it may be a polypharmacological drug, which additionally targets angiogenesis via inhibition of VEGFR2. Therefore ibrutinib carries potential to treat other VEGFR2 associated disease. Structure-based drug repositioning explains ibrutinib’s anti VEGFR2 action through the conservation of a specific pattern of interactions of the drug with BTK and VEGFR2. Overall, structure-based drug repositioning was able to predict these findings at a fraction of the time and cost of a conventional screen.

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis.

Autophagy plays an essential role in cell survival/death and functioning. Modulation of autophagy has been recognized as a promising therapeutic strategy against diseases/disorders associated with uncontrolled growth or accumulation of biomolecular aggregates, organelles, or cells including those caused by cancer, aging, neurodegeneration, and liver diseases such as α1-antitrypsin deficiency. Numerous pharmacological agents that enhance or suppress autophagy have been discovered. However, their molecular mechanisms of action are far from clear. Here, we collected a set of 225 autophagy modulators and carried out a comprehensive quantitative systems pharmacology (QSP) analysis of their targets using both existing databases and predictions made by our machine learning algorithm. Autophagy modulators include several highly promiscuous drugs (e.g., artenimol and olanzapine acting as activators, fostamatinib as an inhibitor, or melatonin as a dual-modulator) as well as selected drugs that uniquely target specific proteins (~30% of modulators). They are mediated by three layers of regulation: (i) pathways involving core autophagy-related (ATG) proteins such as mTOR, AKT, and AMPK; (ii) upstream signaling events that regulate the activity of ATG pathways such as calcium-, cAMP-, and MAPK-signaling pathways; and (iii) transcription factors regulating the expression of ATG proteins such as TFEB, TFE3, HIF-1, FoxO, and NF-κB. Our results suggest that PKA serves as a linker, bridging various signal transduction events and autophagy. These new insights contribute to a better assessment of the mechanism of action of autophagy modulators as well as their side effects, development of novel polypharmacological strategies, and identification of drug repurposing opportunities.

Synthetic Derivatives of (+)-epi-α-Bisabolol Are Formed by Mammalian Cytochromes P450 Expressed in a Yeast Reconstituted Pathway

Identification of the enzyme(s) involved in complex biosynthetic pathways can be challenging. An alternative approach might be to deliberately diverge from the original natural enzyme source and use promiscuous enzymes from other organisms. In this paper, we have tested the ability of a series of human and animal cytochromes P450 involved in xenobiotic detoxification to generate derivatives of (+)-epi-α-bisabolol and attempt to produce the direct precursor of hernandulcin, a sweetener from Lippia dulcis for which the last enzymatic steps are unknown. Screening steps were implemented in vivo in S. cerevisiae optimized for the biosynthesis of oxidized derivatives of (+)-epi-α-bisabolol by coexpressing two key enzymes: the (+)-epi-α-bisabolol synthase and the NADPH cytochrome P450 reductase. Five out of 25 cytochromes P450 were capable of producing new hydroxylated regioisomers of (+)-epi-α-bisabolol. Of the new oxidized bisabolol products, the structure of one compound, 14-hydroxy-(+)-epi-α-bisabolol, was fully elucidated by NMR while the probable structure of the second product was determined. In parallel, the production of (+)-epi-α-bisabolol derivatives was enhanced through the addition of a supplementary genomic copy of (+)-epi-α-bisabolol synthase that augmented the final titer of hydroxylated product to 64 mg/L. We thus demonstrate that promiscuous drug metabolism cytochromes P450 can be used to produce novel compounds from a terpene scaffold.

The Qi Site of Cytochrome b is a Promiscuous Drug Target in Trypanosoma cruzi and Leishmania donovani.

Available treatments for Chagas’ disease and visceral leishmaniasis are inadequate, and there is a pressing need for new therapeutics. Drug discovery efforts for both diseases principally rely upon phenotypic screening. However, the optimization of phenotypically active compounds is hindered by a lack of information regarding their molecular target(s). To combat this issue we initiate target deconvolution studies at an early stage. Here, we describe comprehensive genetic and biochemical studies to determine the targets of three unrelated phenotypically active compounds. All three structurally diverse compounds target the Qi active-site of cytochrome b, part of the cytochrome bc1 complex of the electron transport chain. Our studies go on to identify the Qi site as a promiscuous drug target in Leishmania donovani and Trypanosoma cruzi with a propensity to rapidly mutate. Strategies to rapidly identify compounds acting via this mechanism are discussed to ensure that drug discovery portfolios are not overwhelmed with inhibitors of a single target.