Library Design, Chemical Space, and Drug Likeness

ABSTRACTHIV-1 attachment, despite being an ideal target stage to stop infection from the beginning, remains as one of the HIV lifecycle phases with less amount of designed and commercially available inhibitors. To contribute to the urgently needed discovery of new active compounds that could become part of the current highly active antiretroviral therapy, and as an attempt to explore a massive chemical space, high-throughput virtual screening of 16.3 million combinatorially generated and piperazine-cored compounds, was accomplished. Docking calculations, molecular dynamics simulations, and QSAR analyses were carried out to assess the suitability of each ligand to bind gp120 envelope glycoprotein, thus preventing it from binding to CD4 co-receptor. Ligand 255 stands out as a promising candidate to be tested beyond computational methodologies, and the 4,5,6,7-tetrahydroindole fragment is reported as a better group to bind inside the Phe43 cavity than the substituted indoles reported in the literature.

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Analysis of the uncharted, druglike property space by self-organizing maps

Molecular Diversity ◽

10.1007/s11030-021-10343-y ◽

2021 ◽

Author(s):

Gergely Takács ◽

Márk Sándor ◽

Zoltán Szalai ◽

Róbert Kiss ◽

György T. Balogh

Keyword(s):

Drug Discovery ◽

Chemical Space ◽

Chemical Databases ◽

Library Design ◽

Self Organizing Maps ◽

Chemical Libraries ◽

Drug Candidates ◽

Property Space ◽

Hit Identification ◽

Self Organizing

AbstractPhysicochemical properties are fundamental to predict the pharmacokinetic and pharmacodynamic behavior of drug candidates. Easily calculated descriptors such as molecular weight and logP have been found to correlate with the success rate of clinical trials. These properties have been previously shown to highlight a sweet-spot in the chemical space associated with favorable pharmacokinetics, which is superior against other regions during hit identification and optimization. In this study, we applied self-organizing maps (SOMs) trained on sixteen calculated properties of a subset of known drugs for the analysis of commercially available compound databases, as well as public biological and chemical databases frequently used for drug discovery. Interestingly, several regions of the property space have been identified that are highly overrepresented by commercially available chemical libraries, while we found almost completely unoccupied regions of the maps (commercially neglected chemical space resembling the properties of known drugs). Moreover, these underrepresented portions of the chemical space are compatible with most rigorous property filters applied by the pharma industry in medicinal chemistry optimization programs. Our results suggest that SOMs may be directly utilized in the strategy of library design for drug discovery to sample previously unexplored parts of the chemical space to aim at yet-undruggable targets. Graphic abstract

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Total Synthesis of Axially-Chiral Cannabinols: A New Platform for Cannabinoid-Based Drug Discovery

10.26434/chemrxiv.10251035.v1 ◽

2019 ◽

Cited By ~ 1

Author(s):

Primali Navaratne ◽

Jenny Wilkerson ◽

Kavindri Ranasinghe ◽

Evgeniya Semenova ◽

Lance McMahon ◽

...

Keyword(s):

Drug Discovery ◽

Total Synthesis ◽

Ground State ◽

Chemical Space ◽

Modern Medicine ◽

The Novel ◽

Pharmaceutical Development ◽

Bioactive Component ◽

Axially Chiral ◽

New Directions

<div> <div> <div> <p>Phytocannabinoids, molecules isolated from cannabis, are gaining attention as promising leads in modern medicine, including pain management. Considering the urgent need for combating the opioid crisis, new directions for the design of cannabinoid-inspired analgesics are of immediate interest. In this regard, we have hypothesized that axially-chiral-cannabinols (ax-CBNs), unnatural (and unknown) isomers of cannabinol (CBN) may be valuable scaffolds for cannabinoid-inspired drug discovery. There are multiple reasons for thinking this: (a) ax-CBNs would have ground-state three-dimensionality akin to THC, a key bioactive component of cannabis, (b) ax-CBNs at their core structure are biaryl molecules, generally attractive platforms for pharmaceutical development due to their ease of functionalization and stability, and (c) atropisomerism with respect to phytocannabinoids is unexplored “chemical space.” Herein we report a scalable total synthesis of ax-CBNs, examine physical properties experimentally and computationally, and provide preliminary behavioral and analgesic analysis of the novel scaffolds. </p> </div> </div> </div>

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Metal-, and Organocatalyst-Free One-Pot Assembly of Chiral Aza-Tricyclic Molecules: Creating Six Contiguous Stereocenters from 2-D-Structures and an Amino Acid

10.26434/chemrxiv.12757943.v1 ◽

2020 ◽

Author(s):

Dung Do

Keyword(s):

Amino Acid ◽

Chemical Space ◽

Structural Diversity ◽

Therapeutic Agents ◽

Chiral Molecules ◽

One Pot ◽

Complex Molecules ◽

Chiral Catalyst ◽

Chiral Complex ◽

Free Process

<p>Chiral molecules with their defined 3-D structures are of paramount importance for the study of chemical biology and drug discovery. Having rich structural diversity and unique stereoisomerism, chiral molecules offer a large chemical space that can be explored for the design of new therapeutic agents.<sup>1</sup> Practically, chiral architectures are usually prepared from organometallic and organocatalytic processes where a transition metal or an organocatalyst is tailor-made for desired reactions. As a result, developing a method that enables rapid assembly of chiral complex molecules under metal- and organocatalyst-free condition represents a daunting challenge. Here we developed a straightforward route to create a chiral 3-D structure from 2-D structures and an amino acid without any chiral catalyst. The center of this research is the design of a <a>special chiral spiroimidazolidinone cyclohexadienone intermediate</a>, a merger of a chiral reactive substrate with multiple nucleophillic/electrophillic sites and a transient organocatalyst. <a>This unique substrate-catalyst (“subcatalyst”) dual role of the intermediate enhances </a><a>the coordinational proximity of the chiral substrate and catalyst</a> in the key Aza-Michael/Michael cascade resulting in a substantial steric discrimination and an excellent overall diastereoselectivity. Whereas the “subcatalyst” (hidden catalyst) is not present in the reaction’s initial components, which renders a chiral catalyst-free process, it is strategically produced to promote sequential self-catalyzed reactions. The success of this methodology will pave the way for many efficient preparations of chiral complex molecules and aid for the quest to create next generation of therapeutic agents.</p>

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Reaction-based Enumeration, Active Learning, and Free Energy Calculations to Rapidly Explore Synthetically Tractable Chemical Space and Optimize Potency of Cyclin Dependent Kinase 2 Inhibitors

10.26434/chemrxiv.7841270.v2 ◽

2019 ◽

Author(s):

Kyle Konze ◽

Pieter Bos ◽

Markus Dahlgren ◽

Karl Leswing ◽

Ivan Tubert-Brohman ◽

...

Keyword(s):

Free Energy ◽

Drug Discovery ◽

Active Learning ◽

Large Scale ◽

Chemical Space ◽

Population Based ◽

Free Energy Calculations ◽

Computational Technique ◽

Cyclin Dependent Kinase ◽

Energy Calculations

We report a new computational technique, PathFinder, that uses retrosynthetic analysis followed by combinatorial synthesis to generate novel compounds in synthetically accessible chemical space. Coupling PathFinder with active learning and cloud-based free energy calculations allows for large-scale potency predictions of compounds on a timescale that impacts drug discovery. The process is further accelerated by using a combination of population-based statistics and active learning techniques. Using this approach, we rapidly optimized R-groups and core hops for inhibitors of cyclin-dependent kinase 2. We explored greater than 300 thousand ideas and identified 35 ligands with diverse commercially available R-groups and a predicted IC<sub>50</sub> < 100 nM, and four unique cores with a predicted IC<sub>50</sub> < 100 nM. The rapid turnaround time, and scale of chemical exploration, suggests that this is a useful approach to accelerate the discovery of novel chemical matter in drug discovery campaigns.

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Reaction-based Enumeration, Active Learning, and Free Energy Calculations to Rapidly Explore Synthetically Tractable Chemical Space and Optimize Potency of Cyclin Dependent Kinase 2 Inhibitors

10.26434/chemrxiv.7841270 ◽

2019 ◽

Author(s):

Kyle Konze ◽

Pieter Bos ◽

Markus Dahlgren ◽

Karl Leswing ◽

Ivan Tubert-Brohman ◽

...

Keyword(s):

Free Energy ◽

Drug Discovery ◽

Active Learning ◽

Large Scale ◽

Chemical Space ◽

Population Based ◽

Free Energy Calculations ◽

Computational Technique ◽

Cyclin Dependent Kinase ◽

Energy Calculations

We report a new computational technique, PathFinder, that uses retrosynthetic analysis followed by combinatorial synthesis to generate novel compounds in synthetically accessible chemical space. Coupling PathFinder with active learning and cloud-based free energy calculations allows for large-scale potency predictions of compounds on a timescale that impacts drug discovery. The process is further accelerated by using a combination of population-based statistics and active learning techniques. Using this approach, we rapidly optimized R-groups and core hops for inhibitors of cyclin-dependent kinase 2. We explored greater than 300 thousand ideas and identified 35 ligands with diverse commercially available R-groups and a predicted IC<sub>50</sub> < 100 nM, and four unique cores with a predicted IC<sub>50</sub> < 100 nM. The rapid turnaround time, and scale of chemical exploration, suggests that this is a useful approach to accelerate the discovery of novel chemical matter in drug discovery campaigns.

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General Cyclopropane Assembly via Enantioselective Redox-Active Carbene Transfer to Aliphatic Olefins

10.26434/chemrxiv.7436795 ◽

2018 ◽

Author(s):

Marc Montesinos-Magraner ◽

Matteo Costantini ◽

Rodrigo Ramirez-Contreras ◽

Michael E. Muratore ◽

Magnus J. Johansson ◽

...

Keyword(s):

Total Synthesis ◽

Asymmetric Synthesis ◽

Chemical Space ◽

Synthetic Approach ◽

Asymmetric Cyclopropanation ◽

Redox Active ◽

Wide Range ◽

Leaving Group ◽

Stereoelectronic Properties ◽

Carbene Transfer

Asymmetric cyclopropane synthesis currently requires bespoke strategies, methods, substrates and reagents, even when targeting similar compounds. This limits the speed and chemical space available for discovery campaigns. Here we introduce a practical and versatile diazocompound, and we demonstrate its performance in the first unified asymmetric synthesis of functionalized cyclopropanes. We found that the redox-active leaving group in this reagent enhances the reactivity and selectivity of geminal carbene transfer. This effect enabled the asymmetric cyclopropanation of a wide range of olefins including unactivated aliphatic alkenes, enabling the 3-step total synthesis of (–)-dictyopterene A. This unified synthetic approach delivers high enantioselectivities that are independent of the stereoelectronic properties of the functional groups transferred. Our results demonstrate that orthogonally-differentiated diazocompounds are viable and advantageous equivalents of single-carbon chirons<i>.</i>

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