Proteochemometric study of the pyrimidine-based scaffold derivatives as pjDHFR inhibitors

Pneumocystis jirovecii pneumonia (PJP) is a serious fungal infection that most appears in the lungs of immunocompromised patients. Many functions such as cancer, HIV/AIDS, long-term use of corticosteroids, and bone marrow transplant can cause weakened immune systems [1]. Dihydrofolate reductase (DHFR) is a ubiquitous enzyme with an indispensable role in the folate metabolism pathway and is considered as an important target of antibacterial, antiprotozoal, antifungal, anti-inflammatory, andanticancer drugs [2]. The most problematic subject concerning the design of pjDHFR inhibitor is the lack of X-ray crystal structure information and the absence of animal models for human PJP. Due to several reasons including side effects, resistance, and causing host cell toxicity, existing drugs are not potent enough and selective to achieve the goal of effective treatment [3]. Computer-aided drug design (CADD) approaches play a key role in drug design and development. Proteochemometric (PCM) modeling is a biostatistical method that can incorporate information of multiple ligands and multiple targets and correlates between this information and bioactivity of ligands by one of the machine learning techniques [4].