Bhanot Amritansh, Sundriyal Sandeep
Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Vidya Vihar, Pilani, Rajasthan 333 031, India.
ACS Omega. 2021 Feb 25;6(9):6424-6437. doi: 10.1021/acsomega.1c00104. eCollection 2021 Mar 9.
To understand the property space of antimalarials, we collated a large dataset of research antiplasmodial (RAP) molecules with known potencies and advanced stage antimalarials (ASAMs) with established oral bioavailability. While RAP molecules are "non-druglike", ASAM molecules display properties closer to Lipinski's and Veber's thresholds. Comparison within the different potency groups of RAP molecules indicates that the potency is positively correlated to the molecular weight, the calculated octanol-water partition coefficient (clog ), aromatic ring counts (#Ar), and hydrogen bond acceptors. Despite both categories being bioavailable, the ASAM molecules are relatively larger and more lipophilic, have a lower polar surface area, and possess a higher count of heteroaromatic rings than oral drugs. Also, antimalarials are found to have a higher proportion of aromatic (#ArN) and basic nitrogen (#BaN) counts, features implicitly used in the design of antimalarial molecules but not well studied hitherto. We also propose using descriptors scaled by the sum of #ArN and #BaN (SBAN) to define an antimalarial property space. Together, these results may have important applications in the identification and optimization of future antimalarials.
为了解抗疟药物的性质空间，我们整理了一个包含具有已知效力的研究性抗疟原虫（RAP）分子和具有已确定口服生物利用度的晚期抗疟药物（ASAM）的大型数据集。虽然RAP分子“非类药”，但ASAM分子表现出更接近Lipinski和Veber阈值的性质。在RAP分子的不同效力组内进行比较表明，效力与分子量、计算的正辛醇 - 水分配系数（clog ）、芳香环数（#Ar）和氢键受体呈正相关。尽管两类药物都具有生物利用度，但ASAM分子相对更大且更具亲脂性，具有较低的极性表面积，并且与口服药物相比具有更高的杂芳环数。此外，发现抗疟药物具有较高比例的芳香氮（#ArN）和碱性氮（#BaN）计数，这些特征在抗疟分子设计中被隐含使用，但迄今尚未得到充分研究。我们还建议使用由#ArN和#BaN之和（SBAN）缩放的描述符来定义抗疟性质空间。总之，这些结果可能在未来抗疟药物的鉴定和优化中具有重要应用。
