Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties
TL;DR: Based on six physicochemical properties commonly used by medicinal chemists, the CNS MPO function may be used prospectively at the design stage to accelerate the identification of compounds with increased probability of success.
Abstract: The interplay among commonly used physicochemical properties in drug design was examined and utilized to create a prospective design tool focused on the alignment of key druglike attributes. Using a set of six physicochemical parameters ((a) lipophilicity, calculated partition coefficient (ClogP); (b) calculated distribution coefficient at pH = 7.4 (ClogD); (c) molecular weight (MW); (d) topological polar surface area (TPSA); (e) number of hydrogen bond donors (HBD); (f) most basic center (pKa)), a druglikeness central nervous system multiparameter optimization (CNS MPO) algorithm was built and applied to a set of marketed CNS drugs (N = 119) and Pfizer CNS candidates (N = 108), as well as to a large diversity set of Pfizer proprietary compounds (N = 11 303). The novel CNS MPO algorithm showed that 74% of marketed CNS drugs displayed a high CNS MPO score (MPO desirability score ≥ 4, using a scale of 0−6), in comparison to 60% of the Pfizer CNS candidates. This analysis suggests that this algorithm could p...
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17 May 2013
TL;DR: This research presents a novel and scalable approach called “Smartfitting” that automates the very labor-intensive and therefore time-heavy and therefore expensive and expensive process of designing and implementing statistical models for regression models.
Abstract: General Strategies.- Regression Models.- Classification Models.- Other Considerations.- Appendix.- References.- Indices.
3,672 citations
TL;DR: The utility of QED is extended by applying it to the problem of molecular target druggability assessment by prioritizing a large set of published bioactive compounds and may also capture the abstract notion of aesthetics in medicinal chemistry.
Abstract: Drug-likeness is a key consideration when selecting compounds during the early stages of drug discovery. However, evaluation of drug-likeness in absolute terms does not reflect adequately the whole spectrum of compound quality. More worryingly, widely used rules may inadvertently foster undesirable molecular property inflation as they permit the encroachment of rule-compliant compounds towards their boundaries. We propose a measure of drug-likeness based on the concept of desirability called the quantitative estimate of drug-likeness (QED). The empirical rationale of QED reflects the underlying distribution of molecular properties. QED is intuitive, transparent, straightforward to implement in many practical settings and allows compounds to be ranked by their relative merit. We extended the utility of QED by applying it to the problem of molecular target druggability assessment by prioritizing a large set of published bioactive compounds. The measure may also capture the abstract notion of aesthetics in medicinal chemistry.
1,161 citations
TL;DR: This work systematically gives a comprehensive review in current developments of imidazole‐based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti‐inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology.
Abstract: Imidazole ring is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron-rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole-based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole-based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.
558 citations
TL;DR: Novel drug delivery methods, including nanoparticles and prodrugs and computational multi-parameter optimization to assess the blood-brain barrier (BBB) permeability of small molecules in clinical trials for GBM treatment are discussed.
Abstract: Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, has a high mortality rate despite extensive efforts to develop new treatments. GBM exhibits both intra- and intertumor heterogeneity, lending to resistance and eventual tumor recurrence. Large-scale genomic and proteomic analysis of GBM tumors has uncovered potential drug targets. Effective and "druggable" targets must be validated to embark on a robust medicinal chemistry campaign culminating in the discovery of clinical candidates. Here, we review recent developments in GBM drug discovery and delivery. To identify GBM drug targets, we performed extensive bioinformatics analysis using data from The Cancer Genome Atlas project. We discovered 20 genes, BOC, CLEC4GP1, ELOVL6, EREG, ESR2, FDCSP, FURIN, FUT8-AS1, GZMB, IRX3, LITAF, NDEL1, NKX3-1, PODNL1, PTPRN, QSOX1, SEMA4F, TH, VEGFC, and C20orf166AS1 that are overexpressed in a subpopulation of GBM patients and correlate with poor survival outcomes. Importantly, nine of these genes exhibit higher expression in GBM versus low-grade glioma and may be involved in disease progression. In this review, we discuss these proteins in the context of GBM disease progression. We also conducted computational multi-parameter optimization to assess the blood-brain barrier (BBB) permeability of small molecules in clinical trials for GBM treatment. Drug delivery in the context of GBM is particularly challenging because the BBB hinders small molecule transport. Therefore, we discuss novel drug delivery methods, including nanoparticles and prodrugs. Given the aggressive nature of GBM and the complexity of targeting the central nervous system, effective treatment options are a major unmet medical need. Identification and validation of biomarkers and drug targets associated with GBM disease progression present an exciting opportunity to improve treatment of this devastating disease.
470 citations
Cites methods from "Moving beyond Rules: The Developmen..."
...An analysis of FDA-approved CNS drugs demonstrated 74% have a CNS MPO desirability score $4 (Wager et al., 2010)....
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...To ameliorate this problem, a CNS multiparameter optimization (CNS MPO) algorithm was designed by Pfizer scientists with the goal of streamlining the CNS drug discovery process (Wager et al., 2010)....
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TL;DR: A current review of the literature reveals a continued reliance on the synthesis of novel structures with increased potency, rather than a focus on maintaining optimal physicochemical properties associated with ADMET throughout drug optimization, which may contribute significantly to the overall quality of candidate drugs at different stages of discovery.
Abstract: Introduction: The role of lipophilicity in drug discovery and design is a critical one. Lipophilicity is a key physicochemical property that plays a crucial role in determining ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and the overall suitability of drug candidates. There is increasing evidence to suggest that control of physicochemical properties such as lipophilicity, within a defined optimal range, can improve compound quality and the likelihood of therapeutic success. Areas covered: This review focuses on understanding lipophilicity, techniques used to measure lipophilicity, and summarizes the importance of lipophilicity in drug discovery and development, including a discussion of its impact on individual ADMET parameters as well as its overall influence on the drug discovery and design process, specifically within the past 15 years. Expert opinion: A current review of the literature reveals a continued reliance on the synthesis of novel structures with increased...
433 citations
Cites methods from "Moving beyond Rules: The Developmen..."
...Thus if a log P of > 3 were used as a strict cutoff, drug design of appropriate CNS drugs may be significantly restricted [88]....
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References
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TL;DR: The pharmaceutical industry faces considerable challenges, both politically and fiscally, and the fiscal pressures that face the industry from the perspective of R&D are dealt with.
Abstract: The pharmaceutical industry faces considerable challenges, both politically and fiscally. Politically, governments around the world are trying to contain costs and, as health care budgets constitute a very significant part of governmental spending, these costs are the subject of intense scrutiny. In the United States, drug costs are also the subject of intense political discourse. This article deals with the fiscal pressures that face the industry from the perspective of R&D. What impinges on productivity? How can we improve current reduced R&D productivity?
3,746 citations
TL;DR: This topic is explored in terms ofDrug-like physicochemical features, drug-like structural features, a comparison of drug- like and non-drug-like in drug discovery and a discussion of how drug-Like features relate to clinical success.
3,499 citations
TL;DR: The method, termed topological PSA (TPSA), provides results which are practically identical with the 3D PSA, while the computation speed is 2-3 orders of magnitude faster and may be used for fast bioavailability screening of virtual libraries having millions of molecules.
Abstract: Molecular polar surface area (PSA), i.e., surface belonging to polar atoms, is a descriptor that was shown to correlate well with passive molecular transport through membranes and, therefore, allows prediction of transport properties of drugs. The calculation of PSA, however, is rather time-consuming because of the necessity to generate a reasonable 3D molecular geometry and the calculation of the surface itself. A new approach for the calculation of the PSA is presented here, based on the summation of tabulated surface contributions of polar fragments. The method, termed topological PSA (TPSA), provides results which are practically identical with the 3D PSA (the correlation coefficient between 3D PSA and fragment-based TPSA for 34 810 molecules from the World Drug Index is 0.99), while the computation speed is 2-3 orders of magnitude faster. The new methodology may, therefore, be used for fast bioavailability screening of virtual libraries having millions of molecules. This article describes the new methodology and shows the results of validation studies based on sets of published absorption data, including intestinal absorption, Caco-2 monolayer penetration, and blood-brain barrier penetration.
2,400 citations
TL;DR: Analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development.
Abstract: The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity--the most important drug-like physical property--include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making.
1,954 citations
TL;DR: Relationships between physicochemical drug properties and toxicity were inferred from a data set consisting of animal in vivo toleration studies on 245 preclinical Pfizer compounds; an increased likelihood of toxic events was found for less polar, more lipophilic compounds.
702 citations