Consideration of molecular weight during compound selection in virtual target-based database screening
Consideration of molecular weight during compound selection in virtual target-based database screening
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DOI：
10.1021/ci020055f
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发表时间：
2003-01-01
期刊：
影响因子：
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通讯作者：
MacKerell, AD
中科院分区：
文献类型：
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作者：
Pan, YP;Huang, N;MacKerell, AD
虚拟数据库筛选允许根据已知抑制剂的结构互补性或生物大分子上的目标结合位置通过计算选择数百万种化合物。当以生物大分子为靶标时，虚拟数据库筛选中的化合物选择通常基于化合物与目标大分子之间的相互作用能。在目前的研究中，由于化合物尺寸对能量分数的贡献，这种方法偏向于选择高分子量化合物。为了在基于能量的筛选中考虑分子量，我们提出了基于被筛选化合物中重原子总数的归一化策略。这种方法在计算上是有效的，并且产生所选化合物的分子量分布，其可以被选择为(1)低于用于虚拟筛选的原始数据库的分子量分布，这可能是选择含铅化合物所需要的，或者(2)类似于原始数据库的分子量分布，这可能是选择类药物化合物所需要的。通过消除基于靶点的数据库筛选中对较高分子量化合物的偏见，预计所提出的程序将提高计算机辅助药物设计的成功率。
Virtual database screening allows for millions of chemical compounds to be computationally selected based on structural complimentarity to known inhibitors or to a target binding site on a biological macromolecule. Compound selection in virtual database screening when targeting a biological macromolecule is typically based on the interaction energy between the chemical compound and the target macromolecule. In the present study it is shown that this approach is biased toward the selection of high molecular weight compounds due to the contribution of the compound size to the energy score. To account for molecular weight during energy based screening, we propose normalization strategies based on the total number of heavy atoms in the chemical compounds being screened. This approach is computationally efficient and produces molecular weight distributions of selected compounds that can be selected to be (1) lower than that of the original database used in the virtual screening, which may be desirable for selection of leadlike compounds or (2) similar to that of the original database, which may be desirable for the selection of drug-like compounds. By eliminating the bias in target-based database screening toward higher molecular weight compounds it is anticipated that the proposed procedure will enhance the success rate of computer-aided drug design.