Physicochemical Property Profiles Research Articles

Chemspace Atlas: Multiscale Chemography of Ultralarge Libraries for Drug Discovery.

Nowadays, drug discovery is inevitably intertwined with the usage of large compound collections. Understanding of their chemotype composition and physicochemical property profiles is of the highest importance for successful hit identification. Efficient polyfunctional tools allowing multifaceted analysis of constantly growing chemical libraries must be Big Data-compatible. Here, we present the freely accessible ChemSpace Atlas (https://chematlas.chimie.unistra.fr), which includes almost 40K hierarchically organized Generative Topographic Maps (GTM) accommodating up to 500 M compounds covering fragment-like, lead-like, drug-like, PPI-like, and NP-like chemical subspaces. They allow users to navigate and analyze ZINC, ChEMBL, and COCONUT from multiple perspectives on different scales: from a bird's eye view of the entire library to structural pattern detection in small clusters. Around 20 physicochemical properties and almost 750 biological activities can be visualized (associated with map zones), supporting activity profiling and analogue search. Moreover, ChemScape Atlas will be extended toward new chemical subspaces (e.g., DNA-encoded libraries and synthons) and functionalities (ADMETox profiling and property-guided de novo compound generation).

Synthesis, Biological Evaluation, and Docking Studies of Antagonistic Hydroxylated Arecaidine Esters Targeting mAChRs.

The muscarinic acetylcholine receptor family is a highly sought-after target in drug and molecular imaging discovery efforts aimed at neurological disorders. Hampered by the structural similarity of the five subtypes’ orthosteric binding pockets, these efforts largely failed to deliver subtype-selective ligands. Building on our recent successes with arecaidine-derived ligands targeting M1, herein we report the synthesis of a related series of 11 hydroxylated arecaidine esters. Their physicochemical property profiles, expressed in terms of their computationally calculated CNS MPO scores and HPLC-logD values, point towards blood–brain barrier permeability. By means of a competitive radioligand binding assay, the binding affinity values towards each of the individual human mAChR subtypes hM1–hM5 were determined. The most promising compound of this series 17b was shown to have a binding constant towards hM1 in the single-digit nanomolar region (5.5 nM). Similar to our previously reported arecaidine-derived esters, the entire series was shown to act as hM1R antagonists in a calcium flux assay. Overall, this study greatly expanded our understanding of this recurring scaffolds’ structure–activity relationship and will guide the development towards highly selective mAChRs ligands.

Physicochemical Factors Affecting Microbiota Dynamics During Traditional Solid-State Fermentation of Chinese Strong-Flavor Baijiu.

Spontaneous solid-state fermentation (SSF) of Chinese Baijiu involves diverse microbes from Daqu and pit mud (PM). Given that the transfer of interphase microflora during the fermentation is a continuous and dynamic process, longitudinal studies are essential to provide ecological insights into community stability and response to consecutive disturbances in the process. In this context, this study aimed to generate a comprehensive longitudinal characterization of the microbiota during the fermentation processes of Chinese strong-flavor Baijiu (CSFB) differing in cellar ages with consideration for potential relation to physicochemical variables. The microecology variations observed during the 6-years cellar SSF (SCSSF) and 30-years cellar SSF (TCSSF) processes reveal that fungal composition contributes to a larger extent than bacterial composition to such variations. Orders of Lactobacillales, Anaerolineales, Enterobacteriales, Bacillales, Eurotiales, and Saccharomycetales dominated (average relative abundances >10%) the microbiota in both SCSSF and TCSSF processes but with a different percentage in the operational taxonomic unit (out) abundances. Compared with the SCSSF process, TCSSF possessed slower microbial succession rates, which were in accordance with the profile of physicochemical properties. From a network perspective, the microbial community structure observed in the TCSSF processes was more stable than that in the SCSSF. This may benefit from the milder physicochemical conditions of the TCSSF processes, especially the temperature, which is also more beneficial to the growth of some groups that have negative effects on fermentation, such as Staphylococcus, Pseudomonas, and Acinetobacter.

ProtPCV: A Fixed Dimensional Numerical Representation of Protein Sequence to Significantly Reduce Sequence Search Time.

Protein sequence is a wealth of experimental information which is yet to be exploited to extract information on protein homologues. Consequently, it is observed from publications that dynamic programming, heuristics and HMM profile-based alignment techniques along with the alignment free techniques do not directly utilize ordered profile of physicochemical properties of a protein to identify its homologue. Also, it is found that these works lack crucial bench-marking or validation in absence of which their incorporation in search engines may appears to be questionable. In this direction this research approach offers fixed dimensional numerical representation of protein sequences extending the concept of periodicity count value of nucleotide types (2017) to accommodate Euclidean distance as direct similarity measure between two proteins. Instead of bench-marking with BLAST and PSI-BLAST only, this new similarity measure was also compared with Needleman-Wunsch and Smith-Waterman. For enhancing the strength of comparison, this work for the first time introduces two novel benchmarking methods based on correlation of "similarity scores" and "proximity of ranked outputs from a standard sequence alignment method" between all possible pairs of search techniques including the new one presented in this paper. It is found that the novel and unique numerical representation of a protein can reduce computational complexity of protein sequence search to the tune of O(log(n)). It may also help implementation of various other similarity-based operation possible, such as clustering, phylogenetic analysis and classification of proteins on the basis of the properties used to build this numerical representation of protein.

Profile of Physico-Chemical Properties of Spilled Crude Oil in Marine Sediments in Niger Delta

This paper presents profile of the physico-chemical properties of study areas of the research. Most frequently, in the Niger Delta zone spilled oil in the marine sediments is prevalent. The research paper therefore focused at first instance to evolve the parametric control properties which have direct interactions with the spilled oil. Samples sediments A, B, C, and D were collected from the designated study areas of Southern Ijaw, Ekeremor, Ogbia, Brass and Nembe local government areas hosting the major oil producing companies along the coastal regions of Niger Delta-Nigeria. The samples were subjected to instrumental analysis for determination of pH 5.2 (acidic); electrical conductivity 169 µS/cm; redox potential -134 mv; temperature 25.7 centigrade; bulk density 3.3; particle density 2.75; porosity 41.6; organic matter 8.60; clay 28.70; silt 56.80; sand 14.5; total hydrocarbon content 83.33; and the metallic components of the samples (mg/kg) stood as follows- Zinc (Zn) 1.47; Lead (Pb) 0.070; copper (Cu) 2.06; cadmium (0.51); Nickel (Ni) 0.82; manganese (Mn) 4.75; iron (Fe) 7.60; and chromium (Cr) 0.98. Table II showed sample Sediment A gave appreciable values on all the parameters for good judgment on the rest samples Sediment B, Sediment C and Sediment D results. The possible reasons being there are much physico-chemical interactions down the samples which bring concomitant effects on animals, fishes, humans’ health and regions degradation tendencies and perennial consequences of social agitations for remediation and compensations.

The Profile of Physico-Chemical Properties of Spilled Crude Oil in Marine Sediments in Niger Delta

This paper presents profile of the physico-chemical properties of study areas of the research. Most frequently, in the Niger Delta zone spilled oil in the marine sediments is prevalent. The research paper therefore focused at first instance to evolve the parametric control properties which have direct interactions with the spilled oil. Samples sediments A, B, C, and D were collected from the designated study areas of Southern Ijaw, Ekeremor, Ogbia, Brass and Nembe local government areas hosting the major oil producing companies along the coastal regions of Niger Delta-Nigeria. The samples were subjected to instrumental analysis for determination of pH 5.2 (acidic); electrical conductivity 169 µS/cm; redox potential -134 mv; temperature 25.7 centigrade; bulk density 3.3; particle density 2.75; porosity 41.6; organic matter 8.60; clay 28.70; silt 56.80; sand 14.5; total hydrocarbon content 83.33; and the metallic components of the samples (mg/kg) stood as follows- Zinc (Zn) 1.47; Lead (Pb) 0.070; copper (Cu) 2.06; cadmium (0.51); Nickel (Ni) 0.82; manganese (Mn) 4.75; iron (Fe) 7.60; and chromium (Cr) 0.98. Table II showed sample Sediment A gave appreciable values on all the parameters for good judgment on the rest samples Sediment B, Sediment C and Sediment D results. The possible reasons being there are much physico-chemical interactions down the samples which bring concomitant effects on animals, fishes, humans’ health and regions degradation tendencies and perennial consequences of social agitations for remediation and compensations.

BIOFACQUIM: A Mexican Compound Database of Natural Products.

Compound databases of natural products have a major impact on drug discovery projects and other areas of research. The number of databases in the public domain with compounds with natural origins is increasing. Several countries, Brazil, France, Panama and, recently, Vietnam, have initiatives in place to construct and maintain compound databases that are representative of their diversity. In this proof-of-concept study, we discuss the first version of BIOFACQUIM, a novel compound database with natural products isolated and characterized in Mexico. We discuss its construction, curation, and a complete chemoinformatic characterization of the content and coverage in chemical space. The profile of physicochemical properties, scaffold content, and diversity, as well as structural diversity based on molecular fingerprints is reported. BIOFACQUIM is available for free.

Are the physicochemical properties of antibacterial compounds really different from other drugs?

BackgroundIt is now widely recognized that there is an urgent need for new antibacterial drugs, with novel mechanisms of action, to combat the rise of multi-drug resistant bacteria. However, few new compounds are reaching the market. Antibacterial drug discovery projects often succeed in identifying potent molecules in biochemical assays but have been beset by difficulties in obtaining antibacterial activity. A commonly held view, based on analysis of marketed antibacterial compounds, is that antibacterial drugs possess very different physicochemical properties to other drugs, and that this profile is required for antibacterial activity.ResultsWe have re-examined this issue by performing a cheminformatics analysis of the literature data available in the ChEMBL database. The physicochemical properties of compounds with a recorded activity in an antibacterial assay were calculated and compared to two other datasets extracted from ChEMBL, marketed antibacterials and drugs marketed for other therapeutic indications. The chemical class of the compounds and Gram-negative/Gram-positive profile were also investigated. This analysis shows that compounds with antibacterial activity have physicochemical property profiles very similar to other drug classes.ConclusionsThe observation that many current antibacterial drugs lie in regions of physicochemical property space far from conventional small molecule therapeutics is correct. However, the inference that a compound must lie in one of these “outlier” regions in order to possess antibacterial activity is not supported by our analysis.Graphical abstract.Electronic supplementary materialThe online version of this article (doi:10.1186/s13321-016-0143-5) contains supplementary material, which is available to authorized users.

Analysis of Physicochemical Properties for Drugs of Natural Origin.

The impact of time, therapy area, and route of administration on 13 physicochemical properties calculated for 664 drugs developed from a natural prototype was investigated. The mean values for the majority of properties sampled over five periods from pre-1900 to 2013 were found to change in a statistically significant manner. In contrast, lipophilicity and aromatic ring count remained relatively constant, suggesting that these parameters are the most important for successful prosecution of a natural product drug discovery program if the route of administration is not focused exclusively on oral availability. An examination by therapy area revealed that anti-infective agents had the most differences in physicochemical property profiles compared with other areas, particularly with respect to lipophilicity. However, when this group was removed, the variation between the mean values for lipophilicity and aromatic ring count across the remaining therapy areas was again found not to change in a meaningful manner, further highlighting the importance of these two parameters. The vast majority of drugs with a natural progenitor were formulated for either oral and/or injectable administration. Injectables were, on average, larger and more polar than drugs developed for oral, topical, and inhalation routes.

Physicochemical property profiles of marketed drugs, clinical candidates and bioactive compounds

We performed a comparison of several simple physicochemical properties between marketed drugs, clinical candidates and bioactive compounds using commercially available databases (GVKBIO, Hyderabad, India). In contrast to previous studies this comparison was performed at the individual target level. Confirming earlier studies this shows that marketed drugs have, on average and taken as a single set, lower physicochemical property values than the corresponding clinical candidates and bioactive compounds but that there is considerable variation between drug targets. This work complements earlier studies by using a much larger annotated dataset and confirms that there is a shift in physicochemical properties for targets with launched drugs and clinical candidates compared to bioactive compounds.

A Comparison of Physicochemical Property Profiles of Marketed Oral Drugs and Orally Bioavailable Anti-Cancer Protein Kinase Inhibitors in Clinical Development

This manuscript describes a comparison of the physicochemical properties of marketed oral drugs with those of 45 structurally confirmed orally bioavailable anti-cancer protein kinase inhibitors currently in different phases of clinical development. It is evident from the data presented that these kinase inhibitors are on average larger (over 110 Da), more lipophilic (over 1.5 log units) and more complex (approximately two more rotatable bonds) than those of marketed oral drugs. In contrast, hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) counts are not significantly different.

The Design and Synthesis of a Herbicide Targeted Library of N-[1-(1,3- Benzoxazol-2-yl)Alkyl]-6-Alkyl-1,3,5-Triazine-2,4-Diamines

Amino acids were immobilised by attaching them via a carbamate linker to Wang resin. These intermediates were converted to 1-(1,3-benzoxazol-2-yl)alkanamines over three steps, followed by coupling with 4-alkyl-6-chloro-1,3,5-triazine-2-amines to furnish the desired N-[1-(1,3-benzoxazol-2-yl)alkyl]-6-alkyl-1,3,5-triazine-2,4-diamines. Physico-chemical property profiles were used to support design and development of a combinatorial library. The synthetic methodology described herein was validated with the production of a herbicide targeted library of 300 members.

Optimizing the size and configuration of combinatorial libraries.

This paper addresses a major issue in library design, namely how to efficiently optimize the library size (number of products) and configuration (number of reagents at each position) simultaneously with other properties such as diversity, cost, and drug-like physicochemical property profiles. These objectives are often in competition, for example, minimizing the number of reactants while simultaneously maximizing diversity, and thus present difficulties for traditional optimization methods such as genetic algorithms and simulated annealing. Here, a multiobjective genetic algorithm (MOGA) is used to vary library size and configuration simultaneously with other library properties. The result is a family of solutions that explores the tradeoffs in the objectives. This is achieved without the need to assign relative weights to the objectives. The user is then able to make an informed choice on an appropriate compromise solution. The method has been applied to two different virtual libraries: a two-component aminothiazole library and a four-component benzodiazepine library.

A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases.

The discovery of various protein/receptor targets from genomic research is expanding rapidly. Along with the automation of organic synthesis and biochemical screening, this is bringing a major change in the whole field of drug discovery research. In the traditional drug discovery process, the industry tests compounds in the thousands. With automated synthesis, the number of compounds to be tested could be in the millions. This two-dimensional expansion will lead to a major demand for resources, unless the chemical libraries are made wisely. The objective of this work is to provide both quantitative and qualitative characterization of known drugs which will help to generate "drug-like" libraries. In this work we analyzed the Comprehensive Medicinal Chemistry (CMC) database and seven different subsets belonging to different classes of drug molecules. These include some central nervous system active drugs and cardiovascular, cancer, inflammation, and infection disease states. A quantitative characterization based on computed physicochemical property profiles such as log P, molar refractivity, molecular weight, and number of atoms as well as a qualitative characterization based on the occurrence of functional groups and important substructures are developed here. For the CMC database, the qualifying range (covering more than 80% of the compounds) of the calculated log P is between -0.4 and 5.6, with an average value of 2.52. For molecular weight, the qualifying range is between 160 and 480, with an average value of 357. For molar refractivity, the qualifying range is between 40 and 130, with an average value of 97. For the total number of atoms, the qualifying range is between 20 and 70, with an average value of 48. Benzene is by far the most abundant substructure in this drug database, slightly more abundant than all the heterocyclic rings combined. Nonaromatic heterocyclic rings are twice as abundant as the aromatic heterocycles. Tertiary aliphatic amines, alcoholic OH and carboxamides are the most abundant functional groups in the drug database. The effective range of physicochemical properties presented here can be used in the design of drug-like combinatorial libraries as well as in developing a more efficient corporate medicinal chemistry library.