Lead-like Drugs: A Perspective

Abstract

Lead-like drugs, or drugs below molecular weight 300, are an important and sometimes overlooked component of the current pharmacopeia and contemporary medicinal chemistry practice. To examine the recent state-of-the-art in lead-like drug discovery, we surveyed recent drug approvals from 2011 to 2017 and top 200 prescribed medications, as well as provide case studies on recently approved lead-like drugs. Many of these recent drugs are close analogs of previously known drugs or natural substrates, with a key focus of their medicinal chemistry optimization being the choice of a low molecular weight starting point and maintaining low molecular weight during the optimization. However, the identification of low molecular weight starting points may be limited by the availability of suitable low molecular weight screening sets. To increase the discovery rate of lead-like drugs, we suggest an increased focus on inclusion and prosecution of lead-like starting points in screening libraries.

Discovery and Mechanism of SARS-CoV-2 Main Protease Inhibitors

“…As observed in Table 2 , log D values are generally in the ideal range for most orally available drugs ( Table 2 , entries1–3). 30 − 33 Furthermore, log D values were broadly observed to correlate with the antiviral activity, where compounds with higher logD values (E18, and E24) showed greater antiviral potencies than those with low logD values (E07, E19, and E20). These data indicate that the log D value is a critical parameter for optimizing the antiviral potencies of these compounds.…”

Azetidines kill Mycobacterium tuberculosis without detectable resistance by blocking mycolate assembly

“…3 There are several enzyme candidates involved in the latter stages of mycolic acid biosynthesis and incorporation into the cell envelope. Specifically, These encode the polyketide synthase (Pks13) responsible for the last condensation reaction in mycolate biosynthesis, 7 the essential membrane transporter responsible for translocating TMM across the cytoplasmic membrane (MmpL3), 8,9 and the mycolyltransferase responsible for the formation of TMM, TDM, and the covalent attachment of mycolic acids to arabinogalactan by the antigen 85 complex enzymes (FbpA, FbpB and FbpC), 10 respectively. Target engagement over-expression studies ruled out MmpL3 as a BGAz target, while experiments conducted in C. glutamicum demonstrate that Pks13 is equally not inhibited by these compounds.…”

Overview of Recent Strategic Advances in Medicinal Chemistry

“…155,156 In other words, drug discovery is a multiparameter optimization (MPO) process in which the aim is to find novel pharmaceutical molecules that meet the multiple drug-like criteria. Examples are "rule of 5", "beyond rule of 5", "lead-like drugs") [157][158][159][160] and ligand efficiency metrics (such as lipophilic efficiency). 161 Half of all therapeutic targets cannot be modulated with small-molecules that comply with the rule of 5.…”