Generating Multibillion Chemical Space of Readily Accessible Screening Compounds

Abstract

Summary An approach to the generation of ultra-large chemical libraries of readily accessible (“REAL”) compounds is described. The strategy is based on the use of two- or three-step three-component reaction sequences and available starting materials with pre-validated chemical reactivity. After the preliminary parallel experiments, the methods with at least ∼80% synthesis success rate (such as acylation – deprotection – acylation of monoprotected diamines or amide formation – click reaction with functionalized azides) can be selected and used to generate the target chemical space. It is shown that by using only on the two aforementioned reaction sequences, a nearly 29-billion compound library is easily obtained. According to the predicted physico-chemical descriptor values, the generated chemical space contains large fractions of both drug-like and “beyond rule-of-five” members, whereas the strictest lead-likeness criteria (the so-called Churcher's rules) are met by the lesser part, which still exceeds 22 million.

Automated discovery of noncovalent inhibitors of SARS-CoV-2 main protease by consensus Deep Docking of 40 billion small molecules

“…Make-on-demand chemical libraries will soon exceed the 100 billion threshold [1][2][3] , while structure-based virtual screening (SBVS) is well projected to remain the gold standard method for early-stage drug discovery. Molecular docking implemented on high-performing computational resources has already been proven successful in identifying potent ligands from extensive databases (from 100s of millions to up to 1 billion chemicals) for several targets [4][5][6][7][8] .…”

A Diversity‐Oriented Approach to Large Libraries of Artificial Macrocycles

“…In addition to that, the library members 4 bearing a Boc-protected amino function were deprotected in silico to give 74,093 functionalized macrocycles 6 suitable for further "post-pairing" modification at the amino group. Taking into account our previous experience with REadily AccessibLe (REAL) Space methodology, [51] a chemical space of at least billion (10 9 ) macrocycles can be reached with such modifications.…”

“…The "couple" phase was performed according to a convenient modified one-pot protocol that was used by us for similar three-step reaction sequences previously. [51] It was found that 323 out of 383 experiments were successful for the preparation of dienes 5 (84 % synthesis success rate, 45 % average yield). 22 library members 5 were obtained in less than 10 mg amount and were discarded for the next step.…”

“…"Couple" step [51] N-Boc-diamine 1 (0.5 mmol), carboxylic acid 2 (0.6 mmol), iPr 2 NEt (1.25 mmol*), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (0.575 mmol) were mixed in dry DMSO (appr. 1.4 mL).…”

“…[48] The utility of such virtual (but readily accessible) compound collections for efficient lead discovery became evident with recent major advances in computational techniques, which enabled fast and efficient virtual screening of such ultra-large libraries. [49][50][51] In this work, we describe a diversity-oriented methodology to generate large libraries of artificial macrocycles which is based on the strategy expounded above (Scheme 1). Ringclosing metathesis (RCM) was selected as the well-known and reliable macrocyclization method for the "pair" step.…”