The role of ligand efficiency metrics in drug discovery

The judicious application of ligand or binding efficiencies, which quantify the molecular properties required to gain binding affinity for a drug target, is gaining traction in the selection and optimisation of fragments, hits, and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimised ligand efficiency values for their target. Optimising ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the developability of drug candidates

The impact of binding thermodynamics on medicinal chemistry optimizations

Ligand binding thermodynamics has been attracted considerable interest in the past decade owing to the recognized relation between binding thermodynamic profile and the physicochemical and druglike properties of compounds. In this review, the relation between optimization strategies and ligand properties is presented based on the structural and thermodynamic analysis of ligand–protein complex formation. The control of the binding thermodynamic profile is beneficial for the balanced affinity and physicochemical properties of drug candidates, and early phase optimization gives more opportunity to this control. </jats:p

Validity of Ligand Efficiency Metrics

A recent viewpoint article (Improving the plausibility of success with inefficient metrics. ACS Med. Chem. Lett. 2014, 5, 2-5) argued that the standard definition of ligand efficiency (LE) is mathematically invalid. In this viewpoint, we address this criticism and show categorically that the definition of LE is mathematically valid. LE and other metrics such as lipophilic ligand efficiency (LLE) can be useful during the multiparameter optimization challenge faced by medicinal chemists

Molecular topology, a novel descriptor for compound quality assessment

Abstract The pharmaceutical industry is currently facing a high clinical attrition rate. In order to prevent the late-stage clinical failure, many investigations on compound quality and drug-likeness of compounds have been carried out. It has been widely accepted that molecular size and lipophilicity plays an important role in compound quality. Many attempts have been done to find out other factors which can influence compound quality beyond size and lipophilicity. Recently, a molecular topology concept has been put forward and its influence on compound quality has been investigated. It has been shown that drugs have higher fraction of compounds with only one ring system compared to clinical candidate and bioactive compounds. As an extension to the previous studies, the aim of this project is to further investigate how the molecular topology influences some of the most important physicochemical properties of molecules as well as the compound potency efficiency indices in general. Our results show that among reported molecules in the literature, compounds with only one ring system are smaller in size, less lipophilic and therefore has a higher probability to be less toxic. Interestingly compounds which have a simple topology also show advantage in terms of potency efficiency such as ligand efficiency (LE), ligand lipophilic efficiency (LLE) and ligand-efficiency-dependent lipophilicity index (LELP) compared with compounds which have a more complex topology. Thus a novel hypothesis why compounds with only one ring system are abundant among drugs has been proposed. On average molecules with only one ring system seems to bind more strongly to its protein target; this might reduce the necessary size of the molecule to reach a certain potency level. The reduction in size and lipophilicity reduces the risk of failure in clinical trials. Popular science summary: Molecular topology, A novel descriptor for compound quality assessment Drug discovery and development is a time consuming process which typically takes 15 to 20 years from the target identification until a drug makes it to the market. During this lengthy process, numerous compounds are tested, synthesized and validated in order to achieve the optimal efficacy and safety profile. Historically drug discovery was an iterative process of compound synthesis and in vivo screening. This paradigm has changed by the advancement of in vitro high-throughput screening technology and in silico techniques. The paradigm shift has largely improved hit identification efficiency; however the pharmaceutical industry still faces a high attrition rate. It is critical to identify compounds which are unlikely to succeed (low quality compounds) and to terminate the development of these compounds as early as possible. Recently molecular topology class was proposed; basically, it classifies compounds according to the number of ring systems. It has been reported that the fraction of compounds with only one ring system (1TR) is higher in drugs compared to clinical candidates and general bioactive compounds. This thesis aims to better understand the earlier observation of 1TR compounds’ enrichment in drugs. In this project, how the molecular topology influences some of the most important physicochemical properties of molecules as well as the compound potency efficiency indices was investigated. It showed that among reported molecules in the literature, compounds with only one ring system are smaller in size, less lipophilic and therefore has a higher probability to be less toxic. On average, molecules with only one ring system bind more strongly to its protein target; this reduces the necessary size of the molecule to reach a certain potency level. The reduction in size and lipophilicity reduces the risk of failure in clinical trials. By understanding what properties determine the quality of a compound, it will be possible to deliver drugs to the market more efficiently. Advisor: Ola Engkvist, Hongming Chen (Computational Chemistry, AstraZeneca R&D Mölndal) Master´s Degree Project 60 credits in Bioinformatics, 2011-2012 Department of Biology., Lund Universit

Fragment-to-Lead Medicinal Chemistry Publications in 2018

This Perspective, the fourth in an annual series, summarizes fragment-to-lead (F2L) success stories published during 2018. Topics such as target class, screening methods, physicochemical properties, and ligand efficiency are discussed for the 2018 examples as well as for the combined 111 F2L examples covering 2015-2018. While the overall properties of fragments and leads have remained constant, a number of new trends are noted, for example, broadening of target class coverage and application of FBDD to covalent inhibitors. Moreover, several studies make use of fragment hits that were previously described in the literature, illustrating that fragments are versatile starting points that can be optimized to structurally diverse leads. By focusing on success stories, the hope is that this Perspective will identify and inform best practices in fragment-based drug discovery.</p

Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach

The bacterial sliding clamp (SC), also known as the DNA polymerase III β subunit, is an emerging antibacterial target that plays a central role in DNA replication, serving as a protein-protein interaction hub with a common binding pocket to recognize linear motifs in the partner proteins. Here, fragment-based screening using X-ray crystallography produced four hits bound in the linear-motif-binding pocket of the Escherichia coli SC. Compounds structurally related to the hits were identified that inhibited the E. coli SC and SC-mediated DNA replication in vitro. A tetrahydrocarbazole derivative emerged as a promising lead whose methyl and ethyl ester prodrug forms showed minimum inhibitory concentrations in the range of 21-43 μg/mL against representative Gram-negative and Gram-positive bacteria species. The work demonstrates the utility of a fragment-based approach for identifying bacterial sliding clamp inhibitors as lead compounds with broad-spectrum antibacterial activity. © 2014 American Chemical Society

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

Virtual screening (VS) is an outstanding cornerstone in the drug discovery pipeline. A variety of computational approaches, which are generally classified as ligand-based (LB) and structure-based (SB) techniques, exploit key structural and physicochemical properties of ligands and targets to enable the screening of virtual libraries in the search of active compounds. Though LB and SB methods have found widespread application in the discovery of novel drug-like candidates, their complementary natures have stimulated continued e orts toward the development of hybrid strategies that combine LB and SB techniques, integrating them in a holistic computational framework that exploits the available information of both ligand and target to enhance the success of drug discovery projects. In this review, we analyze the main strategies and concepts that have emerged in the last years for defining hybrid LB + SB computational schemes in VS studies. Particularly, attention is focused on the combination of molecular similarity and docking, illustrating them with selected applications taken from the literature

Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells

Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. To find new therapeutic agents that could efficiently kill PaCSCs, we screened a chemical library of 680 compounds for candidate small molecules with anti-CSC activity, and identified two compounds of a specific chemical series with potent activity in vitro and in vivo against patient-derived xenograft (PDX) cultures. The anti-CSC mechanism of action of this specific chemical series was found to rely on induction of lysosomal membrane permeabilization (LMP), which is likely associated with the increased lysosomal mass observed in PaCSCs. Using the well characterized LMP-inducer siramesine as a tool molecule, we show elimination of the PaCSC population in mice implanted with tumors from two PDX models. Collectively, our approach identified lysosomal disruption as a promising anti-CSC therapeutic strategy for PDAC

Going Small: Using Biophysical Screening to Implement Fragment Based Drug Discovery

Screening against biochemical targets with compact chemical fragments has developed a reputation as a successful early‐stage drug discovery approach, thanks to recent drug approvals. Having weak initial target affinities, fragments require the use of sensitive biophysical technologies (NMR, SPR, thermal shift, ITC, and X‐ray crystallography) to accommodate the practical limits of going smaller. Application of optimized fragment biophysical screening approaches now routinely allows for the rapid identification of fragments with high binding efficiencies. The aim of this chapter is to provide an introduction to fragment library selection and to discuss the suitability of screening approaches adapted for lower‐throughput biophysical techniques. A general description of metrics that are being used in the progression of fragment hits, the need for orthogonal assay testing, and guidance on potential pitfalls are included to assist scientists, considering initiating their own fragment discovery program

Rational methods for the selection of diverse screening compounds.

Traditionally a pursuit of large pharmaceutical companies, high-throughput screening assays are becoming increasingly common within academic and government laboratories. This shift has been instrumental in enabling projects that have not been commercially viable, such as chemical probe discovery and screening against high-risk targets. Once an assay has been prepared and validated, it must be fed with screening compounds. Crafting a successful collection of small molecules for screening poses a significant challenge. An optimized collection will minimize false positives while maximizing hit rates of compounds that are amenable to lead generation and optimization. Without due consideration of the relevant protein targets and the downstream screening assays, compound filtering and selection can fail to explore the great extent of chemical diversity and eschew valuable novelty. Herein, we discuss the different factors to be considered and methods that may be employed when assembling a structurally diverse compound collection for screening. Rational methods for selecting diverse chemical libraries are essential for their effective use in high-throughput screens.We are grateful for financial support from the MRC, Wellcome Trust, CRUK, EPSRC, BBSRC and Newman Trust.This is the author accepted manuscript. The final version is available from American Chemical Society via http://dx.doi.org/10.1021/cb100420