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What’s Hot in PhysChem

November 16, 2023
by Sanji Bhal, Director, Marketing & Communications, ACD/Labs


Every year the PhysChem Forum meeting brings together scientists from industry and academia to discuss topics on physical chemistry, and Absorption, Distribution, Metabolism, Excretion (ADME) and toxicity. ACD/Labs is a regular attendee and sponsor of the PhysChem Forum with this year being no exception. We asked Andrius Sazonovas, the Head of Development of Percepta, to share his hot takes. Here are the top 3 topics that he wanted to share from the meeting:

1. Beyond Rule of 5 (bRo5)—Balancing Lipophilicity and Permeability in Drug Discovery

The well-known ‘rule of 5’ (Ro5) was published in 1997 by Pfizer chemist Christopher Lipinski, after systematic analysis of the company’s internal data on drug candidate successes and failures across a rich history of past drug development projects. The Ro5 was intended to provide a rule-of-thumb for chemists to keep in mind when evaluating the pharmacokinetics and drug-likeness in drug discovery. Since then, it has been used to estimate if a biologically active molecule has the appropriate chemical and physical properties to be orally bioavailable in humans.

According to the Ro5, molecules that were considered orally bioavailable passed at least 3 of these rules.

The Rule of 51:

  • Molecular weight less than 500 Da
  • Partition coefficient (logP) no greater than 5
  • No more than 5 hydrogen bond donors
  • No more than 10 hydrogen bond acceptors

Over the years, however, others at various pharmaceutical organizations have done similar analyses of their drug portfolio’s and identified numerous examples of compounds that break the rule of 5 yet are effective permeable oral medicines. As a result, both the list of registered oral drugs and the in-house pipelines of pharmaceutical companies these days, contain plenty of what has come to be known as “beyond Rule of 5” (bRo5) compounds.

At the PhysChem forum, Andrius noted increasing interest in bRo5—both in sharing existing success stories and in trying to identify new ones—which suggests that perhaps the universal application of the rule of 5 should be reviewed. After all, Chris Lipinski himself didn’t want them to be used as a prescription of limitations. The Ro5 was meant to be a set of guidelines to help scientists identify leads most likely to make successful drugs, thereby speeding up the drug discovery process.

According to Dr. Henrik Moebitz from Novartis who presented on this topic at the PhysChem Forum, bRo5 drugs often exhibit chameleonicity, which is the capacity of a molecule to adapt its conformations to the environment 2. Since the chameleonic property is related to molecular flexibility and the ability to adopt specific conformations, any new classification criteria introduced for the compounds of this type ideally should involve parameters related to 3D structure. Dr. Moebitz highlighted that Neutral topological polar surface area (TPSA), defined as TPSA minus 3D- polar surface area (PSA), has been demonstrated as a useful design parameter in bRo5 exploration projects at Novartis. Nevertheless, much simpler measures, such as the TPSA/MW ratio have also shown to effectively discriminate between the permeable and non-permeable bRo5 compounds, indicating that even the most basic physicochemical parameters can still be of great value in modern drug discovery, especially in the early stages, when the throughput of the screening matters the most.

Many have published on the topic of beyond rule of 5 and this is likely to continue as pharma/biopharma look to broaden the space of druggable diseases with biologic therapies, accelerate drug discovery and development, and lower R&D costs.3-7

2. Lipid Nanoparticles (LNPs) are Gaining Substantial Interest in Preclinical and Clinical Research

LNP-based therapies, such as Pfizer-BioNTech Comirnaty® and Moderna’s Spikevax (mRNA containing COVID-19 vaccines), are capturing the spotlight in preclinical and clinical research due to their promising therapeutic outcomes and pharmacological performance. However, there are certain factors which are crucial for LNP-based therapeutics to be used in clinical applications. The LNP-based therapies need to be manufactured through techniques that ensure stability during storage, compatibility with sterilization, quality control, and regulatory compliance.8

In the presentation given by Dr. Alan Sabirsh, Andrius noted that LNP-based therapies are an active focus in terms of understanding the interactions of multiple components of these complex systems and optimization of their many different attributes. The development of methods for the systematic assessment and quantification of the above factors is currently on the cutting-edge of pharmaceutical research and there are lot of things still to be learned and discovered.

However, even the earliest results indicate that, perhaps unsurprisingly, a lot of the processes in these advanced systems are still guided by good old physicochemical mechanisms. For instance, the pH-induced electrostatic binding of the LNPs with the endosomal membrane during the mRNA release, which in turn depends on the ionization properties of the lipids forming the nanoparticle. This was intriguing and confirms that fundamental physicochemical properties are still essential for any new method development or workflow.

3. Physicochemical Characterization with Assays & In-Silico Models Helps Accelerate Drug Discovery

Progressing compounds with good developable physicochemical properties during the lead optimization process is fundamental to any company’s aspirations for lead and candidate molecule quality. As a result, there is a very strong incentive to rely on the fully experimental characterization of the physicochemical profile of molecules in the drug discovery and development pipeline whenever possible.

GSK’s PhysChem team demonstrated this, presenting their continued efforts to develop assays and in silico models to help find compounds with the right qualities and reduce the chances of late-stage attrition. They made use of automated chromatographic platforms that enable them to study many compounds in early drug discovery, and therefore help them decide which ones are worth pursuing.

Despite the seemingly state-of-the-art modern methods for measuring the physicochemical properties, there is a constantly ongoing effort and investment within the pharmaceutical industry to improve the existing platforms in terms of the quality or reliability of the experimental data they generate, as well as the throughput at which they can deliver results. The latter part is crucial for the ability to enable full experimental characterization of the compounds in the earliest possible research phase. This, again, is an undeniable testament to the unfading importance of fundamental physchem properties in the search for even the most modern or complex drugs.

Software for Physicochemical Property Prediction

ACD/Labs offers predictive software to empower scientists with information for data-driven decision-making without the need for measurement of physicochemical properties. PhysChem Suite provides tools to help you investigate structure modifications that meet the target property profile in addition to calculators for lipophilicity (logP, logD), ionization (pKa), aqueous solubility, rule of 5 compliance, and more.


  1. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev, 23, 3-25. DOI: /10.1016/S0169-409X(96)00423-1
  2. E. Danelius, V. Poongavanam, S. Peintner, L.H.E. Wieske, M. Erdélyi, J. Kihlberg. (2020). Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs. Chemistry, 26, 5231-5244. DOI: 10.1002/chem.201905599
  3. M-Q. Zhang, B. Wilkinson. (2007). Drug discovery beyond the ‘rule-of-five’. Opin, Biotechnol, 18(6), 478-488. DOI: 10.1016/j.copbio.2007.10.005
  4. DeGoey, H-J. Chen, P. Cox, M. D. Wendt. (2018). Beyond the Rule of 5: Lessons Learned from AbbVie’s Drugs and Compound Collection. J Med. Chem., 61(7), 2636-2651. DOI: 10.1021/acs.jmedchem.7b00717
  5. J. Young. (2023). Today’s drug discovery and the shadow of the rule of 5. Expert Opin Drug Discov., 18(9), 965-972. DOI: 10.1080/17460441.2023.2228199
  6. V. Hartung, B. R. Huck, A. Crespo. (2023). Rules were made to be broken. Nat. Rev. Chem., 7, 3-4. DOI: 10.1038/s41570-022-00451-0
  7. B. Halford. (2023). Wrestling with Lipinski’s rule of 5. C&EN, 101(8). Read article
  8. M. Mehta, T.A. Bui, X. Yang, Y. Aksoy, E.M. Goldys, and W. Deng. (2023). Lipid-Based Nanoparticles for Drug/Gene Delivery: An Overview of the Production Techniques and Difficulties Encountered in Their Industrial Development. ACS Mater. Au, 3(6), 600-619. DOI: 10.1021/acsmaterialsau.3c00032

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