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Combining Cloud-Based Free-Energy Calculations, Synthetically Aware Enumerations, and Goal-Directed Generative Machine Learning for Rapid Large-Scale Chemical Exploration and Optimization.
Ghanakota, Phani; Bos, Pieter H; Konze, Kyle D; Staker, Joshua; Marques, Gabriel; Marshall, Kyle; Leswing, Karl; Abel, Robert; Bhat, Sathesh.
Afiliação
  • Ghanakota P; Schrödinger, Inc., 120 West 45th Street, 17th floor, New York, New York 10036, United States.
  • Bos PH; Schrödinger, Inc., 120 West 45th Street, 17th floor, New York, New York 10036, United States.
  • Konze KD; Schrödinger, Inc., 120 West 45th Street, 17th floor, New York, New York 10036, United States.
  • Staker J; Schrödinger, Inc., 120 West 45th Street, 17th floor, New York, New York 10036, United States.
  • Marques G; Schrödinger, Inc., 120 West 45th Street, 17th floor, New York, New York 10036, United States.
  • Marshall K; Schrödinger, Inc., 120 West 45th Street, 17th floor, New York, New York 10036, United States.
  • Leswing K; Schrödinger, Inc., 120 West 45th Street, 17th floor, New York, New York 10036, United States.
  • Abel R; Schrödinger, Inc., 120 West 45th Street, 17th floor, New York, New York 10036, United States.
  • Bhat S; Schrödinger, Inc., 120 West 45th Street, 17th floor, New York, New York 10036, United States.
J Chem Inf Model ; 60(9): 4311-4325, 2020 09 28.
Article em En | MEDLINE | ID: mdl-32484669
ABSTRACT
The hit identification process usually involves the profiling of millions to more recently billions of compounds either via traditional experimental high-throughput screens (HTS) or computational virtual high-throughput screens (vHTS). We have previously demonstrated that, by coupling reaction-based enumeration, active learning, and free energy calculations, a similarly large-scale exploration of chemical space can be extended to the hit-to-lead process. In this work, we augment that approach by coupling large scale enumeration and cloud-based free energy perturbation (FEP) profiling with goal-directed generative machine learning, which results in a higher enrichment of potent ideas compared to large scale enumeration alone, while simultaneously staying within the bounds of predefined drug-like property space. We can achieve this by building the molecular distribution for generative machine learning from the PathFinder rules-based enumeration and optimizing for a weighted sum QSAR-based multiparameter optimization function. We examine the utility of this combined approach by designing potent inhibitors of cyclin-dependent kinase 2 (CDK2) and demonstrate a coupled workflow that can (1) provide a 6.4-fold enrichment improvement in identifying <10 nM compounds over random selection and a 1.5-fold enrichment in identifying <10 nM compounds over our previous method, (2) rapidly explore relevant chemical space outside the bounds of commercial reagents, (3) use generative ML approaches to "learn" the SAR from large scale in silico enumerations and generate novel idea molecules for a flexible receptor site that are both potent and within relevant physicochemical space, and (4) produce over 3 000 000 idea molecules and run 1935 FEP simulations, identifying 69 ideas with a predicted IC50 < 10 nM and 358 ideas with a predicted IC50 < 100 nM. The reported data suggest combining both reaction-based and generative machine learning for ideation results in a higher enrichment of potent compounds over previously described approaches and has the potential to rapidly accelerate the discovery of novel chemical matter within a predefined potency and property space.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Preparações Farmacêuticas / Descoberta de Drogas Tipo de estudo: Prognostic_studies Idioma: En Revista: J Chem Inf Model Assunto da revista: INFORMATICA MEDICA / QUIMICA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Preparações Farmacêuticas / Descoberta de Drogas Tipo de estudo: Prognostic_studies Idioma: En Revista: J Chem Inf Model Assunto da revista: INFORMATICA MEDICA / QUIMICA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos